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• Exome_sequencing_of_patients_with_Ewings_sarcoma_

  Cancer is driven by mutations in the genome. We will uncover the mutations that give rise to Ewing’s sarcoma, a bone tumour that largely affects children. We will use second generation Illumina massively parallel sequencing, and bespoke software, to characterise the genomes and transcriptomes of Ewings’ sarcoma tumours.

  Study EGAS00001000266

• Whole exome sequencing of trio with primary immunodeficiency (IL2RB)

  A novel homozygous mutation in human IL2RB results in decreased IL-2RB protein expression and dysregulated IL-2/15 signaling. This hypomorphic mutation leads to decreased regulatory T cell frequency and abnormal NK cell compartment, with clinical manifestations of autoimmunity and susceptibility to CMV.

  Study EGAS00001003599

• FRCC_Exome_sequencing

  Agilent whole exome hybridisation capture will be performed on genomic DNA derived from FRCC patients. one lane of Illumina Hiseq sequencing will be performed on the resulting exome libraries and mapped to build 37 of the human reference genome to facilitate the identification of novel cancer genes.

  Study EGAS00001000176

• HipSci_RNASEQ_Retinitis_Pigmentosa

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we perform RNAseq on iPS lines from Retinitis Pigmentosa patients

  Study EGAS00001001996

• Targeted_sequencing_of_cylindroma_patients

  Patients with cylindroma show multiple large tumours on the scalp and forehead. These large tumours will allow us to look at clonality within a tumour. We wish to asses the mutational load and diversity within and across tumours as well as compare with perilesional skin.

  Study EGAS00001002708

• Peruvian Genome Project - Whole Genome Sequencing

  In this study, we sequence 150 genomes to high coverage from Native American and mestizo populations in Peru. The majority of our samples possess greater than 90% Native American ancestry, which makes this the most extensive Native American sequencing project to date.

  Study EGAS00001004995

• Nucleosome footprinting in plasma cell-free DNA for diagnosis of ovarian cancer

  Fragmentation patterns of plasma cell-free DNA (cfDNA) are known to reflect nucleosome positions of cell types contributing to cfDNA. Based on cfDNA fragmentation patterns, the deviation in nucleosome footprints was quantified between diagnosed ovarian cancer patients and healthy individuals.

  Study EGAS00001005361

• Study of tumor RNA expression differences between treated and untreated PitNET patients

  The goal of the study is to evaluate response of PitNET to drug therapy before surgery. Patients with and without drug therapy are compared in RNA level. The RNA is extracted from surgery material, sequenced and deferentially expressed genes (DEG) determined.

  Study EGAS00001004736

• Molecular evolution of classic Hodgkin lymphoma revealed through whole genome sequencing of Hodgkin and Reed Sternberg cells

  Here we leveraged whole genome structural variant copy number analysis to report the first whole genome sequencing landscape of HRS cells and reconstruct the chronology and likely etiology of pathogenic events prior to the clinical diagnosis of cHL.

  Study EGAS00001006884

• ESGI-Exome sequencing in Circulating Tumor Cells to determine therapy related markers

  The objectives of this project are the identification of markers related to cancer therapy resistance in the blood of breast cancer patients and to study the genetic changes in cancer cells during this development of resistance. Whole genome amplified DNA from Circulating Tumor Cells (CTCs), selected during the course of systemic treatment from blood of metastatic breast cancer patients, will be exome sequenced . The patients selected for this study did not respond to therapy.

  Dataset EGAD00001001425

• Study to investigate the prevalence of leukaemic mutations in whole blood DNA in a cohort of blood donors

  The aim of this study is to ascertain whether leukaemic mutations exist within the blood of people with otherwise normal haematopoeisis. To satisfy this aim we plan to look for 7 known leukaemic mutations in the whole blood DNA of a large cohort of blood donors who have normal haematopoesis. Genomic regions around mutational sites have been amplified using a 2 step PCR process which involves barcoding of individual patients

  Dataset EGAD00001001319

• National Human Genome Research Institute (NHGRI) Clinical Sequencing Exploratory Research (CSER) The MedSeq Project: Integration of Whole Genome Sequencing into Clinical Medicine (HG006500)

