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• Natural History of and Genetic Modifiers in Spinocerebellar Ataxias

  Spinocerebellar ataxias (SCA) are genetic neurological diseases that cause imbalance, poor coordination, and speech difficulties. There are different kinds of SCA and this study will focus on types 1, 2, 3, and 6 (SCA 1, SCA 2, SCA 3, also known as Machado-Joseph disease and SCA 6). The diseases are rare, slowly progressive, cause increasingly severe neurological difficulties and are variable across and within genotypes. The purpose of this research study is to bring together a group of experts in the field of SCA for the purpose of learning more about the disease. The research questions are: How does the disease progress over time? What are the best ways to measure disease progression? Do some genes, other than the gene that is abnormal in the SCA disease, have any effect on the way the disease behaves?

  Study phs001332

• Mutations in the RAS/MAPK pathway drive replication repair deficient hypermutated tumors and confer sensitivity to MEK inhibition

  The RAS/MAPK pathway is an emerging targeted pathway across a spectrum of both adult and pediatric cancers. Typically, this is associated with a single, well-characterized point mutation in an oncogene. Hypermutant tumors which harbor many somatic mutations may obscure the interpretation of such targetable genomic events. We find that replication repair deficient (RRD) cancers which are universally hypermutant and affect children born with RRD cancer predisposition, are enriched for RAS/MAPK mutations (p=10-8). These mutations are not random, exist in subclones, and increase in allelic frequency over time. The RAS/MAPK pathway is activated both transcriptionally and at the protein level in patient derived RRD tumors and these tumors responded to MEK inhibition in vitro and in vivo. Treatment of patients with RAS/MAPK hypermutant gliomas reveal durable responses to MEK inhibition. Our observations suggest that hypermutant tumors may be addicted to oncogenic pathways resulting in favorable response to targeted therapies.

  Study EGAS00001005008

• Genomic Landscape of High-Grade Neuroendocrine Neoplasms

  This project is a multi-omics study of high grade (grade 3) neuroendocrine neoplasms across diverse organs. Genomic analysis using low-pass whole genome sequencing for copy number analysis, whole exome sequencing and whole transcriptomic sequencing using RNAseq were performed. As high grade neuroendocrine neoplasms are highly lethal with a median survival of approximately 7 months, new insights are urgently needed for better prognosis, diagnosis and management. This study focuses on gene and pathway discoveries in this cancer, and includes samples from a diverse set of organs, including the lungs, gastroenteropancreatic tract, breast, prostate, head and neck and bladder. This study was made possible by a generous donation from The Helen B. Rodde Fund.

  Study phs002070

• Exploring_the_heterogeneity_of_sarcoma_using_single_cell_sequencing_

  Multi region samples are collected from patients, with consent, immediately after resection of the tumour. Samples are digested and sorted using FACS as single cells into lysis buffer. Cells are then stored until further processing for G&T-seq. After sequencing, we will explore intra-tumour heterogeneity using computational approaches to integrate RNA and DNA data onto the tumour phylogeny This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002866

• Exome sequencing of UK Birth Cohorts - Millennium Cohort Study

  Birth cohort studies involve repeated surveys of large numbers of individuals from birth and throughout their lives. They collect information useful for a wide range of life course research domains, and biological samples which can be used to derive data from an increasing collection of omic technologies. This rich source of longitudinal data, when combined with genomic data, offers the scientific community valuable insights from population genetics to rare disease associations. Avon Longitudinal Study of Parents and Children (ALSPAC)recruited 14,775 babies of predominantly White ethnicity in the Avon county of south-west England between 1991 and 1992. Born in Bradford (BiB) is similarly focused on a particular local area, the city of Bradford in the north of England, and recruited 13,858 babies between 2007 and 2011, of whom ~41% self-report as white British and ~59% as other ethnicities, predominantly Pakistani. Millennium Cohort Study (MCS) is a national cohort that recruited 18,827 children born between 2000 and 2002, intentionally over-sampling areas with high child poverty, large ethnic minority populations, and smaller UK nations (Wales, Scotland and Northern Ireland) Available here is a subset of exome-sequenced parents and children from these studies (CRAMS and post-QC VCFs) as detailed in https://doi.org/10.12688/wellcomeopenres.22697 [doi.org]. Phenotypic data is also available by submitting an application to the corresponding cohort: https://cls.ucl.ac.uk/cls-studies/millennium-cohort-study/ [cls.ucl.ac.uk]

  Dataset EGAD00001015372

• Exome sequencing of UK Birth Cohorts - Avon Longitudinal Study of Parents and Children

  Birth cohort studies involve repeated surveys of large numbers of individuals from birth and throughout their lives. They collect information useful for a wide range of life course research domains, and biological samples which can be used to derive data from an increasing collection of omic technologies. This rich source of longitudinal data, when combined with genomic data, offers the scientific community valuable insights from population genetics to rare disease associations. Avon Longitudinal Study of Parents and Children (ALSPAC)recruited 14,775 babies of predominantly White ethnicity in the Avon county of south-west England between 1991 and 1992. Born in Bradford (BiB) is similarly focused on a particular local area, the city of Bradford in the north of England, and recruited 13,858 babies between 2007 and 2011, of whom ~41% self-report as white British and ~59% as other ethnicities, predominantly Pakistani. Millennium Cohort Study (MCS) is a national cohort that recruited 18,827 children born between 2000 and 2002, intentionally over-sampling areas with high child poverty, large ethnic minority populations, and smaller UK nations (Wales, Scotland and Northern Ireland) Available here is a subset of exome-sequenced parents and children from these studies (CRAMS and post-QC VCFs) as detailed in https://doi.org/10.12688/wellcomeopenres.22697 [doi.org]. Phenotypic data is also available by submitting an application to the corresponding cohort: https://www.bristol.ac.uk/alspac/researchers/our-data/[bristol.ac.uk]

  Dataset EGAD00001015371

• Global Microbiome Conservancy Sequence Data

  The human body is a complex ecosystem, hosting tens of billions of bacteria, primarily in the gut. This community, known as the 'gut microbiome', is vital to human health, affecting functions ranging from metabolism, immunity, and development, to behavior. Conversely, reduced microbiome diversity and other imbalances of the gut community (dysbiosis) are associated with many diseases of the industrialized world, such as metabolic syndrome, asthma, and inflammatory bowel diseases among others. Microbiome-based interventions thus hold the potential to revolutionize our understanding of, and therapeutic approaches to, many aspects of human health and disease. Despite many advances, current understanding of the human microbiome is largely limited to majority ethnic groups in industrialized nations, and does not reflect the full diversity of human commensal microbiota. In addition to the scientific ramifications of minority underrepresentation, there are significant translational and ethical implications as well: first, failing to capture the full diversity of healthy human microbiota may limit our ability to understand and generate effective therapeutics for many microbiome-associated diseases. Second, underrepresented groups are less likely to benefit from microbiome-based medical advances tailored to well-studied populations, propagating healthcare inequities.  Human gut microbial diversity is diminishing around the globe, due to the spread of industrialized diets and lifestyles, which are associated with reduced microbiome biodiversity. The Global Microbiome Conservancy (GMbC) is a non-profit collaboration between scientists and communities around the world that aims to 1) preserve the full biodiversity of the human gut microbiome, 2) characterize its evolution across populations and host lifestyles and 3) investigate its interactions with the human host. We are collecting gut microbiome and human DNA samples from diverse populations around the world, from isolated groups to urbanized populations, to culture and study this essential biodiversity and to preserve it in a living "seed bank" of bacterial isolates as a long-term safeguard against future extinctions. Human genetic data for the samples sequenced in this study can be found in phs002205.

  Study phs002235

• Heart Failure Network - Effectiveness of Ultrafiltration in Treating People with Acute Decompensated Heart Failure and Cardiorenal Syndrome (HFN CARRESS - BioLINCC)

  ObjectiveThe CARRESS trial examined the effectiveness of ultrafiltration compared with a strategy of diuretic-based stepped pharmacologic therapy on renal function and weight loss in patients with heart failure who have worsening renal function and persistent congestion.BackgroundAcute cardiorenal syndrome is defined as worsening renal function in patients with acute decompensated heart failure. It occurs in 25 to 33% of patients and is associated with poor outcomes. Current heart failure treatments focus on removing excess fluid buildup, however administration of intravenous diuretics may contribute to worsening renal function. Venovenous ultrafiltration is one alternative therapy that may be effective in patients with acute decompensated heart failure complicated by acute cardiorenal syndrome and persistent congestionSubjectsA total of 188 patients were randomized.DesignHospitalized subjects were randomly assigned to receive either ultrafiltration therapy or pharmacologic therapy. Ultrafiltration was performed at a fluid-removal rate of 200 ml per hour and loop diuretics were discontinued for the duration of the intervention. The addition of intravenous vasodilators or positive inotropic agents was prohibited, unless they were deemed to be necessary as rescue therapy. Patients assigned to stepped pharmacologic therapy received intravenous diuretics to manage congestion and maintain a urine output of 3 to 5 liters per day. In both groups, the assigned treatment strategy was to be continued until the signs and symptoms of congestion in the patient were reduced as much as possible. The primary end points were baseline changes in serum creatinine and weight as assessed at 96 hours after treatment assignment.ConclusionsThe use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function, and there was a similar amount of weight loss between the two groups. Ultrafiltration was associated with a higher rate of adverse events (Bart, et al., 2012, PMID: 23131078).

  Study phs003510

• The ClinSeq Project: Piloting Large-Scale Genome Sequencing for Research in Genomic Medicine

  ClinSeq is a pilot project to investigate the use of whole-genome sequencing as a tool for clinical research. By piloting the acquisition of large amounts of DNA sequence data from individual human subjects, we are fostering the development of hypothesis-generating approaches for performing research in genomic medicine, including the exploration of issues related to the genetic architecture of disease, implementation of genomic technology, informed consent, disclosure of genetic information, and archiving, analyzing, and displaying sequence data. In the initial phase of ClinSeq, we are enrolling roughly 1000 participants; the evaluation of each includes obtaining a detailed family and medical history, as well as a clinical evaluation. The participants are being consented broadly for research on many traits and for whole-genome sequencing. Initially, Sanger-based sequencing of 300-400 genes thought to be relevant to atherosclerosis is being performed, with the resulting data analyzed for rare, high-penetrance variants associated with specific clinical traits. The participants are also being consented to allow the contact of family members for additional studies of sequence variants to explore their potential association with specific phenotypes. Here, we present the general considerations in designing ClinSeq, preliminary results based on the generation of an initial 826 Mb of sequence data, the findings for several genes that serve as positive controls for the project, and our views about the potential implications of ClinSeq. The early experiences with ClinSeq illustrate how large-scale medical sequencing can be a practical, productive, and critical component of research in genomic medicine. Reprinted from Genome Res. 2009 Sep; 19(9): 1665-1674, with permission from Genome Research, PMID: 19602640.

  Study phs000971

• Genomics of Hepatocellular Carcinoma

  Despite the growing incidence of hepatocellular carcinoma (HCC) due to increased hepatitis C virus infection and non-alcoholic steatohepatitis in Western populations, the genetic determinants of this cancer have yet to be established. A minority (15-20%) of HCC occurs in livers without cirrhosis or other chronic disease. Because the liver is functionally preserved in these patients and surgical resection of the tumor may be performed safely, and because of the scarcity of livers available for transplantation, non-cirrhotic patients undergo surgical resection for HCC treatment. These resected tumors present investigatory opportunities in two ways: First, they provide tumor specimen which have not been treated with chemotherapy and embolization. Second, the absence of cirrhosis may provide an unconfounded background from which to investigate the genetic tumorigenesis of HCC. In livers with cirrhosis, genetic instability is prevalent as assessed by assays for microsatellite instability, loss of heterozygosity and aberrant DNA methylation. In contrast, in livers without cirrhosis, the non-tumor tissue surrounding HCC have been found to have fewer genetic aberrations. It has been postulated that the pathologic process of cirrhosis may result in the accumulation of many "passenger"; as well as "driver" mutations, and that the examination of the HCC cancer genome may be facilitated in non-cirrhotic livers because of the absence of an accumulated background noise of mutations.

  Study phs001106

• International Standards for Cytogenomic Arrays

  The International Standards for Cytogenomic Arrays (ISCA) Consortium is a rapidly growing group of clinical cytogenetics and molecular genetics laboratories committed to improving quality of patient care related to clinical genetic testing using new molecular cytogenetic technologies including array comparative genomic hybridization (aCGH) and quantitative SNP analysis by microarrays or bead chip technology. The ISCA Consortium is now working with the sequencing community to extend the goals of standardization, collaboration, and data sharing. To reflect this combined effort, we are becoming ICCG, or the International Collaboration for Clinical Genomics. Efforts of the Consortium include: Clinical Utility: The ISCA Consortium has made recommendations regarding the appropriate clinical indications for cytogenetic array testing (Miller et al. AJHG 2010, PMID: 20466091). Currently, discussions are focused on pediatric applications for children with unexplained developmental delay, intellectual disability, autism and other developmental disabilities. A separate committee has been developed to address appropriate cancer genetic applications (http://www.urmc.rochester.edu/ccmc/). Evidence-based standards for cytogenomic array design: The Consortium will develop recommendations for standards for the design, resolution and content of cytogenomic arrays using an evidence-based process and an international panel of experts in clinical genetics, clinical laboratory genetics (cytogenetics and molecular genetics), genomics and bioinformatics. This design is intended to be platform and vendor-neutral (common denominator is genome sequence coordinates), and is a dynamic process with input from the broader genetics community and evidence-based review by the expert panel (a Steering Committee with international representation). Public Database for clinical and research community: It is essential that a publicly available database be created and maintained for cytogenetic array data generated in clinical testing laboratories. This will be integrated into the current dbGaP database at NCBI/NIH and released through dbVar, and curated by a committee of clinical genetics laboratory experts. The very high quality of copy number data (i.e., deletions and duplications) coming from clinical laboratories combined with expert curation will produce an invaluable resource to the clinical and research communities. Standards for interpretation of cytogenetic array results: Using the ISCA Database, along with other genomic and genetics databases, the Consortium will develop recommendations for the interpretation and reporting of pathogenic vs. benign copy number changes as well as imbalances of uncertain clinical significance. Membership in the ISCA Consortium is open to all individuals and laboratories involved in cytogenetic array testing who are committed to free data sharing and to participation in a process to develop evidence-based standards and guidelines to improve patient care. ISCA is available through dbVar: http://www.ncbi.nlm.nih.gov/dbvar/studies/nstd37/ http://www.ncbi.nlm.nih.gov/dbvar/studies/nstd75/ http://www.ncbi.nlm.nih.gov/dbvar/studies/nstd45/ http://www.ncbi.nlm.nih.gov/dbvar/studies/nstd101/

  Study phs000205

• A Phase I/IB Study of Ipilimumab or Nivolumab in Patients With Relapsed Hematologic Malignancies After Allogeneic Hematopoietic Cell Transplantation

  Relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is characterized by poor outcomes and novel therapeutic options are urgently needed. Immune checkpoint blockade using CTLA-4 and PD-1 blocking antibodies are a potential concept for reinstating a dormant graft-versus-leukemia (GvL) effect.This study investigated transcriptomic changes in biopsies obtained from patients who received immune checkpoint blockade for relapsed hematologic malignancy post-HSCT and elucidated transcriptional programs associated with successful reinvigoration of GvL. Differential gene expression analysis showed evidence of increased T cell infiltration in biopsies of responders to ipilimumab treatment and demonstrated shared gene programs between GvL and GvHD.

  Study phs002377

• A personalised medicine approach for ponatinib-resistant chronic myeloid leukaemia

  Chronic myeloid leukaemia (CML) is characterised by the presence of a fusion driver oncogene, BCR-ABL1, which is a constitutive tyrosine kinase. Tyrosine kinase inhibitors (TKIs) are the central treatment strategy for CML patients and have significantly improved survival rates, but the T315I mutation in the kinase domain of BCR-ABL1 confers resistance to all clinically approved TKIs, except ponatinib. However, compound mutations can mediate resistance even to ponatinib and remain a clinical challenge in CML therapy. Here, we investigated a ponatinib-resistant CML patient through whole genome sequencing (WGS) to identify the cause of resistance and to find alternative therapeutic targets.

  Study EGAS00001001150

• Whole genome sequencing of retinoblastoma reveals the diversity of rearrangements disrupting RB1 and uncovers a treatment related mutational signature

  Background: The development of retinoblastoma is thought to require pathological genetic changes in both alleles of the RB1 gene. However, cases exist where RB1 mutations are undetectable suggesting alternative pathways to malignancy. Methods: We applied comprehensive whole genome sequencing (WGS) and transcriptomics to sporadic retinoblastomas derived from twenty patients attending our clinic, contrasting these results to that obtained through customary clinical testing. We sought RB1 and other driver mutations, investigated mutation burden, mutational signatures and phylogenetic relatedness in one case of bilateral retinoblastoma. Results: At least one RB1 mutation was identified in all retinoblastomas. We confirmed RB1 mutations previously identified by clinical screening, identified three new RB1 mutations and provided clarity to the mechanism behind a further six mutations. Eight tumours carried structural rearrangements involving RB1 ranging from relatively simple to extremely complex rearrangement patterns, including a chromothripsis-like pattern in one tumour. Potential driver mutations included mutations in BCOR (5/20) and amplification of MYCN (2/20) and MDM4 (1/20). We show that RB1 mutations are not mutually exclusive of MYCN amplifications, and further reveal that all tumours demonstrate increased MYCN expression suggesting a universal role in retinoblastoma tumorigenesis.  Bilateral tumours obtained from one patient harboured conserved germline but divergent somatic RB1 mutations, indicating independent evolution. In-keeping with previous WGS of paediatric cancers, the mutation burden in retinoblastomas was extremely low. Mutational signature analysis showed a predominance of signatures associated with cell division and an absence of ultraviolet-related DNA damage. In a tumour exposed to chemotherapy prior to enucleation, a profound platinum-related mutational signature was observed. Conclusions: WGS provides a complete picture of the genomic landscape of retinoblastomas, allowing the discovery of mutations otherwise undetected by conventional clinical screening approaches. The presence of at least one RB1 mutation in all retinoblastomas and the relative paucity of driver mutations in other genes suggests mutations beyond RB1, MYCN and BCOR are rare. Whilst most RB1 mutations are identifiable by clinical screening, the increased resolution and ability to detect otherwise elusive rearrangements of RB1 by WGS, confirming whether they are somatic or germline, has important repercussions on clinical management and advice on recurrence risks.

  Dataset EGAD00001006431

• Tumor-associated neutrophil 1 precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition

  Tumor evolution is one of the major mechanisms responsible for acquiring therapy resistant and more aggressive cancer clones. Whether the tumor microenvironment through immune-mediated mechanisms might promote the development of more aggressive cancer types is crucial for the identification of additional therapeutical opportunities. Here, we identify a subset of tumor-associated neutrophils, defined as tumor-associated neutrophil precursors (PreNeu). These PreNeu are enriched in highly proliferative hormone-dependent breast cancers and impair DNA repair capacity

  Study EGAS00001008154

• Genomic_landscape_of_liver_cirrhosis

  We are interested in the genomic landscape of liver cirrhosis and its potential manifestations for liver physiology and risk for hepatocellular carcinoma. Previous work in CASM has shown that there is a strong element of clonality within cirrhotic nodules and that some recurring mutations have been identified. However how this relates to the overall liver is not known and therefore by taking geographically disparate biospies, we aim to correlate our findings and make conclusions as to the characteristics of the overall genomic landscape.