  Whole genome sequencing (WGS) and whole exome sequencing (WES) services are currently available to and being utilized by physicians and their patients in both research and clinical settings, and recently to anyone in the general public via direct-to-consumer companies. But the widespread availability and use of WGS and WES in the practice of clinical medicine is imminent. In the very near future, sequencing of individual genomes will be inexpensive and ubiquitous, and patients will be looking to the medical establishment for interpretations, insight and advice to improve their health. Developing standards and procedures for the use of WGS information in clinical medicine is an urgent need, but there are numerous obstacles related to integrity and storage of WGS data, interpretation and responsible clinical integration. The MedSeq Project is an exploratory trial of WGS in clinical medicine. At the conclusion of this study, we will have helped create innovative protocols and novel outcome measures that can be applied safely in future large-scale multi-site randomized clinical trials with larger numbers of physicians from broad specialties and with more economically and ethnically diverse patients. Together with our colleagues from across the nation through the U01 consortium formed as a result of this funding from the NIH, we will have invented a process of implementation and evaluation whereby the fruits of the Human Genome Project can be applied for the first time to the daily practice of medicine for the betterment of human health. The objectives of the MedSeq Project are to: Recruit, consent and enroll 2 study groups: 10 primary care physicians and 100 of their healthy middle-aged patients 10 cardiologists and 100 of their patients with cardiomyopathy. Randomize each study group to receive standard of care versus standard of care plus WGS. Monitor the entire protocol for subject safety. Only half the enrolled patients were selected for sequencing. Fifty subjects were selected from the primary care cohort and fifty were selected from the cardiomyopathy cohort. Whole genome sequencing was performed at 30x coverage in Illumina's CLIA-certified laboratory on these 100 individuals. Generate and optimize an algorithm for interpreting WGS data covering the spectrum of human genetic variation, in terms of both previously reported and novel variants likely to influence the health of patients. Create patient reports and provide an interface for communicating clinically relevant genomic information to practicing physicians. Describe physicians' and patients' attitudes toward, and preferences for, the disclosure of WGS results at the start of the study. Evaluate physicians' experiences with receiving and interpreting patients' genetic test results and how they communicate these results to their patients. Explore how patients respond to and use WGS results by administering validated scales of psychological impact, personal utility, and behavioral responses, as well as economic and health outcomes. Although we do not have a large enough sample size for statistical comparisons of outcomes, we will conduct exploratory comparisons: Exploratory Hypotheses: Patients who receive WGS results will show equivalent levels of distress compared to patients who receive family history only. Patients with higher genetic literacy and better understanding will report greater satisfaction and less decisional regret. Patients who receive WGS will (a) be more likely to change health behaviors and (b) utilize more health care resources than those who do not receive WGS.

  Study phs000958

• Coronary Artery Risk Development in Young Adults (CARDIA-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.Related Studies: Other CARDIA data available include:phs000236.v2.p2 PAGE: CALiCo: Coronary Artery Risk Development in Young Adults(CARDIA) phs000309.v3.p2 The CARDIA-GENEVA Study phs000399.v1.p2 NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (CARDIA) phs000613.v1.p2 NHLBI CARDIA Candidate Gene Association Resource (CARe) phs003675.v1.p1 CARDIA Multi-omics Obesity & CVD Substudy – Year 20 Untargeted Metabolomics Data phs001612.v3.p2 NHLBI TOPMed: CARDIA (Coronary Artery Risk Development in Young Adults) phs003045.v1.p1 Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Coronary Artery Risk Development in Young Adults Study (CARDIA) phs000285.v4.p3 CARDIA_Cohort Available Data: Available data for request include exam data through Year 30 and outcomes and death data through 2022. Additionally, data from 28 ancillary studies are available for request.Objectives: The original objectives of CARDIA were to document levels of risk factors for coronary artery disease and potential determinants of these risk factors in young adults; to study the interrelationships of risk factors and lifestyles and to document behavioral and environmental changes during the transition from young adulthood to middle age; to compare cross-sectional and longitudinal data on age-related trends in cardiovascular disease risk factors; and to compare levels and evolution of risk factors between men and women, blacks and whites, and in groups of differing socioeconomic status. Goals of the study have evolved to emphasize understanding determinants of left ventricular mass, emerging obesity and hypertension, and sequelae of hypertension in pregnancy.Background: CARDIA is designed to increase understanding of contributors to changes in cardiovascular disease (CVD) risk factors during the critical years of transition from young adulthood to middle age. CARDIA was funded initially in 1983 for a five-year cycle that included two rounds of examinations. Contract renewals have allowed for subsequent re-examinations.Participants: Black and white men and women; ages 18-30 years at entry with a range of attained education; original sample size: 5,115.Design: CARDIA is a population-based observational study of 5,115 participants aged 18-30 years recruited in 1985-1986. The sample was designed to achieve approximately balanced subgroups of race, gender, education (high school or less and more than high school) and age (18-24 and 25-30). Forty percent of the cohort had no more than a high school education. A total of nine examinations have been completed in the cohort with examination cycles at year 2 of the project and years 5, 7, 10 , 15, 20, 25, and 30.In addition to standard measurements of blood pressure, anthropometry, blood lipids, smoking behavior, physical activity, diet, pulmonary function, and many psychological factors, CARDIA has other included measurements (in subsets or in the full cohort) to obtain unique information on other aspects of risk factor development and early morbidity. These have included: graded exercise treadmill testing; echocardiography, particularly for measurement of left ventricular mass; cardiovascular reactivity; serum cotinine; Lp(a), apoE phenotype, apolipoprotein A1 and B; homocysteine; skin reflectance; body composition by dual X-ray absorptiometry; glucose tolerance testing; vascular resistance and compliance; and plasma renin activity and sympathetic nervous system activity.

  Study phs003739

• Genetic Basis of Developmental Disabilities

  Developmental disabilities are birth defects that cause lifelong problems with how a body part or system works. Developmental disabilities include nervous system insults affecting how the brain, spinal cord and nervous system function; they cause intellectual disability, including Down syndrome and fragile X syndrome; and they also cause learning and behavioral disorders, such as autism spectrum disorders. At the Kennedy Krieger Institute, approximately 450 inpatients and 13,000 outpatients are seen per year (involving 114,000 visits). For most of these disorders, the underlying molecular cause has not been identified. Some, such as chromosomal disorders, have a strongly genetic basis while others, such as traumatic brain injury, are caused by environmental insults but are nonetheless influenced by the genetic background. The purpose of the present study is to identify chromosomal abnormalities underlying a variety of developmental disabilities. The approach is to obtain blood and saliva from children, and from one or both biological parents (and in some cases from siblings and/or additional relatives). Genomic DNA is purified and assayed on single nucleotide polymorphism (SNP) microarrays and/or by sequencing, including whole genome sequencing. These technologies provide high resolution information about chromosomal changes, and the information provided by the parental (and other relatives') DNA allows an interpretation of whether changes in a child are inherited or occur de novo. The study design includes multiple data analysis procedures to interpret the biological significance of findings of chromosomal changes relative to a child's parents, relative to children with similar diagnoses, relative to children with other chromosomal anomalies, and (in some cases) relative to the chromosomal status of siblings. We will further interpret the significance of the findings relative to the general (apparently normal) population by obtaining publicly available data from apparently normal individuals.

  Study phs000337

• Longitudinal Study of Immune Mediated Disorders After Allogenic Hematopoietic Cell Transplantation (HCT)

  Allogeneic hematopoietic cell transplantation (HCT) is the only known curative option for many hematologic disorders. After transplantation, many patients develop immune mediated disorders that may be life-threatening. Post-HCT immune mediated disorders are rare relative to other diseases but the prototype of graft versus host disease (GVHD) develops in 30-70% of patients. The morbidity and mortality associated with these HCT-associated immune mediated disorders are major barriers to successful use of transplantation to cure rare hematologic malignancies such as leukemia, lymphoma, multiple myeloma, myelodysplastic/myeloproliferative syndromes amongst other diseases. The purpose of this study is to characterize and more completely define the onset and course of immune mediated disorders after allogeneic HCT, focusing on participants who develop cutaneous sclerosis, bronchiolitis obliterans syndrome (BOS), late acute graft-vs.-host disease (GVHD), and chronic GVHD. Of the participants undergoing allogeneic hematopoietic cell transplantation (HCT), can we, the researchers better identify who will develop immune-mediated disorders, what types of disorders participants will have, and whether these disorders will be severe or respond to currently available therapies? This is a longitudinal study of 1118 individuals (1081 adults and 100 children). Those participating in this study will be evaluated over a 3 year period at 9 study sites. Participants will be enrolled pre-transplant, or up to day 121 post transplantation. This wide enrollment window will allow sites to use recruitment methods that are most efficient at their institutions. At least 2 years of follow-up will ensure an adequate sample size, and sufficient time for observation of the full spectrum of immune mediated disorders. The data of 1023 individuals have been submitted to dbGaP.

  Study phs001331

• Peripheral Blood Transcriptome Analysis of ALS Patients

  Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders which overlap in their clinical presentation, pathology, and genetic origin. An over-representation of autoimmune disorders exists in both ALS and FTD, but this remains an unexplained epidemiologic observation. Expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene (GeneID:203228) are the most common cause of familial ALS and FTD (C9-ALS/FTD), leading to both repeat containing RNA and dipeptide accumulation coupled with decreased C9orf72 protein expression in brain and peripheral blood cells. Here we show that loss of C9orf72 in myeloid cells is sufficient to recapitulate the age dependent lymphoid hypertrophy and autoinflammation seen in complete C9orf72-/- mice. Dendritic cells isolated from C9orf72-/- mice showed marked early activation of the type I interferon response, and C9orf72-/- myeloid cells were primarily hyperresponsive to activators of stimulator of interferon gene (STING1 GeneID:340061), a key regulator of the innate immune response to cytosolic DNA. STING degradation through the autolysosomal pathway was diminished in C9orf72-/- mice myeloid cells, and blocking STING suppressed hyperactive type I interferon responses in C9orf72-/- myeloid cells and splenomegaly and inflammation in C9orf72-/- mice. Additionally, mice lacking one or both copies of C9orf72 were more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune diseases seen in C9-ALS/FTD patients. Finally, we found that blood derived macrophages, peripheral blood monocytes, and brain tissue from C9-ALS/FTD patients all showed a hyperactive type I interferon signature compared to sporadic ALS/FTD subjects. Collectively, our results indicate that C9-ALS/FTD patients have an altered immunophenotype due to loss of C9orf72 regulation of STING mediated type I interferon activation.