  Study EGAS00001004329

• Illumina HumanCoreExome genotyping data from the British Society for Surgery of the Hand Genetics of Dupuytren’s Disease consortium (BSSH-GODD consortium) collection

  Dupuytren's Disease (DD - OMIM126900) is the most common heritable disorder of connective tissue. It is a fibroproliferative disorder of the palmer fascia, causing flexion contractures of affected digits. DD affects men more commonly than women. DD is an archetypal complex disease, with multiple genetic and environmental factors affecting the final expression of the disease phenotype. The incidence increases with age, and the prevalence of DD is therefore increasing as the UK population ages. Half of all patients present before age 60. DD causes significant functional impairment, and severe contractures can lead to permanent disability. The mainstay of current treatment is surgery, but recurrence and complications are both high. For severe contractures, the only suitable treatment option is amputation. The direct costs to the NHS are high, and underestimate the true economic costs to society. We collected salivary samples from adults in the UK who have had surgery for DD. We have genotyped these samples using the Illumina HumanCoreExome Beadchips. https://research.ndorms.ox.ac.uk/public/dupuytrens/what-is-dupuytrens-disease/

  Study EGAS00001001206

• Kibbutzim Family study

  The Kibbutzim Family Study (KFS) was established in 1992 to investigate the environmental and genetic determinants of cardiometabolic risk factors and their change over time. The participants belong to large families living in close-knit communities, called “Kibbutzim”, in Northern Israel. The Kibbutz has been a communal settlement, which has created a relatively homogeneous environment for its members. Kibbutz members are mostly of Ashkenazi Jewish ancestry, with the remaining members belonging to other Jewish subgroups. Participants were recruited in two phases from six Kibbutzim. In the first recruitment phase of the study (1992–1993) 500 individuals from 80 extended families (range 2 to 43) were examined. During the second phase (1999–2000), all participants from the first phase were invited for repeat examinations (80% response rate) and additional new participants were recruited, giving a total of 922 individuals from 150 extended families (range 2 to 55). Families were invited to participate if they consisted of at least four individuals who (i) lived in the Kibbutz, (ii) spanned at least two generations, and (iii) were at least 15 years old. Families were retained if at least two family members consented to participate in the study. Overall, 1033 participants were recruited; 111 were examined only in the first phase, 533 only in the second phase, and 389 were included in both. 901 individuals were successfully genotyped using Illumina HumanCoreExome BeadChip.

  Study EGAS00001002782

• Kids First: Genomics of Orofacial Clefts in the Philippines

  Orofacial clefts (OFCs) are the most common craniofacial structural birth defect in humans caused by incomplete formation of the upper lip and/or the palate. Over 4,000 children in the Philippines are born with an OFC every year, and the Filipino OFC birth prevalence rate of 1 in 500 live births is one of the highest in the world. Genome-wide association studies support a multifactorial etiology for OFCs, but common variants only account for up to ~25% of the heritable risk in any one population. Sequencing studies in diverse populations is essential to fully understand the genetic architecture of OFCs. The study goals of the Kids First project are to sequence a collection of case-parent trios from the Philippines, in order to identify de novo mutations and inherited rare variants, and understand the population differences in common variant signals in the Philippines versus other populations. Approximately 373 trios from the Philippines were selected for whole genome sequencing (WGS) as part of this Gabriella Miller Kids First project.

  Study phs002595

• Determination of Cross-Reactive Immunological Material (CRIM) status and longitudinal follow-up of individuals with Pompe disease

  Infantile-onset Pompe disease is an inherited disorder that is normally diagnosed within the first months of life. It is caused by lack of or defect in an enzyme (a special protein that carries out normal chemical reactions within the body) called acid alpha-glucosidase (GAA). GAA normally breaks down glycogen (stored sugar) in lysosomes (the part of the cell that digests food and other chemicals). Pompe disease is one of many lysosomal storage diseases (LSDs). LSDs are diseases caused by the malfunction of the lysosome or one of their digestive enzymes. Patients with Pompe disease cannot break down lysosomal glycogen. This causes glycogen to build up and damage cells throughout the body, especially in the heart and muscles. Current treatment for Pompe disease involves enzyme replacement therapy (ERT). In this treatment, the drug alglucosidase alfa (Myozyme) is put into your blood. The drug provides a form of the GAA enzyme to replace the enzyme that is missing or not working properly in the patient's blood. This treatment has allowed babies to live longer and achieve developmental milestones. In this study, researchers will learn about the patient's ability to tolerate ERT. Cross-Reactive Immunological Material (CRIM) is a measurement of natural GAA production. A patient's CRIM status (either positive or negative) is an important factor that affects how he or she responds to ERT with Myozyme. Children who produce some natural GAA are classified as CRIM+, while children who do not produce any natural GAA are classified as CRIM-. Children who are CRIM+ generally tolerate ERT well. But, children who are CRIM-, and some children classified as CRIM+, have a poor response to ERT. Patients who have a poor response to ERT have complications because their body sees Myozyme as "foreign" and triggers an immune response to try to remove it from the body. Treatments are currently being developed to stop this immune response and prevent complications from ERT. We will enroll patients with Infantile Pompe disease in this longitudinal natural history (observational) study. The specific aims of this study are: To determine and correlate Cross-Reactive Immunological Material (CRIM) status with the GAA gene mutations found on these patients To validate an approach for determining CRIM status from whole blood sample, with the gold standard determination of CRIM status by skin fibroblasts and mutation analysis To explore the clinical treatment response and natural history of CRIM-positive and CRIM-negative Pompe disease patients with and without immune modulation To investigate the role of immune response to treatment

  Study phs001555

• Single cell transcriptomics of human kidney organoid endothelium reveals vessel growth processes and arterial maturation upon transplantation

  Human induced pluripotent stem cell-derived kidney organoids have potential for disease modeling and regenerative medicine purposes. However, they lack a functional vasculature in in vitro culture. Here, we transplanted kidney organoids at day 7+12 of differentiation in the coelomic cavity of chicken embryos. We then compared human endothelial cells from transplanted organoids to their respective untransplanted controls at d7+13 and d7+20 using scRNAseq. We demonstrate metabolic and phenotypic effect of transplantation with increased endothelial cell proliferation and differentiation to a fetal-like renal arterial/afferent arteriolar phenotype.

  Study EGAS50000001068

• Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. ObjectivesHypertension Study: To determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease (CHD) or other cardiovascular disease (CVD) events vs treatment with a diuretic.Lipid Study: To determine whether pravastatin compared with usual care reduces all-cause mortality in older, moderately hypercholesterolemic, hypertensive participants with at least an additional CHD risk factor. BackgroundHypertension Study: Antihypertensive therapy is well established to reduce hypertension-related morbidity and mortality, but the optimal first-step therapy is unknown.Lipid Study: Studies have demonstrated that statins administered to individuals with risk factors for coronary heart disease (CHD) reduce CHD events. However, many of these studies were too small to assess all-cause mortality or outcomes in important subgroups.ParticipantsHypertension Study: A total of 33,357 participants. Lipid Study: A total of 10,355 participants. Baseline mean total cholesterol was 224 mg/dL; LDL-C, 146 mg/dL; high-density lipoprotein cholesterol, 48 mg/dL; and triglycerides, 152 mg/dL. Mean age was 66 years; 49% were women, 38% black and 23% Hispanic, 14% had a history of CHD, and 35% had type 2 diabetes. DesignHypertension Study: A randomized, double-blind, active-controlled clinical trial conducted from February 1994 through March 2002. Participants were randomly assigned to receive chlorthalidone, 12.5 to 25 mg/d (n = 15,255); amlodipine, 2.5 to 10 mg/d (n = 9048); or lisinopril, 10 to 40 mg/d (n = 9054) for planned follow-up of approximately 4 to 8 years. The primary outcome was combined fatal CHD or nonfatal myocardial infarction, analyzed by intent-to-treat. Secondary outcomes were all-cause mortality, stroke, combined CHD (primary outcome, coronary revascularization, or angina with hospitalization), and combined CVD (combined CHD, stroke, treated angina without hospitalization, heart failure (HF), and peripheral arterial disease).Lipid Study: Multicenter (513 primarily community-based North American clinical centers), randomized, non-blinded trial conducted from 1994 through March 2002 in a subset of participants from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The interventions in the trial were pravastatin, 40 mg/d, vs usual care. The primary outcome was all-cause mortality, with follow-up for up to 8 years. Secondary outcomes included non-fatal myocardial infarction or fatal CHD (CHD events) combined, cause-specific mortality, and cancer.ConclusionsHypertension Study: Thiazide-type diuretics are superior in preventing one or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.Lipid Study: Pravastatin did not reduce either all-cause mortality or CHD significantly when compared with usual care in older participants with well-controlled hypertension and moderately elevated LDL-C. The results may be due to the modest differential in total cholesterol (9.6%) and LDL-C (16.7%) between pravastatin and usual care compared with prior statin trials supporting cardiovascular disease prevention.

  Study phs004021

• Immune Checkpoint Blockade for Relapsed Hematologic Malignancy Post-HSCT

  Relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is characterized by poor outcomes and novel therapeutic options are urgently needed. Immune checkpoint blockade using CTLA-4 and PD-1 blocking antibodies are a potential concept for reinstating a dormant graft-versus-leukemia (Gvl) effect. This study investigated transcriptomic changes in biopsies obtained from patients who received immune checkpoint blockade for relapsed hematologic malignancy post-HSCT and elucidated transcriptional programs associated with successful reinvigoration of GvL. Differential gene expression analysis showed evidence of increased T cell infiltration in biopsies of responders to ipilimumab treatment and demonstrated shared gene programs between GvL and GvHD.

  Study phs003291

• Molecular Etiology of Early-Onset Dystonia

  Primary torsin dystonias (PTD) are a group of movement disorders characterized by twisting muscle contractures, where dystonia is the only clinical sign (except for tremor) and there is no evidence of neuronal degeneration or an acquired cause. Eleven genes have been mapped for primary dystonia including DYT1 (TOR1A), DYT2, DYT4 (TUBB4A), DYT6 (THAP1), DYT7, DYT13,, DYT17, DYT21, CIZ1, DYT24 (ANO3), and DYT25 (GNAL); however, only 3 genes (TOR1A, THAP1, and GNAL) have mutations in early onset dystonia patients. Each is inherited as an autosomal dominant trait but with reduced penetrance, meaning that individuals can carry the mutation but do not show clinical symptoms. The most common form of PTD is adult onset focal accounting for about 90% of all cases of dystonia with a prevalence estimated at 30/100,000 in the general population. A small percentage of focal cases are due to mutations in CIZ1, ANO3, THAP1, TUBB4A, and GNAL, but the vast majority is unaccounted for and is most likely multigenic or multifactorial. In this grant, focusing on early onset PTD, we will uncover genes that influence the penetrance of DYT1 (TOR1A) dystonia through GWAS and exome sequencing studies. We will identify other genes for early onset PTD using exome sequencing and determine whether variants within the identified early onset PTD genes or the pathways associated with these genes contribute to susceptibility in the most prevalent form of PTD, focal dystonia, using a case:control association study. The proposed research will identify novel PTD risk factors and genes, which in turn should reveal shared and intersecting pathways leading to a better understanding of the molecular basis of PTD and provide the underpinnings for developing new treatments. Additionally, insight into the factors that modulate disease penetrance would be a first step in determine whether these could be modified leading to a reduced incidence of the disease.

  Study phs001733

• RNA_sequencing

  All cancers arise due to somatically acquired mutations in their genomes which alter the function of key cancer genes. Understanding the critical mutational events underlying the development of cancer is paramount for advancing prevention, early detection and effective treatment of the disease. Breast cancer is the most common cause of cancer death among women. Extraordinary recent advances in sequencing now make it a realistic aim to sequence large numbers of breast cancer genomes to find somatic mutations on a massive scale. NB bam files for manuscript A_Proteomic_Chronology_of_Gene_Expression_through_the_Cell_Cycle_in_Human_Myeloid_Leukemia_Cells are now available at the following link:http://www.ebi.ac.uk/ena/data/view/ERP008483

  Study EGAS00001000310

• Transcriptome analysis of Williams syndrome

  Williams syndrome (WS) is a neurodevelopmental disorder caused by microdeletion on chromosome 7q11.23, and has attracted much attention for its distinctive features, such as hypersociability. However, it remains unclear which genes are involved in the complex phenotypes of their condition. Here, we performed transcriptome analysis of peripheral blood to identify genes associated with WS.

  Study JGAS000132

• Adult B-precursor acute lymphoblastic leukemia RoCK and ROI single-cell transcriptome

  Whohle Transcriptome sequencing was performed following the manufactures protocol from BD Rhapsody. Capture of BCR::ABL1 was performed using RoCK and ROI. RoCK and ROI is based on barcoded beads of the BD Rhapsody platform. For RoCKseq specific capture, TSO oligos on BD Rhapsody beads are modified with a/ multiple capture sequence(s) specific to transcripts of interest. ROIseq, on the other hand, is based on specific primers which are spiked in during library generation, directing reads to regions of interest (ROIs). Multiple scRNAseq experiments were performed on several biological samples to validate RoCK and ROI.

  Study EGAS50000001366

• Gene Expression and Regulatory Networks in Human Leukocytes - Immunological Variation Consortium

  Profiling of gene expression with microarrays holds great potential for human health, for illuminating disease pathways or providing biomarkers to monitor disease or its resolution. Using high-throughput approaches for genotyping, immunophenotyping and gene expression analysis, the project will examine the basis for the control of gene expression in human immune cells, and how it is influenced by natural genetic variation or aging. In practice, the project will combine several cross-informative approaches: 1) Building on the established sample/data pipelines and robust protocols of the Immunological Genome (ImmGen) project, and on established cohorts of ethnically diverse healthy volunteers at hand, microarray techniques will be used to generate whole-genome expression profiles from purified naive CD4+ lymphocytes and monocytes from 600 healthy volunteers. A dense genetic map will be established for all donors. The results will elucidate how variation in the human genome affects the expression of immune genes, of key importance in understanding gene variants that bring susceptibility to immune or inflammatory disease. Computational analysis of these rich data will allow the reconstruction of regulatory connections between genes, helping to establish general modules and those specific of a given immune cell type. These data will be complemented by an orthogonal data group, generated from a restricted subset of 10 individuals, in which we will profile a larger set of 28 carefully delineated cell populations that exist in human blood. This work will also benefit from powerful interspecies comparison with similar experiments being performed in mice by ImmGen. 2) In addition, RNA from the same set of 28 defined cell populations will be probed with microarrays that explore other aspects of the transcriptome: i) microRNAs and other non-coding RNAs; ii) exon or splice junction arrays that will establish a map of differential splicing in human blood leukocyte. 3) The composition and reactivity of blood cells from the same donors will be established at the time of sample collection using high-throughput flow cytometry, correlating immune phenotypes with gene expression and genetic variation. 4) Genetic variability conditions the baseline levels of gene expression, but also the responsiveness to activating challenges. With samples from the same donors, NanoString technology for transcript counting will be used to analyze the transcriptional response of defined gene sets, representing response signatures of T or dendritic cells, for a fine-grained dissection of responses to different triggers (different bacterial ligands for dendritic cells, different cytokine environment for T cells). In keeping with the resource aspect of this project, all data and interpretations will be made publicly available rapidly upon curation, allowing public querying and browsing of the data, by using and evolving the existing web architectures of the ImmGen project, of the Broad Institute, and of international repositories. RELEVANCE: Exploration with DNA chips of the genome's expression microarrays holds great potential for human health, to better understand disease and to serve as diagnostic tools. Using a combination of high-throughput genomic techniques and computational biology, we will perform a broad exploration of gene expression in human blood cells across groups of African-American, Asian and European ancestry, asking how these profiles are affected by genetic variation or by age. These results will provide an invaluable reference benchmark for the interpretation of genetic and immunological studies. Additionally, over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, in a second study we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution. 15% of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (ATAC-QTLs). ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression, and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression. In another study we analyzed RNA-seq profiles from primary CD4+ T cells of two healthy donors at six time points from 0 to 72 hours after stimulation with bead-bound antibodies against CD3 and CD28.

  Study phs000815

• A Phase I/II Study of Revlimid (lenalidomide) in Combination with Vidaza (azacitidine) in Patients with Advanced Myelodysplastic Syndrome (MDS)

  This single-arm study design has been selected to investigate the safety of combination therapy with Vidaza® (azacitidine) and Revlimid® (lenalidomide) in a population of 18 participants with advanced MDS for the Phase I portion, and 18 participants for the Phase II portion. The multi-center nature of the study should enhance the general applicability of the results. Participants with advanced MDS were chosen because it is expected that the combination of the two drugs will by myelosuppressive, which can be considered a necessary toxicity to effect improvements in PR and CR rates in this advanced population, akin to participants with AML. Finally, the combination was chosen to be studied because currently available therapies in this population, and their effectiveness, are limited, and single-agent Vidaza® (azacitidine), while effective at delaying transformation to AML or death, is not curative. The doses of Revlimid® (lenalidomide) in this study are similar to those that were demonstrated to have an effect and to be well-tolerated in participants with MDS. Doses for Vidaza® (azacitidine) are similar to those used in the pivotal trial, though for a 5-day treatment period instead of 7 to minimize toxicity for the first 3 blocks of participants, and then at a lower dose over a protracted period of time to explore the safety of a 10-day treatment course.

  Study phs001318

• Defining T cell States Associated with Response to Checkpoint Immunotherapy in Melanoma

  Checkpoint blockade therapy using antibodies targeting CTLA4, PD1 or PDL1 have changed the way cancer patients with advanced disease are being treated, as evident by their FDA approval in a wide variety of malignancies, and their ability to induce high response rates when compared to conventional therapies (e.g. chemotherapy). However, even in melanoma, despite the high response rate, most patients are refractory to therapy or acquire resistance in 10-12 months. To identify key immunological elements coupled with response or resistance to checkpoint immunotherapy, we performed an unbiased analysis on 16,291 CD45+ immune cells from 32 patients (48 samples) treated with checkpoint therapy (anti-PD1=37; anti-PD1/CTLA4=11), using single cell transcriptomics. Initial unsupervised clustering of all CD45+ cells identified 11 clusters. When examining the association of these clusters with clinical outcome, we found that two clusters (B-cells, p=0.005; memory T-cells, p=0.03) were significantly enriched in responder lesions while 4 clusters (monocytes/macrophages, p=0.003; dendritic cells, p=0.015; exhausted CD8+ T-cells, p=0.005; and exhausted/cell-cycle lymphocytes, 1.3x10-5) are enriched in non-responder lesions. Next, by leveraging our unbiased single cell approach, we identified not only clusters but also specific markers associated with either responder lesions (PLAC8, LTB, LY9, SELL, TCF7, IGKC and CCR7) or non-responder ones (CCL3, CD38, HAVCR2, ENTPD1 and WARS), many of which were not previously reported to be associated with clinical outcome to checkpoint therapy. Due to the importance of CD8+ T-cells in controlling tumors, the significant association of T-cell states with clinical outcome, and their high abundance in melanoma tumors, we next focused our analysis on CD8+ T-cells and identified 2 main clusters CD8_G (with increased expression of genes linked to memory) and CD8_B (enriched for genes linked to cell dysfunction), that were significantly enriched in responder (CD8_G, p=1.4x10-6) and non-responder (CD8_B, p=0.005) lesions, respectively. Since cells with both states coexist in each of the responder and non-responder lesions, we decided to calculate the ratio between the number of cells in these 2 clusters and observed a significant separation between responders (CD8_G/CD8_B>1) and non-responders (CD8_G/CD8_B<1) when looking at all samples, baseline or post samples separately. Similar results were detected when looking at the expression of a single transcription factor, TCF7, in CD8 T-cells in an independent cohort (n=43) using a simple immunofluorescence assay. Additionally, we validated the identity and function of some of the newly identified cell states as well as their epigenetic landscape, and found that cells expressing the inhibitory molecules CD39 and TIM3, on top of being enriched in non-responder lesions, are likely to play a crucial role in T-cell exhaustion in melanoma. Collectively, our study provides extensive unbiased data in human tumors for discovery of predictors and therapeutic targets to checkpoint immunotherapy.

  Study phs001680

• IL-27 promotes tumour control by enhancing cytotoxic T cell function

  Cytotoxic CD8+ T lymphocytes (CTL) are essential for anti-tumour immunity but are frequently dysfunctional in established tumours. Here, we show that expression of a CTL signature is strongly associated with IL-27 expression in diverse human and murine tumours. In mice, IL-27 acts directly on tumour-specific CTL to promote their persistence and effector function in the tumor microenvironment. Moreover, treatment with inducible IL-27 overexpression or a half-life-extended IL-27 protein in vivo is well tolerated, induces regression of large established tumours, drives an enhanced cytotoxic program in anti-tumour CTL, and synergizes with PD-L1 blockade. In cancer patients treated with anti-PD-1 or anti-PD-L1 therapy, high expression of IL-27 is associated with improved clinical response. Finally, IL-27 increases cytotoxicity and limits terminal differentiation of human CD8+ T cells during chronic antigen exposure. Our data demonstrate that endogenous IL-27 is essential for anti-tumour immunity and that IL-27 receptor agonism can safely improve anti-tumor T cell responses alone or in combination with PD-L1 blockade.

  Study EGAS50000000694

• Common origin and somatic mutation patterns of composite lymphomas and leukemias

  When two lymphomas occur concurrently or sequentially in a patient, it is a major question whether they derive from the same lymphocyte or hematopoietic precursor cell or developed independently. We studied four composite classic Hodgkin lymphomas (HL) and other mature B-cell lymphomas, and two composite mature B- and T-cell neoplasias by whole exome sequencing (WES) and analyzed shared somatic mutations in the lymphomas of these clonally related composite lymphomas, indicating their derivation from a common, pre-malignant precursor. Most identified mutations were restricted to one or the other of these lymphomas, likely explaining how distinct lymphomas developed from a common ancestral B cell. In the two B-cell/T-cell lymphoma cases, and a composite clonally unrelated HL/chronic lymphocytic leukemia, the lymphoma partners did not share any somatic mutations. In three cases, we identified potentially oncogenic variants also in cells serving as constitutional controls.

  Study EGAS50000001017

• BAM files of total RNA-Seq data of POPS control samples (GRCh37)

  Placental biopsies (n = 64 female placentas, n = 67 male placentas) were selected from healthy pregnancies from the POPs cohort. A quality control process was also applied for the RNA-Seq datasets: reads were trimmed with Trim Galore!, which uses cutadapt internally and were mapped to the same version of human genome reference (hg19). TopHat2, a splice-aware mapper built on top of Bowtie2 short-read aligner, was used in the mapping process in which so-called two-pass (or two-scan) alignment protocol was applied to rescue unmapped reads from the initial mapping step. In the second mapping, previously unmapped reads were re-aligned to the exon-intron junctions detected in the first-mapping by TopHat2 and were combined across all 131 placenta samples. The initial and second mapped reads were merged by samtools

  Dataset EGAD00001003462

• Better Outcomes for Children: GWAS from Cincinnati Children's Hospital Medical Center (CCHMC) - eMERGE Phase II data - (dbGaP Deposit 1)

  This submission includes genotyping data from 6 separate cohorts (named A-E here), each is described in separate paragraphs below. Cohort A) Autism is a neurodevelopmental disorder that affects 1.5 million people in the United States, at an estimated lifetime cost of $4 million. It is part of Pervasive Developmental Disorder characterized by impairments in communication, language and reciprocal social interaction, and by unusual patterns of restricted and repetitive interests or behaviors. Autism, or autistic disorder, is the most severe form of the disease which has a wide range of symptom severity encompassed by the more inclusive term, Autism Spectrum Disorder (ASD). The prevalence of Autistic Disorder is currently estimated to be 4 per 1000, affecting 4 times more boys than girls. Susceptibility to autism is clearly attributable to genetic factors but the extensive clinical and genetic heterogeneity within the disorder have hindered efforts at genetic dissection. Identifying the genetic variants that contribute to this highly heritable disease is crucial to advancing research on autism. Reported concordance rates among monozygotic twins range from 60% − 90% and heritability of autism has been estimated to be 90% or greater. Identifying genetic variants that contribute to this highly heritable disease is crucial to advancing research on autism. Cohort B) The long-term objective of this research is to determine the molecular genetic basis of Cardiovascular (CV) disease in the young; this study seeks to identify gene mutations that cause "structural heart defects". Every year in the USA, 32,000 individuals are born with CV malformations; approximately 20% die during the first year of life. Another 30,000 young people develop a disturbance of cardiac rhythm or conduction. In addition, the life expectancy of another 40,000 young people is shortened by other forms of CV disease. It is becoming more apparent that in spite of the success in diagnosis and treatment, very little is known about the causes of CV disease in the young; understanding the causes will permit insight into the pathophysiologic basis of disease and allow definition of disease risk - two critical elements for disease prevention. Disease prevention and/or risk modification promises to be the new frontier in the management of CV disease in the young. Cohort C) Eosinophilic Esophagitis (EE) is one of the manifestations of eosinophilic gastrointestinal inflammation which have profound effects on a patient's health and development. Results of epidemiologic studies performed through our center demonstrate that eosinophil-associated gastrointestinal disease is not an uncommon entity. While the epidemiology of eosinophilic esophagitis has not been thoroughly studied until recently, there appears to be a significant increase in the diagnosis of EE in the last decade. Based on our research, this mainly reflects increased disease recognition, but there is also a bona-fide increase in disease incidence which coincides with the increasing incidence of asthma and allergic diseases in the industrialized world. In addition, many patients with intractable symptoms thought in the past to represent atypical GERD or other disorders are now being recognized as having EE. Diagnosis of EE requires endoscopy and biopsies to document the characteristic histologic findings of esophageal eosinophilia. In general, this study proposed to elucidate the mechanisms underlying eosinophil growth, survival, migration, and function, and to investigate and further characterize the pathophysiology of, clinical manifestations of, and spectrum of disease severity of eosinophilic esophagitis in humans. Cohort D) Juvenile idiopathic arthritis (JIA) is a debilitating complex genetic disorder characterized by inflammation of the joints and other tissues and shares histopathological features with other autoimmune diseases. It is considered a complex genetic disorder. There are more than 50,000 children with JIA in the USA, approximately 1 per 1000 births, which is about the same incidence as juvenile diabetes. It is believed that genes in the major histocompatibility complex (MHC) play a role in defining genetic risk, and it can be hypothesized that loci in other chromosomal regions are involved in conferring risk in JIA. These candidate chromosomal regions can be identified using genome wide association analyses. The long-term goal is a comprehensive understanding of the genetic basis of these disabling arthropathies for which the molecular basis is not presently understood. The results of recent GWAS for Caucasian JIA were recently published in Arthritis Rheum. 2012 Feb 21 (Published online, PMID=22354554). Cohort E) Childhood Absence Epilepsy (CAE) is characterized by very frequent (several to many per day) absence seizures in an otherwise normal child with an EEG usually demonstrating 3 Hz bilateral, synchronous, symmetrical spikewaves pattern with normal background activity. CAE occurs in 10% to 15% of all children with epilepsy with an annual incidence of 6.3 to 8/100,000 in children <15 years of age. Females are more affected than males. Epilepsy onset is typically between the ages of 4 to 8 years with a peak incidence of 6 to 7 years. CAE does not start after age 13 years. The primary objective of this study is: To identify the optimal anticonvulsant (i.e. the antiepileptic drug (AED) with highest rate of seizure control and lowest incidence of treatment limiting toxicity) used for the initial treatment of children with Childhood Absence Epilepsy (CAE). The secondary objectives are: To determine the pharmacogenetic and other non-heritable factors underlying the interindividual variation in anticonvulsant response efficacy and toxicity. To define and contrast the effects of ethosuximide, lamotrigine, and valproic acid monotherapy on cognition (attention), behavior and quality of life in children with Childhood Absence Epilepsy. Cohort F) Cincinnati Controls. These are local healthy children selected to be representative of the population of Cincinnati with respect to gender and ancestry. Cohort G) Cytogenetics cases are ascertained by the clinical request to obtain cytogenetic analysis. The platform used included genotyping data which are then available for genome wide association analysis

  Study phs000494

• The NCAA-DoD Concussion Assessment, Research, and Education (CARE) Consortium

  Study Description: Established in 2014, the U.S. Department of Defense (DoD) and the National Collegiate Athletic Association (NCAA) funded the Concussion Assessment, Research and Education (CARE) Consortium to inform science, clinical care and public policy related to concussion and repetitive head impact exposure (HIE) in U.S. Military Service Academy (MSA) cadets and collegiate student-athletes. The primary aims of the initial study were to: (1) establish a multisite research consortium to characterize the effects of concussion and repetitive head impact exposure on brain health, (2) characterize the clinical sequelae and natural history of concussion, (3) characterize the effect of concussion and repetitive head impacts on brain structure and brain function. The 30 member institutions of the CARE Consortium (26 civilian universities/colleges and 4 military service academies) agreed to invite all varsity athletes to undergo multimodal clinical assessments at preseason baseline, and at 5 additional timepoints after concussion diagnosis. At the service academies, non-varsity athlete cadets/midshipmen were also studied. Assessment Categories At Each Time Point Baseline: • Demographics • Personal and Family History • Neurocognitive Assessment • Neurological Status • Postural Stability • Symptoms ACUTE POST-INJURY FOLLOW-UP (CARE 1.0) (24 hrs; 48hrs; Asymptomatic; Unrestricted Return to Play (RTP); 6 mos) • Neurocognitive Assessment • Neurological Status • Postural Stability • Symptoms CUMULATIVE & PERSISTENT EFFECTS. (CARE 2.0) In-Person Exit Visit; Post-grad Online • Demographics • Personal and Family History • Neurocognitive Assessment • Neurological Status • Postural Stability • Symptoms • PROs • MROs (at academies only) LONG-TERM EFFECTS (CARE/SALTOS Integrated (CSI))Annual Online Assessment (at MSAs only); In-Person Research Visits • Demographics • Symptoms • Psychological health • PROs • MROs (at academies only)A subset of athletes at 6 of the CARE institutions underwent additional assessments including multimodal MRI, proteomic and genomic biomarker characterization, and head impact quantification (helmet-based sensors). Assessment time points for the ARC/pARC Neurocognitive and Behavioral Testing was done at Baseline, <48hrs Post-Injury, Cleared for Return to Play Progression (Asymptomatic), Unrestricted Return to Play, 7 days following Return to Play, and at >60 days after final game of junior year until end of collegiate career.Blood biomarker collection was done at Baseline, <48hrs Post-Injury, Cleared for Return to Play Progression (Asymptomatic), 7 days following Return to Play, and at >60 days after final game of junior year until end of collegiate career. Multi-modal MRI studies were done at Baseline, <48hrs Post-Injury, Cleared for Return to Play Progression (Asymptomatic), 7 days following Return to Play, and at >60 days after final game of junior year until end of collegiate career. However, please note that only athletes from one study performance site completed a multi-modal MRI study at baseline.

  Study phs002175

• Study of Melanoma Risk in Australia and the United Kingdom

  The results from a small number of melanoma GWAS have been published. Initial studies identified several pigmentation- and nevus-associated loci that mediate an effect on melanoma risk, however, these studies were somewhat limited in that sample number (hence power) was low, they used first-generation low density SNP arrays, or used pools of DNA samples. Subsequently, additional melanoma GWAS have been completed, including a "Phase 2" study by the International Melanoma Genetics Consortium (GenoMEL), a full GWAS of the Australian sample resource previously used in a pooled-DNA GWAS, and study conducted through the MD Anderson Cancer Center and the Brigham and Women's Hospital. The groups who performed these studies have recently shared data and replicated a number of new melanoma susceptibility loci. Aside from the identification of novel loci, there are two additional notable outcomes of these studies. Firstly, an examination of the observed versus expected test statistics (Q-Q plot) from the Australian study, even after removing data from SNPs within known replicated susceptibility loci, reveals that there remains an excess of positive results. Similarly, the latest GenoMEL study finds almost three times as many SNPs reaching p-values between 10-4 and 10-5 as would be expected by chance. In the light of other studies of complex traits [1], these data suggest that studies based on additional melanoma samples from the same population are likely to identify an even larger "polygenic tail" and should prove invaluable in identifying and characterizing the underlying loci. A second observation, is that the effect size for replicated associations differs very little between GWAS. Given the strong effect of ultraviolet radiation (UVR) on risk of melanoma this might be expected to affect penetrance, particularly in the Australian and English samples, which are ethnically similar, but have very different sun exposures. We hypothesize that those SNPs whose effects are strongly mediated by UVR exposure may have smaller marginal effects on risk and are therefore harder to detect initially, suggesting a whole category of genetic effects that are unexplored.Indeed, most melanoma GWAS performed to date used samples from both European and Australian populations in discovery and or replication, and thus, existing studies have been poorly powered to detect associations with a wide difference in effect between these low- and high-UVR populations. Here, we wish to pursue this hypothesis further and plan to genotype additional cases drawn from the English and Australian populations. This will serve two complementary objectives: firstly, it will greatly increase our collective power to detect additional new melanoma risk alleles; secondly, it will highlight associations that are stronger specifically within the context of either low-UVR or high-UVR exposure environments. We posit that these data will be invaluable, not just for identifying novel melanoma-associated loci, but also for addressing gene-environment interactions. We have available a collection of valuable resources to help fulfill our aims. These include a considerable number of well-characterized and ungenotyped Australian and UK melanoma cases, as well as existing genotype data from sets of Australian and UK cases and population-based controls. We propose the following Specific Aims: To extend our current collective melanoma GWAS by genotyping a large number of additional UK and Australian cases. To jointly analyze these data and identify new melanoma risk loci. To determine whether pre-existing and new melanoma risk alleles show different degrees of association between the English and Australian populations, and assess whether these differences might be due to differences in sunlight exposure.

  Study phs000519

• Genetics of Cutaneous T-Cell Lymphoma

  Mycosis fungoides (MF) is a common extranodal T-cell lymphoma primarily arising in the skin. In early disease stages, MF presents as skin patches and plaques that in some cases may progress to tumor and disperse to lymph nodes and other internal organs. The 10-year overall survival is 50% in advanced stages. Early diagnosis is difficult as the histology overlaps with features of inflammatory skin diseases. Even when the diagnosis is established, there are no prognostic markers that predict whether the disease will be aggressive or indolent. Lastly, there are no curative treatments and MF will invariably relapse, even after aggressive chemotherapy. The disease is a diagnostic, prognostic and therapeutic challenge. The main objective of this study is to address the question of tumor heterogeneity in MF. To date, MF is considered to be monoclonal, derived from a transformed, mature memory T-cell. However, clinical observations and preliminary data suggest that MF comprises multiple subclones, which may be of importance for understanding disease evolution and resistance to therapy. We plan to address this objective using Whole Exome Sequencing (WES) of MF tissue prepared by laser microdissection (LMD).

  Study phs001877

• RNA stability controlled by m6A methylation contributes to X-to-autosome dosage compensation in mammals

  In mammals, X-chromosomal genes are expressed from a single copy since males (XY) possess a single X chromosome, while females (XX) undergo X inactivation. To compensate for this reduction in dosage compared to two active copies of autosomes, it has been proposed that genes from the active X chromosome exhibit dosage compensation. However, the existence and mechanism of X-to-autosome dosage compensation are still under debate. Here, we show that X-chromosomal transcripts are reduced in m6A modifications and more stable compared to their autosomal counterparts. Acute depletion of m6A selectively stabilises autosomal transcripts, resulting in perturbed dosage compensation in mouse embryonic stem cells. We propose that higher stability of X-chromosomal transcripts is directed by lower levels of m6A, indicating that mammalian dosage compensation is partly regulated by epitranscriptomic RNA modifications.

  Study EGAS00001007112

• Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure (InterGEN Study)

  This research study focuses on the genomic and psychological environmental effects on blood pressure among mothers and their children. The study includes 250 mothers who self-identify as AA/black, and 250 children between the ages of 3 and 5 years old at the time of enrollment. The study is longitudinal and data collection interviews are scheduled every six months for two years after enrollment, for a total of four participant interviews. Assessment is as follows: genetic (time 1 only) and psychological factors (every six months for two years).

  Study phs001792

• Mapping Genotypes to Chromatin Accessibility Profiles in Single Cells

  In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates1–3. Therefore, somatic mutations likely alter chromatin accessibility patterns, as they disrupt differentiation topologies leading to abnormal clonal outgrowth. However, defining the impact of somatic mutations on the epigenome in human samples is challenging due to admixed mutated and wild-type cells. To chart how somatic mutations disrupt epigenetic landscapes in human clonal outgrowths, we developed Genotyping of Targeted loci with single-cell Chromatin Accessibility (GoT-ChA). This high-throughput platform links genotypes to chromatin accessibility at single-cell resolution, across thousands of cells within a single assay. We applied GoT-ChA to CD34+ cells from myeloproliferative neoplasm (MPN) patients with JAK2V617F-mutated hematopoiesis.

  Study EGAS50000000164

• National Cancer Institute Cancer Genome Characterization Initiative (CGCI)

  The Office of Cancer Genomics at the National Cancer Institute sponsored a series of studies as part of the Cancer Genome Characterization Initiative (CGCI) to assess novel emerging sequencing technologies in cancer. The CGCI program included comprehensive characterization of the genetic aberrations found in different pediatric and/or adult tumors. CGCI characterized a number of B-cell non-Hodgkin lymphomas (including diffuse large B-cell lymphoma (DLBCL) from patients with and without HIV+ infection, follicular lymphoma (FL), as well as adult and pediatric Burkitt lymphomas), and additional HIV-associated tumors (including DLBCL, lung, and cervical cancers). All data from these projects is available at the NCI Genomic Data Commons. Individual project descriptions are available by disease on the substudy pages (links are included at the top of this page). Brief summaries are as follows: Non-Hodgkin Lymphoma (NHL) - CGCI investigators probed genomic alterations more deeply than had previously been possible by using state-of-the-art RNA sequencing (mRNA-seq) and whole genome shotgun sequencing (WGS) coupled with leading edge bioinformatics, data management and analysis approaches. The project sequenced tumor DNA and/or RNA from 117 NHL tumor samples and 10 cell lines. This included the genomes or exomes of 1 Follicular Lymphoma (FL) and 13 diffuse large B-cell lymphoma (DLBCL) cases, all with matched constitutional DNA sequenced to comparable depths, RNA-sequencing (mRNA-seq) of 92 DLBCL, 12 FL and 8 B-cell NHL cases with other histologies and 10 DLBCL-derived cell lines. The DLBCL cases and cell-lines are from the two major subtypes of DLBCL: germinal center B-cell (GCB) and activated B-cell (ABC). HIV+ Tumor Molecular Characterization Project (HTMCP) - This project was a joint effort of the Office of Cancer Genomics (OCG) and the Office of HIV and AIDS Malignancy (OHAM). Its goals were to characterize HIV-associated cancers (obtained from HIV-infected patients) and compare them to the same types of cancers from patients without HIV infection. Investigators performed 30X genome sequencing of 100 cases of paired tumor and germline DNA, along with transcriptome sequencing in each of 3 types of HIV+ tumors (DLBCL, lung and cervical cancers). These platforms allow discovery of mutations both in coding and non-coding genomic regions, gene expression and genomic alterations (including translocations, insertions and deletions). Comparing tumors of cancer patients both with and without HIV-infection provides insight into the potential function of this virus in certain cancers. Burkitt Lymphoma Genome Sequencing Project (BLGSP) - This project was a collaborative effort between the National Cancer Institute and the Foundation for Burkitt Lymphoma Research to develop a databank of the many alterations found in Burkitt lymphoma (BL), an uncommon type of Non-Hodgkin lymphoma that occurs most often in children and young adults. The goal of the BLGSP was to explore potential genetic changes in patients with BL that could lead to better prevention, detection and treatment of the cancer. The project characterized the alterations of the tumors' genomes (with matched normal as control) and transcriptomes by sequencing the DNA and RNA of each case. Using the data generated, the ultimate goals of the project was to discover the molecular changes that are present in BL patients and then determine how those changes correlate with treatment regimen and outcome. CGCI data is accessible at the NCI's Genomic Data Commons (GDC) via the GDC's Data Portal and from each of the CGCI Publication Pages at the GDC (Please see the "Supplemental Links" section of any CGCI publication's "Publication Information and Associated Data Files page" at the GDC.). Available datasets include raw sequencing data, datasets generated by the original CGCI research teams (fully annotated clinical information and higher-level/analyzed molecular characterization data), as well as higher level data generated by the GDC. Please see the CGCI Use and Publication Guidelines for updated details on the sharing of any CGCI substudy data, including how to cite CGCI.To learn more about the CGCI studies, please visit the CGCI Program website.