  Study phs002055

• Mechanisms of Risk for Sulfonamide Hypersensitivity

  Hypersensitivity (HS) reactions to sulfonamide antibiotics occur uncommonly, but with potentially severe clinical manifestations. A familial predisposition to sulfonamide HS is suspected, but robust predictive genetic risk factors have yet to be identified. Strongly linked genetic polymorphisms have been used clinically as screening tests for other HS reactions prior to administration of high-risk drugs. The purpose of this study was to evaluate for genetic risk of sulfonamide HS in the immunocompetent population using genome-wide association. Ninety-one patients with symptoms after trimethoprim-sulfamethoxazole (TMP-SMX) attributable to "probable" drug HS based on medical record review and the Naranjo Adverse Drug Reaction Probability Scale, and 184 age- and sex-matched patients who tolerated a therapeutic course of TMP-SMX, were included in a genome-wide association study using both common and rare variant techniques. Additionally, two subgroups of HS patients with a more refined clinical phenotype (fever and rash; or fever, rash and eosinophilia) were evaluated separately. For the full dataset, no single nucleotide polymorphisms were suggestive of or reached genome-wide significance in the common variant analysis, nor was any genetic locus significant in the rare variant analysis. A single, possible gene locus association (COL12A1) was identified in the rare variant analysis for patients with both fever and rash, but the sample size was very small in this subgroup (n=16), and this may be a false positive finding. No other significant associations were found for the subgroups. No convincing genetic risk factors for sulfonamide HS were identified in this population. These negative findings may be due to challenges in accurately confirming the phenotype in exanthematous drug eruptions, or to unidentified gene-environment interactions influencing sulfonamide HS. Reprinted under PLOS ONE's open access license, CC-BY (http://www.plos.org/open-access).

  Study phs001124

• Analysis of Somatic Mutations in Pediatric AML FAB-M7 Subtype by Whole Transcriptome Sequencing

  High resolution analysis of DNA copy number abnormalities and loss-of-heterozygosity on acute myeloblastic leukemia samples utilizing SNP arrays has demonstrated that in contrast to pediatric ALL, de novo AML is characterized by a very low burden of genomic alterations (Radtke, et al., PNAS, 2009). Samples for this study represented a cross-section of the different subtypes of pediatric AML. The only AML subtype that was an outlier from the above observations was acute megakaryocytic leukemia (AML FAB-M7), with the majority of these cases being characterized by complex chromosomal rearrangements and a high number of copy number alterations. To more fully define the genomic landscape of this subtype, we performed transcriptome sequence analysis on 14 pediatric FAB-M7 cases and mutation recurrence screening in a panel of 62 adult and pediatric AML FAB-M7 samples using the Illumina platform. Our results identified chromosomal rearrangements resulting in the expression of novel fusion transcripts in 11/14 cases. Remarkably, in 7/14 cases we detected an inversion on chromosome 16 that results in the juxtaposition of the CBFA2T3 gene next to the GLIS2 gene resulting in a CBFA2T3-GLIS2 chimeric gene that encoded an in frame fusion protein. This fusion led to the acquisition or preservation of self-renewal in colony forming assays, providing functional evidence for a role in leukemogenesis. In addition to novel chimeric transcripts, we found mutations in genes previously identified to play a role in megakaryoblastic leukemia that carry a proliferative advantage to the cell, such as JAK2 and MPL. These data demonstrate that AML FAB-M7 is characterized by cooperating Class I and Class II mutations leading to leukemogenesis.

  Study phs000413

• Genome Studies in Hereditary Spastic Paraplegia

  Next-generation sequencing technology is opening up new opportunities to rethink the way we identify disease causing genetic variation. An early application, whole exome sequencing, has now been established by a small number of research labs, including ours. Exome sequencing allows obtaining a near complete set of protein coding genomic variation in single individuals for less than $5,000. Promising targets for exome sequencing studies are Mendelian diseases, such as hereditary spastic paraplegias (HSP). HSP comprise a genetically very heterogeneous set of neurological disorders with currently 39 different HSP chromosomal loci being reported; yet, the identified genes explain only 60% of the genetic effect at best. Traditional methods of gene identification require linkage analysis of large families, but face increasing difficulties to identify such extended pedigrees for rare HSP forms. However, the innovative approach described in this application will overcome some of these limitations and utilize relatively small pedigrees for highly effective gene identification. We will apply exome sequencing, which will characterize all coding changes and flanking exonic variation in two individuals of a family. We have developed a multi-tiered strategy to reduce the number of identified novel variants to the very causative change in an individual family. We propose to study at least 60 HSP families, which are too small to yield conclusive results with linkage analysis. If the developing technology permits we will consider a larger sample or perform whole genome sequencing. Beyond the important benefit to genetics of HSP, this study will allow us to further establish this new method, which will benefit a large range of additional disease studies.