  Study phs000235

• Cardiovascular disease biomarkers derived from circulating cell-free DNA methylation

  Acute coronary syndrome (ACS) remains a major cause of worldwide mortality. The syndrome occurs when blood flow to the heart muscle is decreased or blocked, causing muscle tissues to die or malfunction. There are three main types of ACS: Non-ST-elevation myocardial infarction, ST-elevation myocardial infarction, and unstable angina. The treatment depends on the type of ACS, and this is decided by a combination of clinical findings, such as electrocardiogram and plasma biomarkers. Circulating cell-free DNA (ccfDNA) is proposed as an additional marker for ACS since the damaged tissues can release DNA to the bloodstream. We used ccfDNA methylation profiles for differentiating between the ACS types and provided computational tools to repeat similar analysis for other diseases. We leveraged cell type specificity of DNA methylation to deconvolute the ccfDNA cell types of origin and to find methylation-based biomarkers that stratify patients. We identified hundreds of methylation markers associated with ACS types and validated them in an independent cohort. Many such markers were associated with genes involved in cardiovascular conditions and inflammation. ccfDNA methylation showed promise as a non-invasive diagnostic for acute coronary events. These methods are not limited to acute events, and may be used for chronic cardiovascular diseases as well.

  Study EGAS00001007263

• Longitudinal Studies of Patients with Familial Platelet Disorder with Associated Myeloid Malignancy (FPDMM)

  FPDMM (OMIM #601399) is a rare autosomal dominant disease characterized by defective megakaryocytic development, thrombocytopenia, platelet functional defects, and a life-long risk of developing hematological malignancies. FPDMM is caused by germline mutations in the RUNX1 gene, which encodes a master regulator of hematopoiesis. The overall lifetime risk of hematological malignancies in FPDMM patients is 35 - 45%. It is hypothesized that mutations in other genes cooperate with the germline RUNX1 mutations for leukemia development. However, it is not clear which genes need to be mutated for leukemia to develop and which biomarkers or clinical tests can be used to predict which patients will progress to leukemia. Likewise, there are no treatments and/or preventative measures that can reduce or stop disease progression except for stem cell transplantation, which is not available for all patients and may be associated with significant complications. To address these questions, we launched a longitudinal natural history study of patients associated with RUNX1 germline mutations at the NIH Clinical Center in early 2019 (Trial Registration ID: NCT03854318). The goals of this study are to: (1) perform comprehensive longitudinal phenotyping of FPDMM patients to document the full spectrum of both hematopoietic and non-hematopoietic manifestations of the disease; and (2) perform extensive genomic analyses of FPDMM patient samples to identify cooperating genomic variants, which may confer growth advantage that leads to clonal expansion of affected hematopoietic cells that may serve as the precursor to malignancies. The data available through dbGaP include exome sequencing and RNA-seq data from these patients. Diverse germline mutation types were identified in the RUNX1 gene, including splice site mutations and large deletions, in addition to nucleotide substitutions and small indels. Somatic mutations, especially in genes associated with clonal hematopoiesis of indeterminate potential (CHIP), were found in a substantial proportion of FPDMM patients who were leukemia-free. The findings suggest that the genomes in these patients are prone to somatic mutations and monitoring the dynamic changes of these somatic mutations prospectively may provide a way to predict progression to malignancies.

  Study phs003075

• Whole exome sequencing of bladder tumors

  Bladder carcinomas are immunogenic, and patients with bladder cancer benefit from immune checkpoint therapy. This is correlated to a high tumor mutation burden, which provides a higher number of neoepitopes that can be recognized by tumor-specific CD8+ T cells. Intravesical Bacillus Calmette-Guérin (BCG) is used to treat non-muscle invasive bladder cancer (NMIBC), but its mechanism of action remains elusive. Most lymphocytes appearing in the urine of BCG-treated patients are CD4+ T cells though preclinical studies showed that CD8+ T cells are also necessary for BCG treatment efficacy. It is currently unknown which proportion of patients with non-metastatic bladder cancer develop a spontaneous antitumor CD8+ response, and if BCG treatment influences this response. were prepared using the xGen Dual Index UMI Adapters (IDT), and genomic DNA (gDNA) extracted (DNeasy kit, Qiagen) from formalin-fixed paraffin- embedded (FFPE) or snap-frozen tumor tissue, as well as autologous lymphocytes. Libraries were subjected to paired-end sequencing using Illumina HiSeq4000 with a coverage depth of 250X. Library preparation was carried out with the AllType FASTplex NGS 11 Loci Flex Kit (One Lambda), and sequencing was conducted on the Illumina MiSeq platform.

  Study EGAS50000001248

• Identification of cis- and trans-regulatory variation modulating microRNA expression levels in human fibroblasts

  MicroRNAs (miRNAs) are regulatory noncoding RNAs that affect the production of a significant fraction of human mRNAs via post-transcriptional regulation. Interindividual variation of the miRNA expression levels is likely to influence the expression of miRNA target genes and may therefore contribute to phenotypic differences in humans, including susceptibility to common disorders. The extent to which miRNA levels are genetically controlled is largely unknown. In this report, we assayed the expression levels of miRNAs in primary fibroblasts from 180 European newborns of the GenCord project and performed association analysis to identify eQTLs (expression quantitative traits loci). We detected robust expression for 121 miRNAs out of 365 interrogated. We have identified significant cis- (10%) and trans- (11%) eQTLs. Furthermore, we detected one genomic locus (rs1522653) that influences the expression levels of five miRNAs, thus unraveling a novel mechanism for coregulation of miRNA expression

  Study EGAS00000000056

• NHLBI TOPMed: Genetic Epidemiology of COPD (COPDGene)

  Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States, and the only leading cause of death that is steadily increasing in frequency. This project established a racially diverse cohort that is sufficiently large and appropriately designed for genome-wide association analysis of COPD. A total of 10,720 subjects were recruited, including control smokers and nonsmokers, definite COPD cases (GOLD Stage 2 to 4), and subjects not included in either group (GOLD 1 and PRISm). This cohort is being used for cross-sectional analysis, and long-term longitudinal follow-up visits after five years and after ten years are also being performed. The primary focus of the study is to identify the genetic risk factors that determine susceptibility for COPD and COPD-related phenotypes. Detailed phenotyping of both cases and controls, including chest CT scan assessment of emphysema and airway disease, will allow identification of genetic determinants for the heterogeneous components of the COPD syndrome. The aims for this study are: Precise phenotypic characterization of COPD subjects using computed tomography, as well as clinical and physiological measures, that will provide data to enable the broad COPD syndrome to be decomposed into clinically significant subtype; Genome-wide association studies will identify genetic determinants for COPD susceptibility that will provide insight into clinically relevant COPD subtypes; Distinct genetic determinants influence the development of emphysema and airway disease. The TOPMed analysis will include approximately 10,500 subjects with whole genome sequencing after quality control is completed. Comprehensive phenotypic data for COPDGene subjects is available through dbGaP study phs000179.

  Study phs000951

• Reference Standards for Mosaic Variant Detection

  After conception, postzygotic mutations continuously occur throughout life in humans, causing somatic mosaicism in an individual. The variant type, time of origination, and locations of the mosaic mutations result in unique mosaic patterns in a combinatorial manner and further affect phenotypes, including various noncancerous diseases. Several efforts have, thus, been made to identify the mutational landscape and mechanisms underlying the mosaic mutations. From a technical aspect, the accurate detection of mutations is at the core of the mosaicism research, and the construction of a standard reference is a critical first step to serve as the basis for analytical validation and benchmarks for germline and somatic mutation detection. Furthermore, a reference standard for mosaic mutations is urgently needed to enable more advanced research.Herein, we generated robust, large-scale, and cell line mixture-based reference standards that contain abundant mosaic SNVs and INDELs along with wild-type sites and germ line variants. Moreover, the whole reference standard set mimics the cumulative aspect of mosaic variant acquisition in the early developmental stage through a progressive cell line mixing with confirmed genotypes. It can be used for optimizing the current use of mosaic variant detection strategies, as well as developing algorithms for future improvements.We previously generated an NCBI BioProject (PRJNA758606) to release much of these data. Only the data that are subject to authorized access constraints have been included in this submission to dbGaP. The two data sources are thus, complementary to each other.

  Study phs003399

• METABRIC: Data from Batra et al (2021); DNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation

  DNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, RRBS-based profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, the study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors.

  Study EGAS00001004327

• Rapid Acceleration of Diagnostics - Underserved Populations (RADx-UP): COVID-19 Testing and Prevention in Correctional Settings

  This study will work with diverse correctional facilities across MN, RI, WA, and FL to characterize the incidence of COVID-19 disease progression and related outcomes. The goal is to identify barriers and facilitators to develop strategies to improve testing in these under-served populations by: Increasing the reach, access, uptake, and impact of COVID-19 testing among incarcerated people and staff in prison and jails. Individuals in congregate settings have been disproportionately affected by COVID-19, with correctional settings accounting for 39 of the 50 largest cluster outbreaks in the country to date. Schema of Correctional Facilities: Correctional facilities are amplifiers of infectious diseases for structural reasons: 1) Dormitory-style living and overcrowded conditions make social distancing nearly impossible 2) They have a focus primarily on security not health 3) Their medical departments are under-resourced and often disconnected from local public health agencies. Correctional facilities must be the focus of urgent intervention to understand the incidence of COVID-19, how it spreads in correctional facilities, and durable long-term strategies to reduce transmission, including testing and vaccines. However, our work from the COVID Prison Project shows that correctional systems have implemented a range of testing strategies, without coordination, such that synthesizing the information on COVID-19 incidence, outcomes and optimal testing strategies (including repeat testing and contact tracing) has been challenging. Incarcerated people decline testing due to concerns about confidentiality, implications for release, and fear of placement in solitary confinement. Through interviews we will identify ethical concerns and potential solutions for COVID-19 testing and vaccine strategies in correctional facilities using a community-engaged strategy. The project's work from the COVID Prison Project shows that correctional systems have implemented a range of testing strategies, without coordination, such that synthesizing the information on COVID-19 incidence, outcomes and optimal testing strategies (including repeat testing and contact tracing) has been challenging. Incarcerated people decline testing due to concerns about confidentiality, implications for release, and fear of placement in solitary confinement. Through interviews we will Identify ethical concerns and potential solutions for COVID-19 testing and vaccine strategies in correctional facilities using a community-engaged strategy. Goals: 1. Identify ethical concerns and potential solutions for COVID-19 testing and vaccine strategies in correctional facilities using a community-engaged strategy. 2. Characterize incidence of COVID-19, disease progression, and related-outcomes and effectiveness of testing and contact tracing in correctional facilities. Participant Selection: a. Potential subjects must be currently incarcerated at key facilities in Washington, Rhode Island, Minnesota, and Florida. These facilities are Everglades Correctional Institution and Homestead Correctional Institution in Florida, Shakopee and Stillwater correctional facilities in Minnesota, the Rhode Island Department of Corrections, and Yakima County Jail in Washington. b. Participating correctional facilities in Florida, Minnesota, Rhode Island, and Washington will provide de-identified data on approximately 16,859 incarcerated adults and correctional staff. Data sources include deidentified data from medical records, administrative data, and policy documents pertaining to COVID-19. c. 3 series of focus groups (6, 12, 18 months) x 3 distinct groups (incarcerated people, medical providers, and correctional leaders) x 4 sites=36 total focus groups over the study period. d. Will utilize 74,812 COVID-19 tests to test and re-test a total of 16,859 incarcerated people and correctional staff for active infection over a six-month period in the FL, MN, and RI state prison systems and the Yakima County Jail in WA.

  Study phs003361

• Harnessing the Electronic Health Record to Predict Risk of Cardiovascular Disease: Sangre Por Salud (SPS) Biobank GWAS Data

  These data are from subjects in the Sangre Por Salud (SPS) Biobank, a Latino population from the Southwest United States. Subjects were genotyped in 2 batches on the Illumina Multi-ethnic Global Array. Data from this study were used for testing a new cardiovascular risk score and evaluating polygenic risk scores. SPS biobank GWAS data is available on 3699 subjects.

  Study phs003553

• exploration of biomarkers discriminating squamous cell carcinoma from other lung cancers

  Targeted therapies based on the molecular and histological features of cancer types are becoming standard practice. The most effective regimen in lung cancers is different between squamous cell carcinoma (SCC) and adenocarcinoma (AD). Therefore a precise diagnosis is crucial, but this has been difficult, particularly for poorly differentiated SCC (PDSCC) and AD without a lepidic growth component (non-lepidic AD). Biomarkers enabling a precise diagnosis are therefore urgently needed. To achieve this goal, we initially performed CAGE (Cap Analysis of Gene Expression) to quantify promoter activities on 97 frozen tissues from surgically resected lung cancers (22 SCC and 75 AD). We furhter expanded the transcriptome profiling to cover additional 48 malignant neoplasm of bronchus and lung, including mesothelioma and metastatic lung cancers derived from other tissues.

  Study JGAS000488

• National Cancer Institute Clinical and Laboratory Analysis of Familial Cancer

  The purpose of this study is to continue the analysis begun on 09C0079 which was focused on identification of the genetic mutation associated with a new gastric polyposis syndrome, Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS). GAPPS, first described in 2012, is an autosomal dominant gastric polyposis syndrome that confers a substantial risk for gastric adenocarcinoma. The GAPPS phenotype consists of a carpeting of greater than 100 fundic gland polyps (FGPs) in the oxyntic mucosa of the gastric body and fundus, with antral sparing with some FGPs displaying high-grade dysplasia. This is in contrast to sporadic FGPs that are benign, most often are not associated with high-grade dysplasia though low-grade dysplasia has been reported, and are fewer in number. Gastric FGPs have been found to be associated with Familial Adenomatous Polyposis (FAP) and attenuated FAP, which is an autosomal dominant condition associated with germ line mutations in APC which confers a phenotype consisting of multiple (>100) adenomatous polyps in the colon and rectum developing after the first decade of life. FGPs are reported to occur in 12-84% of patients with FAP, whereas sporadic FGPs are identified in ~5% of patients undergoing upper gastrointestinal endoscopy. Gastric adenocarcinoma arising from FGPs in individuals with FAP have been reported. Other manifestations of FAP and AFAP include polyps in the upper gastrointestinal tract, congenital hypertrophy of retinal pigment epithelium, osteomas and epidermoid cysts, supernumerary teeth, desmoid formation, and other malignancies such as thyroid, small bowel cancer, hepatoblastoma, and medulloblastoma. Thus far there are no reports in GAPPS of polyposis arising in the esophagus, gastric antrum, pylorus, small intestine, or colon.

  Study phs001935

• Identification of a Fumarate-Hydratase Deficient-like RCC Subtype with Convergent Pathway Alterations

  The development of molecularly targeted therapies builds upon the identification of tumor clades with shared molecular abnormalities. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a familial syndrome resulting from germline mutation of the two-hit tumor suppressor gene, Fumarate Hydratase (FH). HLRCC renal tumors present often in young adults, exhibit unique histological features and are particularly aggressive. HLRCC is uncommon and poorly understood, and whether there are sporadic renal tumors with similar characteristics, is unclear. Notably, FH can also be inactivated somatically in RCC, and should be included among FH-deficient (FHD) kidney tumors. We identified a tumor clade without FH mutations but with similar morphological and molecular characteristics as well as aggressive clinical behavior, which we name FHDL (FHD-like). We show that FHD/FHDL tumors represent a unique subtype of CIMP (CpG Island Methylator Phenotype) with the highest levels of overall genome methylation and CDKN2A silencing. FHD/FHDL tumors are characterized by convergent activation of the Hippo pathway as determined by frequent and mutually exclusive mutations in NF2 and PTPN14. AKR1B10, an NRF2 target, was upregulated in FHD/FHDL tumors as well as GATA3, which suggests a shared origin in the renal medulla and is consistent with topological studies. There is loss of 5-hydroxymethylcytosine in both FHD and FHDL tumors. These data define a group of particularly aggressive renal cancers with shared molecular features and potential targets for therapeutic intervention.

  Study EGAS00001002646

• A_study_of_the_genetic_basis_of_evation_by_Acute_Myeloid_Leukaemia_of_Graft_vs_Leukaemia_effects_after_allogeneic_bone_marrow_transplantation

  Acute myeloid leukaemia (AML) is an aggressive and molecularly diverse disease with a poor overall survival of 20-25%. With an annual incidence of 2.9 per 100,000, AML is currently the commonest myeloid malignancy in Europe, yet the two main therapeutic options for this disease, anthracyclines and purine analogues, have remained unchanged for over 20 years. Currently patients are stratified at diagnosis according to a series of clinicopathological parameters (e.g. age, white cell count and presence/absence of previous clonal haematological disease) and molecular markers (e.g. chromosomal translocations/deletions, aneuploidy and mutations in genes such as FLT3 and NPM1). Patients with adverse prognostic features, whose prognosis is particularly poor (e.g. <15% long-term survival) are offered treatment with allogeneic bone marrow transplantation (allo-BMT) if a sibling or unrelated donor is available. This can significantly improve survival (e.g. up to 40% long-term survival in some contexts), albeit at the expense of significant toxicity and transplant-related mortality (TRM). Allo-BMT is thought to work in part by allowing the delivery of large doses of chemotherapy followed by haemopoietic "rescue" with donor haemopoietic stem cells (haemopoietic failure would otherwise ensue). However, potentially the most potent effect of allo-BMT is the cytotoxic effect of donor lymphocytes against AML blasts, a phenomenon known as graft-vs-leukaemia (GVL) effect. Increasingly, transplants using reduced chemotherapy intensity (mini-allografts) are being used that partially circumvent the toxicity from chemotherapy and rely on GVL to effect cure. Nevertheless, AML relapse after allo-BMT still occurs at a significant rate of up to 80% depending on the type of transplant. There is accumulating evidence that genetic events in residual leukaemic cells enable them to evade immunodetection and therefore survive the GVL effect and expand to cause relapse. The most striking example of this is the loss of HLA antigens after transplants in which donor and recipient are not fully HLA-matched. In these cases, the leukaemia "deletes" the genomic region containing the disparate HLA antigen which was preferentially targeted as "foreign" by the GVL effect. However, the genetic basis of immune evasion in the majority of transplants, which are fully HLA matched, is not known. One possibility is that loss of genes coding for antigens outside the HLA locus but which are also targets of GVL may operate, alternatively genetic events that affect processes downstream of immunological cytotoxicity may be responsible.The identification of genetic events that mediate immune evasion would not only facilitate the understanding of this process but can help plan therapeutic interventions that improve the outcomes of allogeneic transplantation for AML and other disorders. We intend to study this by conducting exome sequencing on 6 cases of AMLs from patients that attend my clinic at Addenbrooke's hospital and have relapsed after allogeneic transplantation. Samples from AML diagnosis, remission/normal and AML relapse (total n=18) will be studied to identify somatic mutations in the primary AML and those acquired by the relapsed clone. The 18 samples will also be studied by array CGH to detect regions of genomic amplification or deletion.

  Study EGAS00001000145

• NOTCH1 fusion genes in pediatric T-cell lymphoblastic lymphoma hallmark a common high-risk subgroup with blood TARC levels as possible biomarker

  T-cell lymphoblastic lymphoma (T-LBL) is a common pediatric malignancy accounting for approximately 20% of the non-Hodgkin lymphomas during childhood. Survival rates of T-LBL are ~80%, but outcome after relapse is dismal, with salvage rates reaching only ~15. Considering the extremely poor prognosis after relapse and absence of clinically relevant high-risk genetics, there is an urgent need for the identification of molecular risk factors and new prognostic biomarkers in T-LBL, as well as identification of new therapeutic strategies. In this study we present a novel entity of high-risk pediatric T-LBL patients characterized by previously unknown NOTCH1 gene fusions and highly elevated blood TARC levels

  Study EGAS00001007703

• Genesis of Two Most Prevalent Variants Causing Combined Pituitary Hormone Deficiency in 21 Populations

  Two variants (c.[301_302delAG];[301_302delAG] and c.[150delA];[150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG];[301_302delAG] or c.[150delA];[150delA] or c.[301_302delAG];[ 150delA]. They originated from 21 different countries worldwide. We genotyped 21 single nucleotide variant markers flanking the 9.6Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations - a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated ancestral origin of both variants: c.[301_302delAG] was carried on 0.2Mb-long haplotype in a majority of European patients arising approximately 101 generations ago (confidence interval 90.1-116.4). Patients from the Iberian Peninsula displayed a different haplotype which was estimated to have emerged 23.3 (20.1-29.1) generations ago. Subsequently, the data indicated that both haplotypes were transmitted to Latin American patients approximately 13.8 (12.2-17.0) and 16.4 (14.4-20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3Mb was estimated to appear 43.7 (38.4-52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot-spots as previously assumed, but are founder variants.