  Study phs001080

• Asian Immune Diversity Atlas (AIDA) sQTL

  Current efforts within the Human Cell Atlas (HCA) are largely focused on defining reference human cell types using a relatively small number of samples of predominantly European origin. However, the next phase of the HCA is likely to address the topic of human diversity by comprehensively characterizing variation in cell states across age, sex, population groups, diseases and environments. To spur this next phase, and also expand the geographical scope of the HCA, we propose an HCA-Asia seed network to generate an Asian Immune Diversity Atlas (AIDA). AIDA will generate transcriptome variation datasets from 5 major Asian population groups (Chinese, Japanese, Korean, Indian, Malay), define an atlas of Asian cell types and states, and characterize their variation associated with ethnicity, age and sex. We will also formalize a study design based on common controls that can in principle reduce technical artifacts in a broad range of comparative single cell studies. This study design will be complemented with novel algorithms designed to normalize datasets of interest against the common controls, to increase the robustness of biological inferences. In addition to providing new tools and resources to the HCA, this seed network will serve as a template for future comparative studies in the single cell field.The AIDA dataset consists of scRNA-seq (10x 5′ v2 scRNA-seq) and genotype (Illumina Infinium Global Screening Array v.3) data. In the AIDA splicing quantitative trait loci (sQTL) project, we identified 11,577 independent cis-sQTLs, 607 trans-sQTLs, and 107 dynamic sQTLs. The post-imputation genotype for the Japanese and Korean cohort will be available through dbGaP. The Singaporean (ethnically Chinese, Indian and Malay) genotypes require a data access application to the HELIOS Data Access Committee (helios_science@ntu.edu.sg). European samples are used as control.

  Study phs003848

• CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Summary Results from Genomic Studies

  GWAS have successfully identified genetic loci associated with a variety of conditions such as type 2 diabetes and coronary disease. The large number of statistical tests required in GWAS has posed a special challenge because few studies that have DNA and high-quality phenotype data are sufficiently large to provide adequate statistical power for detecting small to modest effect sizes. Even before the era of GWAS, the requirement for large sample sizes and the importance of replication have served as powerful incentives for collaboration. Meta-analyses combining summary data from multiple sources have improved the ability to detect new loci. The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium was formed to facilitate GWAS meta-analyses and replication among multiple large and well-phenotyped cohort studies. The design of the CHARGE Consortium was formed initially from 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility (AGES) - Reykjavik Study, the Atherosclerosis Risk in Communities (ARIC) Study, the Cardiovascular Health Study (CHS), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). Additional studies have expanded the CHARGE consortium based upon the phenotypes and willingness to share information across the research community. In order to facilitate investigators across the world to examine relationships between phenotypes and genetic markers within CHARGE published reports, an open site is made available on dbGaP that provides the rsID and the p-value for inspection. Access to detailed summary statistics (including minor allele frequency, odds ratio/effect size) requires approval of a Data Access Request (DAR).

  Study phs000930

• Efficacy and Immune Effects of Anakinra Prophylaxis for Neurologic Toxicity and Cytokine Release Syndrome in Patients with Lymphoma Receiving Axicabtagene Ciloleucel

  Chimeric antigen receptor T cells have transformed the treatment of multiple hematologic malignancies, but are limited in application due to treatment-related toxicities. Cytokine release syndrome (CRS) and neurotoxicity (NT) are the primary toxicities associated with these therapies and are thought to be mediated by broad immune activation due to robust T-cell expansion. Current treatment of these toxicities utilize anti-IL-6 directed therapy and/or systemic glucocorticoids to mitigate the consequences of this complex inflammatory cascade. We sought to use anakinra, an IL-1R antagonist, as a prophylactic strategy to prevent clinically meaningful CRS/NT, defined as grade 2 or higher toxicity necessitating clinical intervention. Although our study, in line with others, demonstrated that IL-1R antagonism is insufficient to prevent such toxicities entirely, we were able to gain insight into the molecular immune signaling associated with breakthrough CRS & NT in the presence of anakinra prophylaxis using our scRNA dataset of patients treated with and without IL-1R antagonism. We demonstrate that IL-4 and IL-10 anti-inflammatory pathways in infused CAR-T products of both anakinra and non-anakinra cohorts were negatively associated with grade 2+ toxicities. We also found that expression of IFN-gamma pathways and ligand-receptor activities, as well as cytokine levels of IFN-gamma and CXCL10 in CD14+ monocytes, were significantly enriched in patients with breakthrough toxicity in the anakinra cohort. This correlated with an increase in IFN-gamma in the peripheral blood of patients with breakthrough toxicities, among other cytokines. These data identify IFN-gamma as a potential key mechanism in the development of CAR-T cell-associated toxcities and suggest that this pathway is also targetable and not inhibited by anakinra alone.