  Study EGAS00001001165

• AIDS Linked to the Intravenous Experience (ALIVE) Cohort

  The AIDS Linked to the Intravenous Experience (ALIVE) Study is a long-standing community based research effort that includes past and current injection drug users (IDUs). ALIVE has been ongoing since 1988 and is one of the longest-running community-based cohorts of IDUs in existence. The primary objectives when the study started were to characterize the incidence and natural history of HIV among injection drug users (IDUs). At each study visit, participants undergo a series of questionnaires that elicit information about substance use (including drugs used and route of administration) and a blood draw. A subsample of 1200 subjects was selected for genotyping for the NIDA Smokescreen effort who report heroin injection and have existing peripheral blood samples (isolated buffy coat). In addition to injected heroin, ALIVE subjects are assessed on lifetime and previous six months use of marijuana (76.3%), crack (55.5%), snorted cocaine (48.3%), injected cocaine (89.9%), injected speedball (87.0%), and smoking heroin (9.0%). The sample is 33.4% female, ~85% African-American and assessed through a mean maximum age of 49.9 years old. Importantly, subjects are not assessed to meet DSM criteria, but all subjects report having injected drugs. We provide demographic data (age at assessment, sex, self-reported race) and drug use data (lifetime "use" ever endorsed) for each drug class/route described above for each subject

  Study phs001494

• Oncoarray Consortium - Lung Cancer Studies

  The study was conducted under the auspices of the Transdisciplinary Research In Cancer of the Lung (TRICL) Research Team, which is a part of the Genetic Associations and MEchanisms in ONcology (GAME-ON) consortium, and associated with the International Lung Cancer Consortium (ILCCO). Ethics: All participants provided written informed consent. All studies were reviewed and approved by institutional ethics review committees at the involved institutions. Sequencing data are derived from four substudies. The substudies that contributed include Harvard, Liverpool, Toronto, and IARC. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study is a randomized primary prevention trial including 29,133 male smokers enrolled in Finland between 1985 and 1993. Participants ranged between ages of 50 to 69 at enrollment and were randomized in a factorial design to take either 50 milligrams of d-alpha tocopheryl acetate (Vitamin E), 20 mg of all-trans-beta-carotene, both or placebo. The study continued to monitor cancer incidence through 2012 and total mortality through December 2013. The CAncer de PUlmon en Asturias Study (CAPUA) is a hospital-based case-control study conducted in Asturias, Spain by the University of Oviedo. Lung cancer cases were recruited in three main hospitals of Asturias, following an identical protocol from 2002 to 2012. Eligible cases were incident cases of histologically confirmed lung cancer between 30 and 85 years of age and residents in the geographical area of each participating hospital. Controls were selected from patients admitted to those hospitals with diagnoses unrelated to the exposures of interest and individually matched by ethnicity, gender, age (± 5 years) and hospital. Epidemiologic data were collected personally through computer-assisted questionnaires by trained interviewers during the first hospital admission. Structured questionnaires collected information on sociodemographic characteristics, recent and prior tobacco use, environmental exposure (air pollution and passive smoking), diet, personal and family history of cancer, and occupational history from each participant. Peripheral blood samples (or mouthwash samples when they refused to donate blood) were collected from all participants. Coding of histology was based on 2001 WHO/IASLC. Genomic DNA was extracted based on standard protocol. The Canadian Screening Study includes the nested case-control samples from 3 screening programs: IELCAP-Toronto: Ever smokers of more than 10 pack-years age 50 and above were eligible for the I-ELCAP screening program since 2003, and a total of 4782 individuals have been enrolled in the Greater Toronto Area. Participants were administered a LDCT scan along with a standard study questionnaire at baseline. Blood samples were systematically collected at baseline since 2006. Participants who had an abnormality in a CT scan were followed up every 1 to 2 years. The screening program was organized by the Princess Margaret Hospital. PanCan: Ever smokers between the ages of 50-75 with no previous history of invasive cancer are eligible to participate in the study. The study was carried out across Canada in Vancouver, Calgary, Hamilton, Toronto, Ottawa, Quebec, Halifax, and St. John's. A total of 2537 smokers have been screened from 2008 to 2011. All study participants completed a detailed questionnaire, spirometry, collection of blood specimens for biomarker measurement and LDCT at baseline. All participants are followed for a minimum of 3 years. On yearly follow up, an updated shorter questionnaire is administered, blood is collected and CT scans are performed. Blood samples are available from all 2537 individuals. BCCA Screening Program: From 1990 to 2007, 4274 smokers above 40 years old who had smoked 20 pack-years or more were enrolled at BCCA. Upon enrollment, subjects completed a questionnaire for their lifestyle and medical history. Baseline spirometry was conducted using a flow-sensitive spirometer in accordance with the American Thoracic Society recommendations. Since 2000, a LDCT was obtained in 2440 individuals. The participants were followed prospectively to determine whether they developed lung cancer. A total of 9759 individuals participated in the CT screening program in Canada from these 3 programs. The samples included in this project is based on a subset of nested lung cancer case-control pairs based on 1:2 ratio. The Carotene and Retinol Efficacy Trial (CARET) was a randomized, double-blind, placebo-controlled trial of the cancer prevention efficacy and safety of a daily combination of 30 mg of beta-carotene and 25,000 IU of retinyl palmitate in 18,314 persons at high risk for lung cancer. CARET began in 1985, and the intervention was halted in January 1996, 21 months ahead of schedule, with the twin conclusions for definitive evidence of no benefit and substantial evidence of a harmful effect of the intervention on both lung cancer incidence and total mortality. CARET continued to follow and collect endpoints on their participants through 2005. Pathology reports and medical records were reviewed to confirm cancer endpoints, and death certificates obtained to capture cause of death. During the active intervention phase of CARET, serum, plasma, whole blood, and lung tissue specimens were collected on participants. These biospecimens make up the CARET Biorepository. For the OncoArray Project, CARET provided DNA extracted from whole blood of lung cancer cases and controls matched on age at baseline (± 4 years), sex, race, baseline smoking status, history of occupational asbestos exposure (asbestos vs heavy smoker), and year of enrollment (2-year intervals). The European Prospective Investigation into Cancer and Nutrition (EPIC) study is a multi-center cohort study involving 521,000 study participants from 10 European countries. The current study involved EPIC participants from 7 countries (Greece, Netherlands, UK, France, Germany, Spain, and Italy), including 1223 incident lung cancer cases and 1249 smoking matched controls. The Kentucky Lung Cancer Research Initiative is a study conducted by the Markey Cancer Center Cancer Center and the University of Kentucky using a population-based, case-control framework to study the extraordinarily high rates of lung cancer in Southeastern, Appalachian Kentucky. Cancer cases were recruited from the Kentucky Cancer Registry at the time of diagnosis and controls were recruited from a random digit dialing process from the same region. Study accrual began in January 5, 2012 and completed on September 5, 2014 and 520 subjects were recruited in a 4:1 ratio of controls: cases from Appalachian Kentucky. Of the 520 subjects recruited, 231 are included in the OncoArray analysis, including all 93 cancer cases, and 123 controls. Newly diagnosed lung cancer cases and controls underwent blood, toenail (for trace element analysis), urine, buffy coat, water, soil, and radon collection, residence GPS mapping, as well as an extensive epidemiologic, occupational, and health history questionnaire (Clinical Trials.gov Identifier: NCT01648166). The Harvard Lung Cancer Study (HLCS) is a case-control study based at Mass General Hospital (MGH) in Boston, Massachusetts from 1992 to 2004. Details of the study were described previously. Briefly, eligible cases included any person over the age of 18 years with a diagnosis of primary lung cancer that was further confirmed by an MGH lung pathologist. Controls were recruited from the friends or spouses of cancer patients or the friends or spouses of other surgery patients in the same hospital. Potential controls were excluded from participation if they had a diagnosis of any cancer (other than non-melanoma skin cancer). Interviewer-administered questionnaires, a modified version of the standardized American Thoracic Society respiratory questionnaire, collected information on demographics, medical history, family history of cancer, smoking history, and a detailed work history, including job titles and tasks. Genome-wide genotype data were first generated using Illumina Human 610-Quad BeadChips and then imputed by MACH against the 1000 Genome Project dataset (http://browser.1000genomes.org/index.html). The Institutional Review Board of MGH and the Human Subjects Committee of the Harvard School of Public Health approved the study. The Israel study (NICCC-LCA) is an ongoing case-control study of newly diagnosed lung cancer cases of any histology and population age/sex/ethnicity-matched "healthy" controls. All participants undergo face-to-face interviews, provide a venous blood sample (separated into DNA, Sera, lymphocytes) after signing an IRB-approved form. Histology reports, FFPE blocks and clinical follow-up are available for most cancer cases. The MD Anderson Cancer Center (MDACC) Study. Lung cancer cases and frequency-matched controls were ascertained from a large ongoing case-control study at the University of Texas MD Anderson Cancer Center (UTMDACC) since 1991. Detailed study description was provided previously (Spitz et al 2007). In brief, cases were newly-diagnosed and histologically confirmed lung cancer patients recruited from UTMDACC. Controls were healthy individuals without a history of cancer (except for nonmelanoma skin cancer) and recruited from the Kelsey-Seybold Clinics, the largest private multispecialty physician group in the Houston metropolitan area. Controls were frequency-matched to cases on age (±5 years), sex, and race/ethnicity. After providing written informed consent, each study participants completed an in-person interview by staff interviewers to collect information on demographics, smoking status, etc. Blood samples were also drawn from all the study participants. This study was approved by institutional review boards of UTMDACC and Kelsey-Seybold Clinics. The Malmö Diet and Cancer Study (MDCS) is a population-based prospective cohort study that recruited men and women aged at 44 to 74 years old of living in Malmö, Sweden between 1991 and 1996. The main goal of the MDCS is to study the impact of diet on cancer incidence and mortality. It consists of a baseline examination including dietary assessment, a self-administered questionnaire, anthropometric measurements and collection of blood samples. A total of 165 incident lung cancer cases and 174 individually smoking-matched controls were available for this analysis. The Multiethnic Cohort (MEC) Study includes 215,251 men and women aged 45-74 years at recruitment, primarily from five ethnic/racial groups - African Americans and Latinos mostly recruited from CA (mainly from Los Angeles County) and Japanese Americans, Native Hawaiians and whites (mostly recruited from HI). The cohort was assembled in 1993-1996 by mailing a self-administered questionnaire to persons identified primarily through driver's license files. The baseline questionnaire obtained information on demographics, anthropometry, smoking history, medical and reproductive histories, family history of cancer, diet and physical activity. Incident cancer cases are identified by regular linkage with the State of California Cancer Registry and the Hawaii Tumor Registry, both members of the SEER Program of the NCI. In 2001-2006, a prospective biorepository was assembled by collecting a pre-diagnostic blood specimen from 67,594 surviving MEC members. At the time of blood collection a short questionnaire was administered that included information on smoking during the previous 15 days. For this study, cases were all lung cancer cases incident to blood draw and diagnosed before December 2012. For each case, a control was selected among unaffected MEC participants who were alive at time of the case's diagnosis and matched on study site, sex, race/ethnicity, age (age at diagnosis for cases; age at blood collection for controls), and date of blood collection. The Mount-Sinai Hospital-Princess Margaret Study (MSH-PMH) was conducted in the greater Toronto area from 2008 to 2013. Lung cancer cases were recruited at the hospitals in the network of the University of Toronto. Controls were selected randomly from individuals registered in the family medicine clinics databases and were frequency matched with cases on age and sex. All subjects were interviewed, and information on lifestyle risk factors, occupational history and medical and family history was collected using a standard questionnaire. Tumors were centrally reviewed by the reference pathologist, a member of the International Association for the Study of Lung Cancer (IASLC) committee, and a second pathologist in the University Health Network. If the reviews conflicted, a consensus was arrived at after discussion. Coding of histology was based on 2001 WHO/IASLC. Genomic DNA was extracted based on standard protocol. The New England Lung Cancer Study (NELCS) is a population-based case-control study of lung cancer among residents of Northern and Central New Hampshire counties and the bordering region of Vermont. Cases with histologically confirmed primary incident lung cancer were identified from 2005 to 2007 using the New Hampshire State Cancer Registry and the Dartmouth-Hitchcock Medical Center (DHMC) Tumor Registry. Control participants were identified using a commercial database and matched to lung cancer cases within 5-year age groups, sex and county. Genomic DNA was isolated from blood or buccal specimens provided by consenting participants. The study complied with requirements of the Dartmouth College's Committee for Protection of Human Subjects. The Nijmegen Lung Cancer Study. The Netherlands patients with lung cancer were identified through the population-based cancer registry of the Netherlands Comprehensive Cancer Organisation in Nijmegen, the Netherlands. Patients who were diagnosed in one of three hospitals (Radboud University Medical Center, Canisius Wilhelmina Hospital in Nijmegen, and Rijnstate Hospital in Arnhem) since 1989 and who were still alive at April 15th, 2008 were recruited for a study on gene-environment interactions in lung cancer. 458 patients gave informed consent and donated a blood sample. This case series was expanded with 94 patients to a total of 552 by linking three other studies to the population-based cancer registry in order to identify new occurrences of lung cancer among the participants of these other studies. All three other studies (i.e., POLYGENE, the Nijmegen Biomedical Study, and the Radboudumc Urology Outpatient Clinic Epidemiology Study) were initiated to study genetic risk factors for disease and participants to these studies gave general informed consent for DNA-related research and linkage with disease registries. Information on histology, stage of disease, and age at diagnoses was obtained through the cancer registry. Lifestyle information was collected through a structured questionnaire and whole blood for DNA isolation was collected by the regional thrombosis services. The cancer-free controls (46% males) were selected from participants of the "Nijmegen Biomedical Study" (NBS), an age- and sex-stratified random sample of the general population of the municipality of Nijmegen, The Netherlands. All participants provided extensive lifestyle information by structured questionnaires and blood samples for DNA isolation, serum and plasma. All controls are of self-reported European descent. The study protocols of the NBS were approved by the Institutional Review Board of the Radboudumc and all study subjects signed a written informed consent form. The Northern Sweden Health and Disease Study (NSHDS) encompasses several prospective cohorts. The current study involves participants from the Västerbotten Intervention Project (VIP), a sub-cohort within NSHDS. VIP is an ongoing prospective cohort and intervention study intended for health promotion of the general population of the Västerbotten County in northern Sweden. VIP was initiated in 1985 and all residents in the Västerbotten County were invited to participate by attending a health check-up at 40, 50 and 60 years of age. Participants were asked to complete a self-administered questionnaire including various demographic factors such as education, smoking habits, physical activity and diet. In addition, height and weight were measured and participants were asked to donate a fasting blood sample for future research. A total of 243 incident lung cancer cases and 266 individually smoking-matched controls were available for this analysis. Norway National Institute of Occupational Health Study. Early-stage NSCLC cases and healthy controls at the time of enrollment were Caucasians of Norwegian origin and were recruited from the same geographical region (Western Norway). The patients were enrolled in the study, whenever practically feasible among patients admitted for lung cancer at the Haukeland University Hospital in Bergen, Norway. The informed written consents covering analysis of molecular and genetic markers was signed by the patients prior to surgery. Only patients with histologically confirmed early-stage NSCLC were included in our study. The subjects included in this project are a subgroup recruited into the project "lung cancer genetics" at NIOH. The controls were recruited from the same geographical region of Western Norway and frequency-matched with cases on cumulative smoking dose (pack-years). Pack-years smoked [( 20 cigarettes per day) x years smoked] were calculated to indicate the cumulative smoking dose. The Cases and controls were interviewed using similar questionnaires and were categorized as never smokers, ex-smokers or current smokers. Never smokers are subjects indicating having smoked less than 100 cigarettes in their life time. Ex-smokers were defined as those having quitted at least 1 year before sampling, and current smokers were those indicating that they were smokers at the time of sampling. The project has been approved by the Regional Committee for Medical and Health Research Ethics in Southern Norway in accordance with the WMA Declaration of Helsinki. The ethical approval covered access to the NSCLC databank. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) Study, a randomized trial aimed at evaluating the efficacy of screening in reducing cancer mortality, recruited approximately 155,000 men and women age 55 to 74 years from 1992 to 20014. Screening for lung cancer among participants in the intervention arm included a chest x-ray at baseline followed by either three annual x-rays (for current or former smokers at enrollment) or two annual x-rays (for never smokers); participants in the control arm received routine health care. Screening-arm participants provided data on sociodemographic factors, smoking behavior, anthropometric characteristics, medical history, and family history of cancer, as well as blood samples annually for the first 6 years of the study (baseline T0 and T1 through T5). Lung cancers were ascertained through annual questionnaires mailed to the participants, and positive reports were followed up by abstracting medical records or death certificates. Follow-up in the trial as of July 2009 was 96.7%. Patients were excluded because of missing baseline questionnaire, previous history of any cancer, diagnosis of multiple cancers during follow-up, missing smoking information at baseline, missing consent for utilization of biologic specimens for etiologic studies, or unavailability/insufficient quantity of serum or DNA specimens. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT) is an ongoing study conducted in Sheffield from 2006 and due to complete recruitment in 2016. The study recruited pathologically confirmed lung cancer cases diagnosed at age 60 years or younger and family matched controls. Lung cancer cases diagnosed at ages older than 60 years were recruited if they reported a family history of lung cancer. The cases and matched controls were recruited through several major cancer treatment centers, however, the majority were recruited in North Trent. All participants completed a detailed lifestyle questionnaire which included questions about occupational exposures, education, medical history and family history of cancer and lung disease. Participants also donated blood samples for DNA extraction. The ReSoLuCENT study has been funded by the Sheffield Hospitals Charity, Sheffield ECMC and Weston Park Hospital Cancer Charity. First degree relatives were removed from the sample deposited to dbGaP. The Roy Castle Lung Study of Liverpool Lung Project (LLP) is a case-control and cohort study which has recruited over 11,500 individuals since 1996 from the Liverpool region in the UK. Detailed epidemiological and clinical data is collected with associated specimens (i.e. tumor tissue, blood, plasma, sputum, bronchial lavage and oral brushings). The participants have completed a detailed lifestyle questionnaire at recruitment, with repeat questionnaires at intervals; updated data on clinical outcome and hospital events are collected through the Health and Social Care Information Center (including Office of National Statistics mortality data, Cancer Registry and Health Episode Statistics). The project is registered on the UK National Institute for Health Research (NIHR) lung cancer portfolio and has all the required ethical approvals and sponsorship arrangements in place. The lung tumors were reviewed by the reference pathologist. The Seoul Bundang Lung Cancer Study was conducted between 2005 and 2010 to discover genetic and environmental factors related with lung cancer development. Lung cancer cases were recruited at the Seoul National University Hospital in Bundang. Controls were selected randomly from individuals participated in health check-up program and were frequency matched with cases on age and sex. All subjects were interviewed, and information on lifestyle risk factors, occupational history and medical and family history was collected using a standard questionnaire. Tumors were reviewed by the pathologists in the hospital. If the reviews conflicted, a consensus was arrived at after discussion. Coding of histology was based on 2001 WHO/IASLC. Genomic DNA was extracted based on standard protocol. The Shanghai Cohort Study (SCS) consisted of 18,244 men in Shanghai, China, who were 45-64 years old at the time of enrollment during 1986-1989. Approximately 80% of eligible men participated in the study. At the time of recruitment, each cohort subject was interviewed in-person by a trained nurse interviewer using a structured questionnaire that included background information, history of tobacco and alcohol use, current diet, and medical history. At the completion of the interview, the nurse collected a 10 ml blood and a single void urine specimen from the study participant. The buccal cell samples were collected from all surviving cohort members (~15,000) in the 2001-2002 follow-up interviews. The cohort has been followed for the occurrence of cancer and death through routine ascertainment of new cases from the population-based Shanghai Cancer Registry and Shanghai Vital Statistics Units. To maximize the cancer findings and minimize the loss of follow-up, we contacted each surviving cohort member annually. Retired nurses visit the last known address of each living cohort member and record details of the interim health history of the cohort member. As of December 31, 2014, cumulatively 612 (3.4%) original subjects were lost to follow-up, and 574 (3.1%) refused to our continued follow-up interview. A nested case-control study of incident lung cancer cases within the Shanghai Cohort Study was used to examine the association between serum levels of vitamin B6 and other compounds in the one-carbon metabolism pathway and risk of lung cancer. Briefly, 516 lung cancer cases were identified among cohort participants with available serum samples as of 12/31/2006. For each case, we randomly selected one control subject from all cohort members who were free of cancer and alive at the time of cancer diagnosis of the index case. Controls were matched to the index case by age at enrollment (±2 years), date of biospecimen collection (±1 month) and neighborhood of residence at recruitment, and smoking status (current, former and never smokers) as established previously for other studies. For former smokers, cases and controls were further matched by years since quitting smoking (<10 vs ≥10 years). One serum vial per subject was retrieved from biorepository and all serum samples were sent to the laboratory (B-vital) for measurements. DNA samples of 250 lung cancer cases and 250 matched controls were available for the present study. The Singapore Chinese Health Study (SCHS) cohort consisted of 63,257 Chinese men and women in Singapore when they were 45-74 years old at the time of enrollment between April 1993 and December 1998. At recruitment, each study subject was interviewed in person by a trained interviewer using a structured questionnaire that emphasized current diet assessed via a validated, 165-item food frequency questionnaire. The questionnaire also requested information on demographics, lifetime use of tobacco, incense use, current physical activity, usual sleep duration, reproductive history (women only), occupational exposure, medical history, and family history of cancer. Blood or buccal cell, and spot urine samples were collected first from a random 3% sample of cohort participants in April 1994, and extended to all surviving cohort participants starting in January 2000. Overall approximately 60% of eligible cohort participants donated biospecimens. The cohort has been passively followed for death and cancer occurrence through regular record linkage with the population-based Singapore Cancer Registry and the Singapore Registry of Births and Deaths. Migration out of Singapore, especially among housing estate residents, was negligible. As of latest update, only 55 individuals from this cohort were known to be lost to follow-up due to migration and other reason. A nested case-control study of incident lung cancer cases within the Singapore Chinese Health Study was used to examine the association between serum levels of vitamin B6 and other compounds in the one-carbon metabolism pathway and risk of lung cancer. As of 12/31/2011, 422 lung cancer cases were identified among cohort participants with available prediagnostic plasma samples. For each case, one control subject was randomly selected from all eligible cohort members who were alive and free of cancer on the date of cancer diagnosis of the index case. The control subject was individually matched to the index case by gender, dialect group (Hokkien, Cantonese), age at enrollment (±3 years), date of baseline interview (±2 year), date of biospecimen collection (±6 months), and smoking status (current, former, and never smokers). For current smokers, cases and controls were further matched by number of cigarettes per day (<15, ≥15 cigarettes/day). For former smokers, cases and controls were further matched by years since quitting smoking (<10, ≥10 years). One plasma aliquot per subject was retrieved from the biorepository and all plasma samples were sent to the laboratory (B-vital) for measurements, and one aliquot of DNA per subject for the present study. The International Agency for Research on Cancer (IARC) L2 Study. Lung cancer cases and controls were recruited through a multicentric case-control study coordinated by the IARC in Russia, Poland, Serbia, Czech Republic, and Romania from 2005 to 2013. Cases were incident cancer patients collected from general hospitals. Controls were recruited from individuals visiting general hospitals and out-patient clinics for disorders unrelated to lung cancer and/or its associated risk factors, or from the general population. Information on lifestyle risk factors, medical and family history was collected from subjects by interview using a standard questionnaire. All study participants provided written informed consent. The current study included 1,133 lung cancer cases and 1,117 controls genotyped on the Oncoarray. The Washington State University Lung Cancer Study is a hospital case-control study of 511 subjects with newly-diagnosed (within 1 year of diagnosis) lung cancer and 820 race-, sex- and age-matched controls. Lung cancer cases were recruited from lung cancer clinics within the H. Lee Moffitt Cancer Center while controls were recruited from the Lifetime Cancer Screening Center, a H. Lee Moffitt Cancer Center affiliate. None of the controls were diagnosed with any form of cancer at the time of screening. Detailed questionnaire data and oral buccal cells were collected for all subjects. The Total Lung Cancer (TLC) Study is a hospital-based study that included 458 lung cancer patients recruited for Moffitt Cancer Center's Total Cancer Care™ protocol between April 2006 and August 2010. Total Cancer Care™ is a multi-institutional observational study of cancer patients that prospectively collects self-reported demographic and clinical data, medical record information and blood samples for research purposes. All patients used in this cohort were recruited from the Thoracic Oncology Clinic at the Moffitt Cancer Center. The Vanderbilt Lung Cancer Study (BioVU) is a case-control study nested within the Vanderbilt University Medical Center biobank, BioVU. BioVU is a biorepository of DNA extracted from blood drawn from patients seeking routine clinical care at Vanderbilt University Medical Center and linked to de-identified electronic health records for research purposes. Lung cancer cases and controls were identified from BioVU participants in February 2014. Lung cancer cases were identified from the Vanderbilt tumor registry. All specimens undergo pathologic review for determination of morphology. Coding of histology was based on SEER Program Coding Guidelines. Controls were randomly selected from BioVU participants, excluding cancer patients, and were matched to cases on age (± 5 years), sex, and race. Relevant covariates were identified from electronic health records using natural language processing. Genomic DNA was extracted based on a standard protocol.

  Study phs001273

• Genetics of Lymphatic Anomalies from Center of Applied Genomics (CAG) at CHOP

  Lymphatic anomaly, a rare and devastating disease spectrum of mostly unknown etiologies, is characterized by diffuse or multicentric proliferation of dilated lymphatic vessels, and includes a variety of diagnoses: lymphangiectasia, central conducting lymphatic anomaly, generalized lymphatic anomaly, kaposiform lymphangiomatosis, and Gorham Stout disease. Currently, most treatments are considered palliative; lymphatic anomalies are often chronic debilitating conditions that require multiple yearly outpatient visits and hospital admissions for procedures that ameliorate symptoms, but do not correct the underlying cause. Identifying the causal genes will be hugely informative for our understanding of diseases. This will also allow for the development of affordable and successful diagnostic tests and therapies in keeping with "precision medicine" implementation.

  Study phs001802

• Pediatric Non-Down Syndrome Acute Megakaryoblastic Leukemia is Characterized by Distinct Genomic Subsets with Varying Outcomes

  Acute Megakaryoblastic Leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts.  While extremely rare in adults, AMKL accounts for 4-15% of newly diagnosed childhood AML1-3.  A significant proportion of pediatric AMKL cases occur in children with Down syndrome (DS).  These patients have excellent outcomes and are characterized at the genomic level by a founding GATA1 mutation4-6.  In contrast, AMKL in patients without DS (non-DS-AMKL) is frequently associated with poor outcomes.  Previous efforts have identified chimeric oncogenes in a significant number of cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements and NUP98-KDM5A7-9.  The etiology of 30-40% of cases, however, remains unknown.  To better understand the genomic landscape of non-DS-AMKL, we performed RNA and exome sequencing on specimens from 99 patients (75 pediatric and 24 adult).  We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy that can be divided into seven subgroups with varying outcomes.  These subgroups are characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes.  Overall, these data shed light on the etiology of AMKL and provide useful information for treatment tailoring. 

  Study EGAS00001002183

• GWAS for Membranous Nephropathy

  Primary membranous nephropathy (MN) is a rare autoimmune cause of kidney failure. This dataset is from a genome-wide association study (GWAS) designed to identify novel genetic risk loci for MN. The provided cohort (named as European-1 Cohort) is composed of 611 cases of primary MN and 1,246 healthy controls of European ancestry. This cohort was used in the GWAS meta-analysis, as described in the manuscript entitled "Genetic architecture of membranous nephropathy and its potential diagnostic implications" (Nature Communications 2020, in press).The genome-wide summary statistics, including trans-ethnic meta-analysis across 8 GWAS cohorts of European and East Asian ancestry and ethnicity specific meta-analyses, are freely available for download on the Kiryluk lab website: http://www.columbiamedicine.org/divisions/kiryluk/resources.php.

  Study phs001984

• Targeted Sequencing Data for RESOLVE Clinical Trial

  This is a Phase II clinical trial. This research study is studying a combination of targeted therapies as a possible treatment for estrogen-receptor positive (ER+) endometrial cancer and low-grade serous ovarian cancer. The drugs involved in this study are: - Abemaciclib (also known as Verzenio™) - Letrozole (also known as Femara®) - Metformin (also known as Glucophage®) - Zotatifin (also known as eFT226) - Gedatolisib (also known as PF-05212384)

  Dataset EGAD50000001711

• eMERGE: Northwestern (NUgene) WGS

  The NUgene Project is a biorepository with longitudinal medical information from participating patients at Northwestern Medicine affiliated hospitals and outpatient clinics. Participants' DNA samples are coupled with data from a self-reported questionnaire (2 versions were used, 1 before and 1 after February 2006, both are included) and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 3 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated enterprise data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators. The electronic MedicalRecords and Genomics (eMERGE) Network is a consortium of 9 clinical sites with EMR linked DNA biobanks, including Northwestern University and its NUgene biobank, funded by the NHGRI (National Human Genome Research Institute) to investigate the use of electronic medical record systems for genomic research. The goal of eMERGE is to conduct genome-wide association studies in approximately 100,000 individuals using EMR-derived phenotypes and DNA from linked biorepositories. Using electronic phenotyping methods, the consortium has been and is using DNA samples from all participating sites to explore the genetic determinants of approximately 80 phenotypes, including both diseases and traits, for which the electronic phenotyping algorithms have or are being published on PheKB.org. Thus, for the eMERGE network, ~900 NUgene subjects were selected, as described in the study inclusion/exclusion criteria section below, to be genotyped using whole genome sequencing (WGS), for use in the eMERGE network as eMERGE subjects. The criteria used below were selected so that these subjects will likely meet the criteria to be cases and/or controls, of diverse races and/or ethnicities, for at least 1 of the ~80 phenotypes being studied within eMERGE, and could be recontacted for future research if needed.

  Study phs001191

• A Phase I/II Trial of Sirolimus (Rapamune®) and Cyclosporine in Patients with Refractory Aplastic Anemia

  The most successful treatment for aplastic anemia is bone marrow transplantation. However, few patients are eligible for this procedure. For others, treatment usually consists of immunosuppressive agents, such as antithymocyte globulin (ATG) and cyclosporine. Unfortunately, even with immunosuppressive therapy, relapse is common. New combinations of medications may offer alternative and more effective treatment options. Sirolimus and cyclosporine are two drugs routinely used to suppress the immune system and prevent rejection in patients who have received organ transplants. While cyclosporine has been proven effective for treating aplastic anemia, sirolimus has not been tested for this disease. This study will evaluate the safety and efficacy of sirolimus in combination with cyclosporine for treating individuals with aplastic anemia that have not responded to other treatments. This study will last at least 6 months. Participants will first be screened to verify diagnosis of aplastic anemia. The screening will include a physical examination, blood test, bone marrow biopsy from the pelvic bone, and review of medications and medical history. Individuals who are eligible will then start the first treatment period. Participants will receive two medications: cyclosporine will be taken twice a day and sirolimus will be taken once a day. Depending on side effects, the dose of either drug may be temporarily stopped or lowered. On Day 1, blood will be drawn and females will undergo a pregnancy test. Subsequent study visits will occur weekly for the first month, every 2 weeks for 2 months, and then once a month for the remainder of the study. Each visit will include a physical examination, vital sign assessment, and review of side effects and medications. Blood tests will be performed weekly for the first 3 weeks, and then every 2 weeks. After 6 months of treatment, if a participant has shown improvements in disease status without major side effects, the treatment will continue. Over time the doses may be lowered. If a participant has not improved while on the study medication, treatment will stop at 6 months. Whenever treatment is discontinued, the participant will again undergo a physical examination, blood tests, and bone marrow biopsy.

  Study phs000695

• Transcriptional_profiling_of_tauopathies_in_human_IPS_derived_neurons

  This project is a pilot study, in collaboration with Maria Grazia Spillantini and Mariangela Iovino (Cambridge Centre for Brain Repair), to investigate the utility of IPS-derived neurons for the study of neurodegenerative disorders. Our aim is to characterise the transcriptional consequences of tauopathies using neurons derived from differentiated IPSCs as a model system. We will use IPS cells derived from six individuals, four with known mutations in the tau protein, 2 without. RNA will be extracted at Day 0 and Day 65 of differentiation by which time the neuronal tauopathy is apparent. RNA will be extracted and the transcriptome of each line characterised using RNAseq. We will then search for genes that are differentially expressed between the transcriptomes of individuals with tau mutations versus those in controls. My lab will analyse the RNAseq data, comparing both affected and controls and both time-points, to establish candidate genes. Darren Logan’s lab, along with our collaborators, will experimentally verify and further investigate these genes in additional lines and animal models. From this analysis we will generate a list of candidate genes that are differentially expressed between cases and controls. This study will not only help us understand the molecular basis of tauopathies, but also identify gene candidates for biomarkers of neurodegenerative disease. It will serve as a proof of principle for future planned studies into generating and transcriptomically analysing an allelic series of Tau mutations in IPSCs with a controlled genetic background.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001000382

• Study of Osteoporotic Fractures (SOF)

  The Study of Osteoporotic Fractures (SOF) is a prospective multicenter study of risk factors for vertebral and non vertebral fractures. The cohort is comprised of 9704 community-dwelling women 65 years old or older recruited from populations-based listings in four U.S. areas: Baltimore, Maryland; Minneapolis, Minnesota; Portland, Oregon; and the Monongahela Valley, Pennsylvania. Women enrolled in the study were 99% Caucasian with African American women initially excluded from the study due to their low incidence of hip fractures. (A cohort of AA women was recruited at the 6th Visit.) The SOF participants were followed up every four months by postcard or telephone to ascertain the occurrence of falls, fractures and changes in address. To date, follow-up rates have exceeded 95% for vital status and fractures. All fractures are validated by x-ray reports or in the case of most hip fractures, a review of pre-operative radiographs. Blood samples were collected in 6795 women at their Year 2 exam (Visit 2) and with written consent for use of DNA in genetic studies. Of these, we have GWAS data on 3625 Caucasian participants. As a separate study, the SOF Osteoarthritis Project was funded separately to collect data about risk factors for osteoarthritis (OA) and analyze baseline hip and hand films for the presence and severity of OA. Raw GWAS data is housed at the study's coordinating center and not released as part of the dbGaP release. The raw data can be requested from the study's coordinating center. Only QC cleaned PLINK files are available at dbGaP. Auxiliary files are also available for duplicates and HapMap participants.

  Study phs000510

• Kidney Two-Hit Mapping

  Germ-line genetic variants identified thus far generally account for only part of the genetic risk predicted for most cancers. A component of the remaining risk may be explained by functionally consequent genetic variants that are individually very rare (or private to that individual's family). While their identification may be highly informative for cancer etiology and biological knowledge, strategies that allow for agnostic (genome-wide) identification of such genes are not straight forward. This is particularly true for rare cancers where sufficient numbers of patients may simply not be available for appropriate statistically powered studies. In this project we have explored a study design based around the concept of "two-hit mapping" using the co-occurrence of germ-line and somatic mutations in the same gene to assist in the identification of susceptibility genes. The dataset includes 54 kidney cancer patients selected for enrichment of genetic disease, that is patients with: early age of onset and/or family history and/or bilateral disease. Germ-line and somatic (kidney cancer) tumor sequencing was carried out. These data may improve our understanding of kidney cancer.

  Study phs001971

• Genotypic data of the individuals in HPP project

  Dataset contains imputed SNP genetics data for human phenotype project https://humanphenotypeproject.org/. The samples are genotypes of 8958 individuals that underwent genetic sequencing based on buccal swab.Sequencing is performed at Neogen GeneSeek Laboratories using Illumina Novaseq at low-pass, targeting coverage levels of 0.5× and 1×. Imputation was done using loimpute-v0.1.0 over the aligned reads. Imputation is done for the autosomal chromosomes (1-22) using The 1000 Genomes phase 3 haplotypes (1KGP3) as a reference panel. The samples are provided in merged PLINK 1 binaries (.bed/.bim/.fam)

  Dataset EGAD00010002714

• Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS)

  GERFHS is a population-based, case-control study of hemorrhagic stroke in the Greater Cincinnati/Northern Kentucky region. Cases are recruited from within 50 miles of the University of Cincinnati and population-based controls are matched to cases by age (+/- 5 years), race and gender from the same population as cases. All study participants are of self-reported non-Hispanic Caucasian ethnicity and the data show consistency with the principal component projections. The current submission includes genome wide genotyping on a subset of these cases and controls.

  Study phs000874

• Mapping_genetic_variants_underlying_gene_regulation_in_inflammed_intestinal_cell_types_to_identify_novel_IBD_drug_targets

  Biopsies from the terminal ileum and rectum of individuals with Crohn's disease are digested on ice to single cells and processed for single-cell RNA-sequencing (10X Genomics and Illumina) This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001003770

• Dynamics of Tumor Heterogeneity from Primary to Metastatic Dissemination in Prostate Cancer

  PRO-SPeCT: PROstate cancer heterogeneity deconvolution through Single cell Profiling of Chromatin accessibility and Transcriptomic output Identifying drivers of cancer progression to guide treatment selection is hindered by limited abilities to understand tumor heterogeneity’s impact on evolution. Here, we delineated the phenotypic variability across ~300,000 prostate tumor cells collected from multiple loci in primary and matched locoregional metastases. We found inter-patient heterogeneity to be confined to malignant populations. While malignant cell populations exhibit intra-locus heterogeneity, they maintain inter-loci phenotypic similarity within a patient’s prostate gland. In addition, the intra-locus heterogeneity between malignant cell populations is paired with a common clonal architecture. Lastly, we show that malignant cell populations disseminating to locoregional lymph nodes mirror the clonal architecture and phenotypic heterogeneity observed across primary tumor loci while showcasing cell state transition toward inflammatory phenotypes. These findings provide insights into distinct measures of tumor heterogeneity, revealing diverse evolutionary paths across patients converging to common phenotypic adaptations in early prostate cancer progression.

  Study EGAS50000000524

• Evolutionary dynamics of residual disease in human glioblastoma

  Glioblastoma is the most common and aggressive adult brain malignancy against which conventional surgery and chemoradiation provide limited benefit. Even when a good treatment response is obtained, recurrence inevitably occurs either locally (c.80%) or distally (c.20%), driven by cancer clones that are often genomically distinct from those in the primary tumour. Glioblastoma cells display a characteristic infiltrative phenotype, invading the surrounding tissue and often spreading across the whole brain. We hypothesised that cancer cells responsible for relapse reside in two compartments of residual disease that are left behind after treatment: the infiltrated normal brain parenchyma, and the sub-ventricular zone (SVZ). In this model, residual disease subclones diverge early during glioblastoma evolution, may remain dormant in the normal parenchyma and are responsible for recurrence. To test our hypothesis, we performed whole-exome sequencing of 69 multi- region samples collected using fluorescence-guided resection from 11 patients, including the infiltrating tumour margin (M) and the SVZ for each patient, as well as matched blood. We used a phylogenomic approach to dissect the spatio-temporal evolution of each tumour and unveil the relation between residual disease and the main tumour mass. We also analysed two patients with paired primary-recurrence samples with matched residual disease. Our results suggest that the infiltrative phenotype is an early evolutionary trait of glioblastoma, giving rise to the tumour mass detected at surgery. After treatment, the same infiltrative clone may seed the growth of a recurrent tumour, thus representing the ‘missing link’ between the primary tumour and recurrent disease. These results are consistent with recognised clinical phenotypic behaviour and suggest that more specific therapeutic targeting of cells in the infiltrated brain parenchyma may improve patient’s outcome.