  Study phs003655

• Clonal Lineage Tracing of Primary Human Cortical Progenitors, Cell Type Profiles in the Brain Vasculature and Genotyping Data for 22q11DS and Control iPS Lines

  We sought to characterize the cell types produced by individual human cortical progenitors and describe their lineage relationships. We labeled individual human cortical cells with a massively complex lentivirus library encoding a GFP reporter gene and a molecular barcode that could be captured by standard 3' scRNA-seq methodologies. We then cultured the labeled human cells for 6 weeks in either a 1) mouse cortical astrocyte co-culture system or 2) in the mouse cortex as a xenograft. In a separate experiment, we maintained human cortical tissue slices in organotypic slice culture for 12 days. GFP+ cells were then isolated by FACS and then captured on the 10x chromium scRNA-seq platform. An additional sample was labeled by lentivirus and briefly cultured for 3 days prior to being mixed with mouse 3T3 cells in order to perform a cell mixing experiment ("barnyard") to benchmark our methodologies. We found that human individual cortical progenitors gave rise to both excitatory and inhibitory neurons as well as glia.We also sought to characterize the adult brain vasculature in both vascular malformations and non-malformed tissue. We use the 10x chromium scRNA-seq platform across 10 individuals (5 control and 5 arteriovenous malformations). We find broad disregulation across multiple cell types including the immune cells and find a specific monocyte subtype to contribute to a rupture phenotype. We also find a novel population of fibromyocytes in both conditions.Finally, we confirmed the genotype status of iPS lines that were derived from either karyotypically normal control individuals or from DiGeorge Syndrome patients carrying the 22q11.2 deletion using the Illumina Infinium Global Screening Array v3.0.

  Study phs002624

• National Emphysema Treatment Trial (NETT-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. Available Data: The current release of the NETT study dataset includes follow-up data through May of 2013.Objectives: To compare lung-volume-reduction surgery with medical therapy for severe emphysema, and to identify participant selection criteria for lung volume reduction surgery.Background: Lung-volume-reduction surgery has been proposed as a palliative treatment for severe emphysema. Effects on mortality, the magnitude and durability of benefits, and criteria for the selection of participants have not been established.Participants: A total of 1,218 participants with severe emphysema underwent pulmonary rehabilitation and were randomly assigned at 17 centers to undergo lung-volume-reduction surgery (bilateral stapled wedge resection) or to receive continued medical treatment. Participants were randomized after a 6-10 week pulmonary rehabilitation period and participants with a forced expiratory volume in one second (FEV1) that was 20 percent or less of predicted and a homogeneous distribution of emphysema or carbon monoxide diffusing capacity 20 percent or less of predicted were not eligible for randomization due to poor post-surgery prognosis for death or functional improvement.Conclusions: Overall, lung-volume-reduction surgery increases the chance of improved exercise capacity but does not confer a survival advantage over medical therapy. It does yield a survival advantage for participants with both predominantly upper-lobe emphysema and low base-line exercise capacity. Participants previously reported to be at high risk and those with non-upper-lobe emphysema and high base-line exercise capacity are poor candidates for lung-volume-reduction surgery, because of increased mortality and negligible functional gain. (NEJM 2003;348:2059-2073).

  Study phs004077

• Confronting historical legacies of biological anthropology in South Africa—Restitution, redress and community-centered science: The Sutherland Nine

  We describe a process of restitution of nine unethically acquired human skeletons to their families, together with attempts at redress. Between 1925–1927 C.E., the skeletonised remains of nine San or Khoekhoe people, eight of them known-in-life, were removed from their graves on the farm Kruisrivier, near Sutherland in the Northern Cape Province of South Africa. They were donated to the Anatomy Department at the University of Cape Town. This was done without the knowledge or permission of their families. The donor was a medical student who removed the remains from the labourers’ cemetery on his family farm. Nearly 100 years later, the remains are being returned to their community, accompanied by a range of community-driven interdisciplinary historical, archaeological and analytical (osteobiographic, craniofacial, ancient DNA, stable isotope) studies to document, as far as possible, their lives and deaths. The restitution process began by contacting families living in the same area with the same surnames as the deceased. The restitution and redress process prioritises the descendant families’ memories, wishes and desire to understand the situation, and learn more about their ancestors. The descendant families have described the process as helping them to reconnect with their ancestors. A richer appreciation of their ancestors’ lives, gained in part from scientific analyses, culminating with reburial, is hoped to aid the descendant families and wider community in [re-]connecting with their heritage and culture, and contribute to restorative justice, reconciliation and healing while confronting a traumatic historical moment. While these nine individuals were exhumed as specimens, they will be reburied as people.

  Study EGAS50000000971

• Out with the Java, in with the Python - new EGA data download client unveiled

  We will shortly be deprecating the Java-based download client also known as API V2. The Java client began its life at the back end of 2014, and during its time has seen many developments that have served our users well. During its tenure, the Java client enabled distribution of over 6.5 million files totalling nearly 15 petabytes of data to researchers around the globe. Recent increases in genomic and phenotypic data file sizes, the number of datasets archived in the EGA, the number of users downloading data, and the diversity of download locations has meant that at times the Java client struggled to distribute data efficiently. In response, our team of developers have built a new download client with more robust features and better functionality and reliability. Enter stage left our shiny new API V3.1! The new API V3.1 will replace both API V2 and API V3. The download client for the new API V3.1 is written in Python, and the code is openly available on Github. This Python client makes https calls to the EGA AAI (https://ega.ebi.ac.uk:8443/) and to the EGA Data API (https://ega.ebi.ac.uk:8052), both of which must be accessible from the client location. In addition to general updates to improve performance, the API V3.1 has three new features enhancing the EGA distributions services. First, requested data are now downloaded over secure https connections rather than http, meaning that data can be delivered unencrypted. Instead of separately requesting, downloading, and decrypting data using the Java client, data can now be requested and downloaded using a single command without the need for decrypting. The API V3.1 also automatically verifies each file’s unencrypted md5 after download to ensure the file has downloaded correctly. Second, the new API supports segmenting and automatic resuming. To enable quicker download speeds, the API breaks files into up to four segments and downloads them in parallel. With the new resume feature, downloads - both segmented and continuous stream - will automatically resume if they encounter any errors or the connection is interrupted. These features result in both a faster and more reliable download experience. Finally, the new API V3.1 implements the GA4GH-compliant htsget protocol for supporting requests over genomic ranges. This exciting new feature means that for data files with accompanying index files (e.g. .crai for CRAM files) users can download specific regions of interest rather than the entire file saving both time and storage space. The new features of the Python-based API V3.1 represent significant improvements in security, speed, reliability, and flexibility that are sure to provide a better data download experience. To take full advantage of these features, users must update to Python 3.X. Considering the changes in the data structures with the new API, the upgrade to a new version of the Python client is also mandatory. Updating the client to the latest version can be achieved by running the following command: pip3 install pyega3 -U We are excited for users to try out the new features and take advantage of the multifariously growing EGA distribution services for human biomedical omics data. If you have any questions or feedback, please email the EGA Helpdesk team. We'd love to hear from you!

  Blog new-ega-data-download-client

• Integrated Genomic, Epigenetic, and Expression Analyses of Ovarian Cancer Cell Lines

  Epithelial ovarian carcinoma of all subtypes has one of the worst outcomes of any human cancer. To improve our understanding of underlying biology and therapeutic possibilities in this disease, we performed whole genome sequencing, methylation, and expression analyses of a comprehensive set of 47 ovarian cancer cell lines representing different histologic tumor subtypes. Given the challenges of genomic analyses in tumors without matched normal samples, we developed novel approaches for detection of somatic alterations and used these to identify sequence, copy number, and rearrangement changes and integrated these with genome-wide epigenetic and expression alterations. Ovarian cancer cell lines had molecular changes in genes involved in cell cycle, PI3K, RAS, BRCA, chromatin regulating, and p53 pathways, and displayed global mutation and methylation changes similar to primary ovarian carcinoma. We identified alterations not previously implicated in ovarian cancer including amplification or overexpression of ASXL1 and H3F3B, deletion or underexpression of CDC73 and members of the TGF beta receptor pathway, including TGFBR2, SMAD3 and SMAD4, in-frame rearrangements of YAP1-MAML2 and IKZF2-ERBB4, and fusions involving MET, NF1, FBXW7 and CCND1. Integrating cell line alterations with dose-response data using three targeted therapies revealed novel molecular dependencies, including increased sensitivity of tumors with PIK3CA and PPP2R1A alterations to PI3K inhibitor GNE-493, those with MYC amplifications to PARP inhibitor BMN673, and SMAD4 alterations to MEK inhibitor MEK162. Genome-wide analyses revealed intrachromosomal rearrangements as an improved measure of sensitivity to PARP inhibition compared to the homologous recombination defect (HRD) score. This study provides a comprehensive resource of molecular information for ovarian cancer cell line models and a pharmacogenomic platform for developing rational cancer therapeutic strategies.

  Study EGAS00001002998

• The University of Hong Kong Gastric Cancer Organoids RHO Signaling Study

  Objective: Cell-cell (CC) and cell-matrix (CM) adhesions are essential for epithelial cell survival, yet dissociation-induced apoptosis is frequently circumvented in malignant cells. Design: We explored CC and CM dependence in 58 gastric cancer (GC) organoids by withdrawing either ROCK inhibitor, matrix, or both, to evaluate their tumorigenic potential in terms of apoptosis resistance, correlation with oncogenic driver mutations and clinical behaviour. We performed mechanistic studies to determine the role of diffuse-type GC drivers: ARHGAP fusions, RHOA, and CDH1, in modulating CC (CCi) or CM (CMi) adhesion independence. Results: 97% of the tumour organoids were CMi, 66% were CCi and 52% were resistant to double withdrawal (CCi/CMi), while normal organoids were neither CMi nor CCi. Clinically, the CCi/CMi phenotype was associated with an infiltrative tumour edge and advanced tumour stage. Moreover, the CCi/CMi transcriptome signature was associated with poor patient survival when applied to 3 public GC datasets. CCi/CMi and CCi phenotypes were enriched in diffuse-type GC organoids, especially in those with oncogenic driver perturbation of RHO signalling via RHOA mutation or ARHGAP fusions. Inducible knockout of ARHGAP fusions in CCi/CMi tumour organoids led to re-sensitization to CC/CM dissociation-induced apoptosis, upregulation of focal adhesion and tight junction genes, partial reversion to a more normal cystic phenotype, and inhibited xenograft formation. Normal gastric organoids engineered with CDH1 or RHOA mutations became CMi or CCi, respectively. Conclusions: The CCi/CMi phenotype has a critical role in malignant transformation and tumour progression, offering new mechanistic information on RHO-ROCK pathway inhibition that contributes to GC pathogenicity.