  Study EGAS00001003043

• A unidirectional histone code in bidirectional promoters across cell types

  Recent studies indicate that thousands of genes are expressed from bidirectional promoters (BDPs). Gene regulation at BDPs is poorly understood, in particular how the cell is able to regulate them differently. Here we investigate the effect of histone Modifications in BDP regulation. In this study, we model the gene activity using different gene expression assays, such as RNA-Seq, GRO-cap, and CAGE around the BDP transcription start sites (TSSs) using different histone modifications in various cell types. We develop a new statistical approach that links histone modifications to gene expression at BDPs. It improves over previous methods, because it is able to capture spatial dependencies of histone modifications along a promoter and leads to more interpretable results. We predict a general histone code that is independent of transcript orientation, cell type, and promoter configuration. The histone code at BDPs reveals that promoters are regulated unidirectionally, such that the majority of histone marks associated with gene expression occur downstream of the gene's TSS. By contrasting associations of histone marks with steady-state levels of capped RNAs in CAGE and nascent capped RNAs in GRO-cap, we show which histone marks have a preference for initiating polymerases and actively elongating polymerases. Using single-cell data we show that the bidirectional histone signal of activating marks is often due averaging of a heterogeneous cell population. Our results have implications for other experiments where the relationship between histone modification and gene initiation or gene elongation is investigated on a genome-wide scale.

  Study EGAS00001001656

• Center for Craniofacial and Dental Genetics (CCDG): Genetics of Orofacial Clefts and Related Phenotypes

  The purpose of this study is to investigate the genetics of orofacial clefts (OFCs) in a large study population, and importantly, to incorporate subclinical phenotypic features into these studies. Orofacial clefts (OFCs) comprise a significant fraction of human birth defects (about 1/700 live births (Rahimov et al. 2012) and represent a major public health challenge, as individuals with these anomalies require surgical, nutritional, dental, speech, medical and behavioral interventions, thus imposing a substantial economic and personal burden (Berk and Marazita 2002*). The most common forms include OFCs of the lip alone (CL, Figure 1A), CL plus cleft palate (CL+CP, Figure 1B) or of the palate only (CP, Figure 1C). Individuals born with OFC may have their first surgical repair at age 3 months, but this initial surgery is just the beginning of a lifetime of health burdens. An individual born with an OFC has a hospital use rate increased for most ages (up to 233% increase for children ages 0-10 years and 16% for middle aged adults (Wehby et al. 2012). Healthcare costs for children with OFCs are estimated to be 800% greater compared with their unaffected peers (Boulet et al. 2009). Data from Denmark show that people born with CL with or without CP (CL/P) have an increased mortality up to age 55, which may be attributed to an increased risk of suicide and/or certain cancers (Christensen et al. 2004). The focus of most OFC genetic research has been CL and/or CP. Furthermore, the majority of OFC, i.e. about 70% of CL/P and 50% of CP is considered "nonsyndromic" (Jones 1988), i.e. isolated anomalies with no other apparent cognitive or structural abnormalities. Figure 1 Sample OFC Types A: Bilateral Cleft Lip; B:Cleft Lip plus Cleft Palate; C:Cleft Palate Alone The factors leading to the majority of nonsyndromic OFCs are still unclear, particularly at an individual family level. As is true for many complex traits, substantial progress in gene identification has occurred in the OFC field in the last two years (Dixon et al. 2011; Marazita 2012). Genome Wide Association Studies (GWAS) and sequencing studies to date by our research team and others have focused on genetic risk factors for overt CL/P and CPO-and have been very successful. A major finding from this work is that OFCs exhibit significant genetic heterogeneity, i.e., multiple genetic regions have been implicated (Beaty et al. 2010; Ludwig et al. 2012). Thus, approaches are needed to understand this genetic heterogeneity. Are there GxG interactions at work? Are there subsets of families, each due to a different gene? Our research group has shown that a promising approach to dissect the etiology of OFC is to focus on subclinical phenotypic features within entire cleft families (not just in affected cases, but also in their non-cleft relatives). These subtle features are believed to represent mild manifestations of the same underlying genetic susceptibility responsible for OFCs; as such, their inclusion in case-control and family-based genetic studies can help to clarify and refine the relationship between genotype and phenotype. The study population comprises a large number of families and individuals (~12,000 individuals) from multiple populations worldwide (Caucasians from the US and Europe, Asians from China and the Philippines, Mixed Native American/Caucasians from South America, and Africans from Nigeria and Ethiopia). There are cases, case families (nuclear families and extended kindreds), as well as controls with no history of OFC nor other developmental defects. *Berk NW, Marazita ML (2002) Costs of Cleft lip and Palate: Personal and Societal Implications. In: Wyszynski DF (ed) Cleft Lip and Palate: From Origin to Treatment. Oxford University Press, Inc., New York, pp 458-467.

  Study phs000774

• Identification of genes involved in congenital disorders of glycosylation and 3-methylglutaconic aciduria (2018-03-14)

  Identification of genes involved in congenital disorders of glycosylation and 3-methylglutaconic aciduria. There are more than 100 genes known for congenital disorders of glycosylation and new disorders are discovered each year. WE included patients with a so far unsolved glycosylation disease. The diagnostic group 3-methyglutaconic aciduria is a heterogenous group of disorders mostly caused by abnormal phospholipid synthesis or in association with mitochondrial dysfunction. We included patients with a so far unsolved disease and 3-methylglutaconic aciduria. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2018-03-14.

  Dataset EGAD00001004038

• Genetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo

  Oncogenic alterations in EGFR frequently co-occur with additional genetic alterations in EGFR-driven lung adenocarcinoma (LUAD), but how specific combinations of mutations affect tumor phenotypes and responses to targeted therapy is yet unknown. We leveraged a genetically engineered mouse model of EGFR mutant/Trp53-deficient LUAD to study the consequences of inactivating 10 different tumor suppressor genes on the fitness and tyorosine kinase inhibitor (TKI) sensitivity of these tumors. We found that loss of Keap1 is associated with a reduced response to therapy. In patients, we found that mutations in the KEAP1/NFE2L2/CUL3 pathway are associated with a significantly shorter time to treatment failure for EGFR TKI therapy compared to matched patients with wild-type KEAP1/NFE2L2/CUL3 tumors. We also analyzed whole exome sequencing data from tumor specimens before TKI treatment and at the time of treatment resistance for mutations in the KEAP1 pathway and these data are being submitted here.  

  Study phs002334

• Molecular diagnosis of albinism (2018-03-14)

  Albinism is genetically heterogeneous rare genetic condition affecting 1:17000 in the Western world (but more frequent in Africa) whose main feature is a profound visual impairment, characterised by foveal hypoplasia, abnormal chiasmatic connections, nystagmus and photofobia. All these features result in severly altered visual acuity (<0,1), absent depth perception and poor night vision. People with albinism are primarily visually handicapped. In addition, for some types of albinism, the visual phenotype can be presented with partial or total hypopigmentation, hence resulting in a secondary phenotype which can lead to skin cancer if skin is not adequately protected. Recently a new syndrome has been described, FHONDA, with the same visual abnormalities of albinism but without pigment alteration. The traditional classification differentiates Oculoculatenous albinism (OCA), where hypopigmentation involves hair, skin and eyes versus Ocular Albinism (OA), where hypopigmentation only affects the eyes. These are non-sydrimic types of albinism. Some syndromic forms (Hermansky-Pudlak=HPS, Chediak-Higashi=CHS) affect cells beyond pigment cells, present in the lungs, immune system, platelets and intestines, resulting in more severe phenotypes that can be fatal. Mutations in at least 19 genes are assocaited with the corresponding types of albinism. Most hospitals will only diagnose the most frequent cases using traditional Sanger, MLPA approaches. Some will use CGH arrays. We aim to diagnose all cases of albinism through the Albinochip proposal, which combines a Sequenom first step of known mutations combined with subsequent NGS approaches. In some cases we fail to find a second mutation, these are good candidates for further full exome analyses. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2018-03-14.

  Dataset EGAD00001004039

• NIDA Genetic Epidemiology of Opioid Dependence in Bulgaria (GEODB)

  The study was conducted in Bulgaria as a collaboration between the Molecular Medicine Center (Medical University, Sofia), the Bulgarian Addictions Institute (Sofia), the Initiative for Health Foundation (Sofia) and Washington University School of Medicine (Saint Louis, MO, USA). This is a case-population control study. Participants (N=2,499 interviews; N=1,995 with GWAS data) in our study are primarily active heroin users (78%) aged 18 and over, with a median 8.9 years of daily heroin use (minimum of 12 months). Virtually all participants (99.1%) qualified for a lifetime DSM-IV diagnosis of dependence, symptom endorsement probabilities ranging from 77% to 99.3%; and 61% endorsing all symptoms. 85% were heroin injectors and 97% reported using (or having used) heroin daily. Anonymized, population-representative control samples (no phenotypic data, N = 1,062 with GWAS data) were drawn from the MMC repository. Unlike other studies, where samples are clinically ascertained (e.g., from ORT programs), our participants are primarily untreated. PTSD, major depression, suicidality, mania, alcohol, nicotine and substance dependence (separating heroin and opioids) were assessed using the MAGIC (Todd et al., 2003, PMID: 14627881), a broad semi-structured psychiatric assessment tool with good reliability and prospective stability. The onset of (any) illicit drug use in this sample is not particularly remarkable (age~16), but the age of onset of heroin use is much lower than in the USA: 25% by age 16; 50% by age 19, with no differences between ethnicities or gender. This is consistent with findings from other studies in Bulgaria. In contrast, in 2008, SAMHSA estimated an average age of 23.4 for new heroin initiates in the USA. Further, progression from first use to regular use appears to be more rapid, with the majority of participants reporting onset of dependence problems within one year of initiation. Another unique aspect of this study population are the comparatively low levels of polysubstance use (outside of nicotine and alcohol). This early-use, fast-transition and monosubstance heroin pattern stands in sharp contrast to what is reported in many studies in the Western World. In our study, 47% of Ethnic Bulgarians and 66% of Roma used only opioids, even years after the onset of drug use. 15.4% of Ethnic Bulgarians and 66.2% of Roma reported heroin as the very first illicit drug used. Lifetime, 12.5% of Ethnic Bulgarians and 52.8% of Roma report never having used another illicit drug other than heroin more than five times. While both Roma and Ethnic Bulgarians certainly experiment with other drugs, abuse/dependence rates for these drugs are low in Ethnic Bulgarians (from 8.4% for inhalants to 28% for stimulants) and in the Roma population (from 1.3% for hallucinogens to 11.2% for stimulants).

  Study phs001804

• Fetal origins of malignant germ cell tumours

  Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells (PGCs). They are uniquely able to generate embryonic and extraembryonic tissues, which in malignant GCTs carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood. Here, we studied the phylogenetic and transcriptional diversity of 15 malignant gonadal GCTs and four normal testis biopsies by sequencing 131 whole genomes and 416 transcriptomes from 14 gonadal histologies, excised by laser capture microdissection. Our findings demonstrate that tumours were initiated by whole genome duplication likely in embryogenesis, within ~5-8 cell divisions post-PGC specification, followed by chromosome 12p gains associated with invasive disease. Of note, 12p imbalances were not only generated through GCT-typical isochromosomes, but also through non-isochromosomic configurations. Whilst tumours developed along homogenous phylogenetic pathways, they spawned manifold tissues independent of genetic subclonal diversification. A key feature of GCT tissues was the expression of fetal-specific genes. The transcriptional diversity notwithstanding, we found universal transcriptional elements correlated with hallmark 12p gains. Overall, our study reveals stereotyped phylogenies and transcriptomes underpinning the development of GCT that originate in fetal life and may lend themselves to therapeutic manipulation.

  Dataset EGAD00001007037

• DNA methylation atlas of normal human cell types

  DNA methylation is a fundamental epigenetic mark that governs chromatin organization, cell identity, and gene expression. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell-type are >99.5% identical, demonstrating robustness of cell identity programs to genetic variation and environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny, and identifies methylation patterns retained since gastrulation. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hyper-methylated loci are rare and are enriched for CpG islands, polycomb targets, and CTCF binding sites, suggesting a novel role in shaping cell type-specific chromatin looping. The atlas provides an essential resource for interpretation of disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.

  Study EGAS00001006791

• NHLBI TOPMed - NHGRI CCDG: Massachusetts General Hospital (MGH) Atrial Fibrillation Study

  The Massachusetts General Hospital (MGH) Atrial Fibrillation Study was initiated in 2001. The study has enrolled serial probands, unaffected and affected family members with atrial fibrillation. At enrollment participants undergo a structured interview to systematically capture their past medical history, AF treatments, and family history. An electrocardiogram is performed; the results of an echocardiogram are obtained; and blood samples are obtained. For the TOPMed WGS project only early-onset atrial fibrillation cases were sequenced. Early-onset atrial fibrillation was defined as an age of onset prior to 66 years of age. Comprehensive phenotypic and pedigree data for study participants are available through dbGaP phs001001.

  Study phs001062

• Genome-Wide Assessment of DNA Methylation in Systemic Lupus Erythematosus-Related Autoantibodies

  Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can have debilitating effects on multiple organ systems. In SLE, the pivotal immunologic disturbance is the formation of autoantibodies directed against nuclear and cellular antigens. These autoantibodies are associated with specific organ manifestations. Our previous work has shown that certain single nucleotide polymorphisms (SNPs) are associated with the production of SLE-related autoantibodies. However, these genetic associations do not completely explain autoantibody development in SLE. Therefore, we examined whether epigenetic factors such as DNA methylation may be associated with the development of SLE-related autoantibodies. In this study, we examined whether differential DNA methylation is associated with anti-dsDNA, anti-SSA/Ro, anti-Smith, and anti-RNP autoantibodies. Using the Illumina HumanMethylation450 Beadchip, over 450,000 DNA methylation sites were characterized in 325 female SLE cases of European descent. Using a multivariable regression analyses, the methylation status of 16 CpG sites in 11 genes was found to be associated with the SLE-related autoantibodies under study. This study shows that epigenetic factors are associated with autoimmune disease phenotypes, and epigenetic studies are a complementary method to genetic association studies for understanding the biologic mechanisms contributing to autoimmune disease.

  Study phs000947

• Federated discovery and sharing of genomic data using Beacons

  The Beacon Project is a Global Alliance for Genomics & Health (GA4GH) initiative that enables genomic and clinical data sharing across federated networks. The project is working toward developing regulatory, ethics and security guidance to ensure proportionate safeguards for distribution of data according to the GA4GH-developed “Framework for Responsible Sharing of Genomic and Health-Related Data”. Within this Nature Biotechnology Correspondence a description of the Beacon protocol and how it can be used as a model for the federated discovery and sharing of genomic data is offered to the community. A Beacon is defined as a web-accessible service that can be queried for information about a specific allele. A user of a Beacon can pose queries of the form “Have you observed this nucleotide (e.g., C) at this genomic location (e.g., position 32,936,732 on chromosome 13)?” to which the Beacon responds with either “yes” or “no.” In this way, a Beacon allows allelic information of interest to be discovered by a remote searcher with no reference to a specific sample or patient, thereby mitigating privacy risks. The Beacon API (represented as a RESTful web application) provides a technical specification that a Beacon server must implement. The specification is open source and available online here. To simplify the process of lighting a Beacon, a free, open-source reference implementation of the latest specification has been developed. GA4GH is promoting different levels of data access (open, registered, and controlled) for convenience and for compatibility across its projects. Each so-called access tier has distinct visibility and requirements for authorization. For example, ‘open access’ Beacons are accessible to anonymous users of the internet, whereas ‘registered access’ Beacons are accessible to registered users (for example, bona fide researchers and clinicians) who have agreed to a set of conditions of data use. Many of the largest genomic archives, such as dbGaP, the European Genome-phenome Archive and the European Variation Archive, have provided access to variation data through Beacons for some or all of their datasets. Beacons can be interconnected through the Beacon Network, a directory and search engine for Beacons. Although individual Beacons answer the question “Have you observed this allele?”, the Beacon Network answers the question “Who has observed this allele?”. Beacons can be freely registered to the Beacon Network and can be searched independently or in aggregate with other connected Beacons.

  Blog federated-discovery-using-beacons

• Multi-omics profiling identifies two epithelioid sarcoma molecular subtypes with distinct signaling and immune characteristics

  Epithelioid sarcoma (EpS) is an aggressive sarcoma, characterized by the loss of SMARCB1 expression. EpS is traditionally classified as distal or proximal according to clinicopathological features, but its molecular characteristics remain largely unknown. To establish an EpS molecular classification and uncover determinants of inter- and intra-patient heterogeneity in EpS, we used multi-omics profiling and integrated the genomic, transcriptional and methylome landscapes with single-cell RNA sequencing on fresh samples as well as spatial transcriptomics. We identified two molecular subtypes of EpS: “distal-like” and “proximal-like”, which were distinct from the histological subtypes. Distal-like tumors include all morphological distal subtypes and a subset of proximal and hybrid EpS. They express a specific molecular single-cell derived epithelial-to-mesenchymal transition signature, which associates with improved patient survival and includes Desmoglein 2 (DSG2), which we identify as a potential routine immunohistochemical biomarker to improve diagnosis. Distal-like EpS also display increased peri-tumoral CD8+ T cell infiltrates and specific tumor-immune cell interactions. Conversely, proximal-like EpS harbor a higher inter-tumoral molecular heterogeneity with some cases resembling other SMARCB1-deficient tumors by DNA methylation profiling, and increased intra-tumoral pro-tumoral macrophage infiltrates. Our study introduces a novel molecular classification of EpS with prognostic value, associated diagnostic biomarkers and distinct tumor immune microenvironments, which extends beyond traditional clinicopathological classification. This paves the way for precision medicine-based therapeutic strategies for patients with EpS.

  Dac EGAC50000000552

• TCGA WGS Variants Across 18 Cancer Types

  Even though whole genome sequence (WGS) data has been generated and published in many studies, much of this information is not yet processed for use in down-stream analysis. This study's aim is to provide 1342 WGS normal-tumor paired single nucleotide variations (SNP) over 18 different cancer types provided by The Cancer Genome Atlas (TCGA) project. Individual level data for TCGA can be accessed by requesting access for phs000178. This data includes variations within self-reported white and African-American populations. Variations that exist within the tumor tissue but are absent in associated normal organ tissue (as compared to the human reference genome) are reported. Data published includes SNP and small insertions and deletions, which were generated through a pipeline including the VarScan2 variant calling software.

  Study phs003155

• Genetics of Antinuclear Antibodies

  Antinuclear antibodies (ANA) are antibodies that react against self-antigens in the cell. While it has been reported that 12 to 20% of the general population have a positive ANA test, the genetics of ANA positivity is unknown. We performed a genome wide-association study for positive ANA tests among individuals without an ANA related autoimmune disease in the Vanderbilt University Medical Center (VUMC) DNA biobank linked to the de-identified electronic health record (EHR) system. The study is funded by the National Institute of Arthritis and Musculoskeletal and Skin diseases (NIAMS) grant R01AR076516.

  Study phs003189

• The Oral Mycobiome and Risk of Pancreatic Cancer

  The purpose of our study was to assess the influence of oral microbiota on the development of pancreatic cancer. Our preliminary case-control studies showed that oral carriage of a periodontal pathogen is related to increased risk for pancreatic cancer. We hypothesize that the oral bacteria and fungi are associated with risk of pancreatic cancer. We conducted a prospective study nested in two large well-established U.S. cohorts to determine whether the oral bacterial and fungal microbiome is associated with subsequent risk of pancreatic cancer.

  Study phs003994

• Gene mutation and rescue in congenital diaphragmatic hernia

  Congenital Diaphragmatic Hernia (CDH) is a common and life-threatening malformation. The most common phenotype is left-sided posterolateral (Bochdalek-type) hernia accompanied by pulmonary hypoplasia. Due to the high mortality, most of the cases have no family history for CDH. The rare presumed Mendelian instances of CDH have the potential to be extremely informative about the molecular mechanisms generating this phenotype. Three multiplex families were deemed meritorious for study by whole exome sequencing: Parents who were 1st cousins gave birth to 2 children with CDH (one of whom also had cleft lip and palate), both now deceased. A DNA sample was available from one child. We proposed to perform a SNP array to identify regions of homozygosity by descent and intersect these regions with variants detected on exome sequencing. This effort has led to the identification of 3 confirmed variants. We are determining which if any are expressed in the primordial developing diaphragm and are also using bioinformatic approaches to determine which of these candidates interact with known CDH genes. This non-consanguineous couple gave birth to 2 affected boys with an identical and lethal CDH phenotype (consisting of diaphragmatic hernia, epigastric hernia, and facial dysmorphism) and one healthy boy. We predicted X-linked inheritance and findings from X chromosome microsatellite marker analysis are consistent with this. Accordingly, we are focusing on sequence variants mapping to the X chromosome. We have identified a single candidate gene and confirmed that the variant follows an X-linked pattern of inheritance in all family members. Expression studies are underway. These affected males are second cousins. By virtue of their position in the pedigree, we predicted an inheritance pattern consistent with X-linked inheritance. Data from WES and microsatellite marker analysis are currently being integrated.

  Study phs000485

• Genetic Epidemiology Network of Arteriopathy (GENOA)

  The Genetic Epidemiology Network of Arteriopathy (GENOA) is one of four networks in the NHLBI Family-Blood Pressure Program (FBPP). GENOA's long-term objective is to elucidate the genetics of target organ complications of hypertension, including both atherosclerotic and arteriolosclerotic complications involving the heart, brain, kidneys, and peripheral arteries. The longitudinal GENOA Study recruited European-American and African-American sibships with at least 2 individuals with clinically diagnosed essential hypertension before age 60 years. All other members of the sibship were invited to participate regardless of their hypertension status. Participants were diagnosed with hypertension if they had either 1) a previous clinical diagnosis of hypertension by a physician with current anti-hypertensive treatment, or 2) an average systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg based on the second and third readings at the time of their clinic visit. The Family Blood Pressure Program (FBPP), GENOA's parent program, is an unprecedented collaboration to identify genes influencing blood pressure (BP) levels, hypertension, and its target-organ damage. This program has conducted over 21,000 physical examinations, assembled a shared database of several hundred BP and hypertension-related phenotypic measurements, completed genome-wide linkage analyses for BP, hypertension, and hypertension associated risk factors and complications, and published over 130 manuscripts on program findings. The FBPP emerged from what was initially funded as four independent networks of investigators (HyperGEN, GenNet, SAPPHIRe and GENOA) competing to identify genetic determinants of hypertension in multiple ethnic groups. Realizing the greater likelihood of success through collaboration, the investigators created a single confederation with program-wide and network-specific goals.

  Study phs001238

• Investigating Host Genetic Risk Factors for Tuberculosis in Highly Endemic South African Populations

  It is apparent from our recent population genetic and admixture mapping work 1–3 that a substantial part of the ancestral input into the South African Coloured (SAC) population is from the San or Khoe groups, which are not well represented in publicly available genetic databases. It is a reasonable assumption that the SAC population in the Western Cape may have derived more genetic input from the present KhoeSan population in the Northern Cape than the San residing in Namibia. It was concluded by our group that it is indeed the southern African KhoeSan group, the ≠Khomani, that best represent the KhoeSan contribution seen in the SAC 4. More recently, it has been shown that there are ancestry related increases in TB susceptibility, especially with increased Bantu-speaking African and KhoeSan ancestry 5. We aim to elucidate the epidemiological and human-host genetic risk factors for TB and the immunological pathways modulating TB infection. The proposed sub-study will enroll people evaluated for TB at Northern Cape community health clinics and their contacts from their households and/or community. We will conduct a demographic interview, collect saliva, which will be used for genetic analysis, and blood to determine latent TB infection status and capture immunological responses to mycobacterial infections at the cellular level and RNA sequencing.

  Study EGAS00001007850

• Genetic Epidemiology of Ovarian Cancer Histotypes

  Epithelial ovarian cancer is a highly fatal malignancy with known genetic etiology; however, it is estimated that a substantial portion of narrow sense heritability remains to be discovered. The goal of this research was to use genetic information from distantly related ovarian cancer cases to identify regions of the genome that may harbor rare risk variants for epithelial ovarian cancer. The study was conducted in the setting of the Utah Population Database, a statewide data resource in which extensive ancestry data are linked to Utah Cancer Registry records. Focusing on families with a statistically significant excess risk of epithelial ovarian cancer, we used the Infinium Global Screening Array v.3.0 to generate germline genotyping data for distantly related cases. We then applied Shared Genomic Segment Analysis to each set of related cases to identify genomic regions that may harbor ovarian cancer risk variants. Eleven regions were identified. Genotype data are available through dbGaP for one case from each pedigree. Genotype data from other ovarian cancer cases within the high-risk pedigrees as well as the pedigrees' corresponding structures can be requested and made available with approval from the Utah Resource for Genetic and Epidemiologic Research (RGE).

  Study phs003140

• PD-1 Instructs a Tumor Suppressive Metabolic Program to Restrain AP-1 Activity in T Cell Lymphoma

  T cell non-Hodgkin lymphomas (T-NHLs) represent a heterogeneous group of aggressive cancers of mature CD4+ T cells, for which therapeutic options are limited. Recent work uncovered that the PDCD1 encoded immune checkpoint receptor PD-1 is a key tumor suppressor in T cells. PD-1 is recurrently inactivated in T-NHL and the highest frequencies of PDCD1 deletions are detected in advanced disease, predicting worse prognosis. The tumor-suppressive mechanisms of PD-1 signaling remain unknown. In the present study, we identify transcriptional and epigenetic mechanisms underlying PD-1 tumor suppression in T-NHL.Some subjects included in this study overlap with the subjects from phs002456. To establish the link between the overlapping subjects, the Subject Consent datasets will be utilized.

  Study phs003312

• Diet, Genetic Factors, and the Gut Microbiome in Crohn's Disease

  We investigate the hypothesis that consistent changes in the human gut microbiome are associated with Crohn's disease, a form of inflammatory bowel disease, and that altered microbiota contributes to pathogenesis. Analysis of this problem is greatly complicated by the fact that multiple factors influence the composition of the gut microbiota, including diet, host genotype, and disease state. For example, data from us and others document a drastic impact of diet on the composition of the gut microbiome. No amount of sequencing will yield a useful picture of the role of the microbiota in disease if samples are confounded with uncontrolled variables. We aim to characterize the composition of the gut microbiome while controlling for diet, host genotype, and disease state. Diet is controlled by analyzing children treated for Crohn's disease by placing them on a standardized elemental diet, and by testing effects of different diets on the gut microbiome composition in adult volunteers. Genotype is analyzed by large scale SNP genotyping, which is already underway and separately funded--team member Hakon Hakonarson is currently genotyping 50 children a week at ~half a million loci each and investigating connections with inflammatory bowel disease. Clinical status is ascertained in the very large IBD practice in the UPenn/CHOP hospital system. Effects of diet, host genotype, and disease state on the gut microbiome are summarized in a multivariate model, allowing connections between microbiome and disease to be assessed free of confounding factors. This project is divided into four sub-studies. In the Fecal Storage Methods (FSM) study, methods of stool storage and DNA extraction are compared to examine their impact on DNA sequence analysis results. The Controlled Feeding Experiment (CaFE) addresses the effects of controlled diets on the gut microbiome. In the Cross-sectional Study of Diet and Stool Microbiome Composition (COMBO), the effects of diet analyzed using surveys and deep sequencing of stool specimens. The fourth study, Pediatric Longitudinal Study of Elemental Diet and Stool Microbiome Composition (PLEASE), examines the effects of an elemental diet treatment on pediatric patients diagnosed with inflammatory bowel disease (IBD), particularly Crohn's disease. Fecal Storage Methods (FSM): Cross-sectional study Controlled Feeding Experiment (CaFE): Controlled trial Cross-sectional Study of Diet and Stool Microbiome Composition (COMBO): Cross-sectional study Pediatric Longitudinal Study of Elemental Diet and Stool Microbiome Composition (PLEASE): Longitudinal cohort study

  Study phs000252

• Illumina HumanCoreExome genotyping data from the TEENAGE (TEENs of Attica: Genes and Environment) study.

  The TEENAGE study is a cross-sectional study comprising healthy Greek adolescents. The study was conducted according to the guidelines specified in the Declaration of Helsinki and all procedures involving human subjects were approved by the Institutional Review Board of Harokopio University and the Greek Ministry of Education, Lifelong Learning and Religious Affairs. The TEENAGE study target population comprised adolescent students aged 13 to 15 years attending the first three classes of public secondary schools located in the wider Athens area of Attica. The regions across Attica from which students were recruited were physically similar and all urban in nature. Sampling of regions and schools selected to participate was random. Students were enrolled from the wider urban region to ensure that they were coming from families with varying educational background and socio-economic status. Moreover, in order to exclude any vast economic disparities, all participating schools were exclusively public schools, which are free of charge. A total of twenty-four schools participated in the study out of 285 junior secondary public schools in Attica. Anthropometric, medical and dietary information was obtained. DNA samples were genotyped using Illumina HumanCoreExome BeadChips (Illumina, San Diego, CA, USA) at the Wellcome Trust Sanger Institute, Hinxton, UK. Genotypes were called using GenCall (Illumina Genome Studio) followed by zCall and quality control (QC) was performed in two stages (pre- and post-zCall).

  Study EGAS00001001001

• Whole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer

  Genomic alterations in metastatic prostate cancer remain incompletely characterized. Here we analyze 493 prostate cancer cases from the TCGA database and perform whole-genome plasma sequencing on 95 plasma samples derived from 43 patients with metastatic prostate cancer. From these samples, we identify established driver aberrations in a cancer-related gene in nearly all cases (97.7%), including driver gene fusions (TMPRSS2:ERG), driver focal deletions (PTEN, RYBP, SHQ1), and driver amplifications (AR, MYC). In serial plasma analyses, we observe changes in focal amplifications in 40% of cases. The mean time interval between new amplifications was 26.4 weeks (range: 5-52 weeks), suggesting that they represent rapid adaptations to selection pressure. An increase in neuron-specific enolase is accompanied by clonal pattern changes in the tumor genome, most consistent with subclonal diversification of the tumor. Our findings suggest a high plasticity of prostate cancer genomes with newly occurring focal amplifications as a driving force in progression

  Study EGAS00001001018

• Characterization_of_individual_foci_of_multicentric_multifocal_breast_cancer_using_targeted_next_generation_sequencing

  Multifocality or multicentricity in breast cancer may be defined as the presence of two or more tumor foci within a single quadrant of the breast or within different quadrants of the same breast, respectively. This original classification of the breast cancer as multicentric or multifocal was based on the assumption that cancers arising in the same quadrant were more likely to arise from the same ductal structures than those occurring in separate areas of the breast. The problem with these definitions is that the “quadrants” of the breast are arbitrary external designations, as no internal boundaries do exist. This project will therefore focus both on synchronous multifocal and multicentric tumors. The incidence of multifocal and multicentric breast cancers was reported to be between 13 and 75% depending on the definition used, the extent of the pathologic sampling of the breast and whether in situ disease is considered evidence of multicentricity (1). Although this incidence is variable, those figures show that it is a frequent phenomenon. Multiple (multifocal/multicentric) breast carcinomas, especially when occurring in the same breast, represent a real challenge for both pathologists and clinicians in terms of identifying the cellular origin and the best therapeutic management of the cancer. Multifocality or multicentricity has been associated with a number of more aggressive features including an increased rate of regional lymph node metastases and adverse patient outcome when compared with unifocal tumors (2-3), and a possible increased risk of local recurrence following breast conserving surgery (4). For the moment, the literature is divided on whether there is a corresponding impact on survival outcomes. Today, the current convention to stage and to treat multifocal and multicentric tumors is the classical tumor-node-metastasis (TNM) staging guidelines with which tumor size is assessed by the largest tumor focus without taking other foci of disease into consideration. If some papers, as the recent one from Lynch and colleagues, support the current staging convention (3), others, however, as Boyages et al. suggested that aggregate size and not the size of the largest lesion should be considered in order to refine the prognostic assessment of those tumors (5). On the top of that, the question whether multifocal/multicentric carcinomas are due to the spread of a single carcinoma throughout the breast or is due to multiple carcinomas arising simultaneously has been a matter of debate. Some studies suggested that multifocal breast cancer may result from either intramammary spread from a single primary tumor or multiple synchronous primary tumors; whereas others suggest that multiple breast carcinomas always arise from the same clone (6-8). Recently, Pietri and colleagues analyzed the biological characterization of a series of 113 multifocal/multicentric breast cancers (8) which were diagnosed over a 5-year period. The expression of estrogen (ER) and progesterone (PgR) receptors, Ki-67 proliferative index, expression of HER2 and tumor grading were prospectively determined in each tumor focus, and mismatches among foci were recorded. Mismatches in ER status were present in 5 (4.4%) cases and PgR in 18 (15.9%) cases. Mismatches in tumor grading were present in 21 cases (18.6%), proliferative index (Ki-67) in 17 (15%) cases and HER2 status in 11 (9.7%) cases. Interestingly, this heterogeneity among foci has led to 14 (12.4%) patients receiving different adjuvant treatments compared with what would have been indicated if we had only taken into account the biologic status of the primary tumor. This study therefore showed that differences in biological characteristics of multifocal/multicentric lesions play a crucial role in the adjuvant treatment decision making process. In this study, we will concentrate on a larger series of patients with multifocal invasive ductal breast cancer lesions. We aim at: 1. Evaluating the incidence of multifocality according to the different breast cancer molecular subtypes (ER-/HER2-, HER2+, ER+/HER2-). 2. Evaluating the incidence of multifocality in patients with hereditary breast cancer disease (presence of germline BRCA1 or BRCA2 mutations). Moreover, we would like to investigate if multifocal lesions with BRCA1 or BRCA2 mutations exhibit a characteristic combination of substitution mutation signatures and a distinctive profile of deletions as demonstrated recently by Nik-Zainal and colleagues (9). 3. Correlating multifocality with clinical information in order to define its influence on patients’ survival (DFS and OS). 4. Carrying high coverage targeted gene sequencing of driver cancer genes and genes whose mutation is of therapeutic importance in order to compare clinically-relevant genetic differences between several multifocal breast cancer lesions. 5. Evaluating the impact of the distance between the different lesions on the clinical outcome but also on the genetic differences. 6. Comparing gene expression patterns between several multifocal breast cancer lesions and correlate them with the results of the targeted genes screen. 7. Characterizing the genomic and transcriptomic status of cancer related genes in metastatic lesions (local recurrence, positive lymph node or distant metastatic sites) from the same multifocal invasive ductal breast cancer patients in order to evaluate the consequence of genomic and transcriptomic heterogeneity of multifocal lesions on metastatic lesions. Multiple (multifocal/multicentric) breast carcinomas, especially when occurring in the same breast, represent a real challenge for both pathologists and clinicians in terms of identifying the cellular origin and the best therapeutic choice. This project has the potential to identify genetic/transcriptomic differences existing between several lesions constituting multifocal breast cancers, which in the routine clinical practice are usually considered to be homogeneous among them. We foresee validating significant results in a larger series of patients and this, in turn, could have a remarkable impact on the treatment and clinical management of multifocal breast cancers. Indeed, we hope to provide some evidence whether or not each focus matters in multifocal and multicentric breast cancer to define the adequate therapeutic approach, especially in the context of targeted therapies. The work to be done at Sanger will be target gene screen pooling of 1400 samples.

  Study EGAS00001000407

• Sporadic Amyotrophic Lateral Sclerosis (ALS): Parent-Offspring and Twin Sequencing Study

  Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that affects the nerves in the brain and spinal cord, leading to muscle weakening and eventual paralysis and death. Ten percent of ALS cases are thought to be familial while the majority of cases are sporadic and the causative factors unknown. Dr. Roger Pamphlett of the University of Sydney has collected a unique cohort of consented trios where the child has ALS but the parents are unaffected. Since the age of onset is so late, it is very difficult to obtain this kind of trio. We have performed whole exome sequencing on these trios to identify de novo and recessive germline variants associated with sporadic ALS. In addition, Dr. Pamphlett has assembled a collection of consented discordant monozygotic twins, where one twin has ALS and the other is unaffected. We performed whole genome sequencing on these twin pairs to identify postzygotic variants that may contribute to sporadic ALS susceptibility. Finally, we have the opportunity to compare the sequence and gene expression in affected and unaffected tissues from blood, brain and/or spinal cord samples from consented ALS patients to look for somatic mutations or gene expression changes that may further our understanding of the disease.

  Study phs000831

• Inferring tumor genomes from peripheral blood i.e. CTCs and plasma-DNA using deep sequencing and targeted enrichment

  In this study we tested whether complex tumor genomes can be inferred from the peripheral blood (plasma DNA /CTCs) of 32 patients with stage IV colorectal carcinoma (CRC). To establish the percentage of mutated plasma DNA fragments we used 8 patient samples with different plasma DNA size distributions and KRAS mutations in their corresponding primary tumors and employed ultra-deep pyrosequencing with 3 different sequencing reaction sizes (i.e., 119 bp, 168 bp, and 323 bp). Furthermore, we used massive parallel sequencing of a panel of 68 CRC-associated genes to establish the mutation spectrum of cancer driver genes in the primary tumors, metastases, and CTCs of two colorectal cancer patients. To investigate, whether mutations found in only one CTC (“private CTC mutations”) are true mutations occurring with allele frequencies below the resolution limits of current detection methods, or whether they are amplification or sequencing artifacts, we performed ultra-deep sequencing of the primary tumors, metastases, plasma DNAs and normal tissues.

  Study EGAS00001000337

• EGA QuickView

  EGA QuickView Secure and Remote Access to EGA Files What is EGA QuickView? EGA QuickView is a FUSE file system that allows secure and remote access to EGA files. It is a hybrid of sshfs and crypt4ghfs, which means it uses ssh to connect to the EGA distribution servers, downloads data in Crypt4GH format, and transparently decrypts those files. It is compatible with Linux and macOS 12. Why use EGA QuickView? EGA QuickView is a highly useful and convenient tool for anyone who needs to access EGA files remotely and securely. The software offers a quick and convenient way to browse through EGA files without the need for complete downloads, thus saving bandwidth and time. Whether you are a medical professional requiring access to sensitive patient data or a research scientist working on a project that involves EGA files, EGA QuickView provides a highly useful solution. The software boasts advanced security features, ensuring that your data is safe and protected at all times. Get started with EGA QuickView To get started with EGA QuickView, visit the EGA QuickView GitHub repository for more information and installation instructions.

  Documentation access/download/visualisation/ega-quickview

• The Acquisition of Molecular Drivers in Pediatric Therapy-Related Myeloid Neoplasms

  Pediatric therapy-related myeloid neoplasms (tMN) occur in children after exposure to cytotoxic therapy and have a dismal prognosis1-4. The somatic and germline genomic alterations that drive these myeloid neoplasms in children and how they arise have yet to be comprehensively described. We use whole exome, whole genome, and/or RNA sequencing to characterize the genomic profile of 85 pediatric tMN cases (tMDS: n=29, tAML: n=56). Our data show that Ras/MAPK pathway mutations, alterations in RUNX1 or TP53, and KMT2A rearrangements are frequent somatic drivers, and we identify cases with aberrant MECOM expression secondary to enhancer hijacking. Unlike adults with tMN5-7, we find no evidence of pre-existing minor tMN clones (including those with TP53 mutations), but rather the majority of cases were unrelated clones arising as a consequence of cytotoxic therapy. These studies also uncover rare cases of lineage switch disease rather than true secondary neoplasms.

  Study EGAS00001004850