  Study EGAS00001006252

• Intra-tumor heterogeneity and clonal evolution patterns towards platinum-resistant high-grade serous ovarian cancer

  Although many high-grade serous ovarian carcinoma (HGSOC) patients are initially sensitive to the standard-of-care platinum-based therapy, intra-tumor heterogeneity may fuel selection towards platinum-resistant clones over subsequent lines of therapy. We performed whole-exome coupled to ultra-deep re-sequencing and copy number alteration (CNA) profiling on 31 matched diagnosis and relapse tumors from HGSOC patients treated with platinum. Genetic heterogeneity within tumor pairs varied extremely, with some recurrent tumors being identical and others completely different from the primary tumor. All primary tumors showed evidence of homologous recombination (HR)-deficiency, but none of them carried reactivating mutations in the HR pathway at relapse, also not when becoming resistant to subsequent lines of platinum. We did also not identify other mutations, CNAs or pathways that were enriched in platinum-resistant clones. However, a platinum score consisting of 13 CNAs correlated significantly with platinum-free interval (PFI) after first-line therapy in multiple cohorts of >450 primary HGSOCs. A relative increase of this score in the relapsed tumor correlated with a change in PFI during subsequent therapy. Clonal evolution under platinum therapy contributes to genetic heterogeneity within tumor pairs, implicating that genetic tests linked to targeted treatment options for recurrent HGSOC need to be performed on biopsies collected at relapse. Platinum resistance of an initially platinum-sensitive HR-deficient HGSOC at relapse is not caused by reactivation of the HR pathway, suggesting that these tumors are still responsive to PARP inhibitors, instead, several chromosomal aberrations contribute to a score predictive of disease outcome under platinum therapy, both in first and subsequent lines of platinum therapy.

  Study EGAS00001001244

• Altered oligodendrocyte heterogeneity in Multiple sclerosis revealed by single nuclei RNA sequencing

  This study is currently hosted by the European Nucleotide Archive. To access the data contained within the Study please follow the link below: https://www.ebi.ac.uk/ena/browser/view/PRJEB39323 Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases, as they are involved in metabolic support of axons and functional cross-talk with other brain cells. Rodent OLs are heterogeneous, with developmental and biological differences, but the extent of heterogeneity in the normal human brain and its contribution to any changes to disease remains unknown. Here we performed single nuclei RNA-sequencing (snRNA-seq) from white matter (WM) areas of post mortem human brain both in control (Ctr) and multiple sclerosis (MS) patients. We identified several sub-clusters of oligodendroglia in the Ctr human WM, some similar to those in mouse, and defined new markers for these cell states. Strikingly, some of these sub-clusters were under-represented in MS tissue, while others were more prevalent than in controls. We found a lack of OL precursor cells (OPCs) and an OL subcluster in an intermediate stage of differentiation in MS lesions and in normal appearing white matter (NAWM), suggesting either depletion by the disease or by a regenerative response. The differences in mature OL sub-clusters indicate different functional states of OLs in MS tissue and, as this is similar in NAWM to lesions, that MS is a more diffuse brain disease than the focal demyelinating lesions suggest. We were also able to identify new putative markers of different MS lesion subtypes. Our findings of an altered heterogeneity of oligodendroglia in MS may have an important contribution to our understanding of disease progression and may alter therapeutic approaches to MS.

  Study EGAS00001003412

• Post_Mortem_Tissue_COVID19_RNA

  Single cell analysis of post mortem tissue samples from SARS-CoV2-infected patients We aim to directly identify the human cell types infected by SARS-CoV-2 and measure the cellular response to COVID19 infection across 20 different tissues from infected patient autopsies. We have examined the expression pattern of viral entry receptors across healthy human tissues to predict several candidate target cell types across the airway and heart. In addition, high prevalence of cardiac failure and abnormal renal function in COVID19 patients implicates heart and kidney involvement, but the pathogenesis of organ specific damage - whether via a direct cytopathic mechanism or an indirect inflammatory response - remains unknown . Currently, we lack confirmation of target cell types and cellular processes in infected tissues as autopsies are discouraged in most countries due to health and safety risks. Our collaborators Drs Michael Osborn and Brian Hanley (Imperial College) have outlined guidelines to perform post-mortem in COVID19 patients (Hanley et al., 2020) and have established a programme of autopsies for research to be performed in a high-risk facility at Westminster Public Mortuary. Here, we propose to identify infected cell types and aberrant molecular pathologies in this precious tissue resource using single cell and spatial genomics. We will prioritise three organ systems: the human airway, heart and the kidney. We will directly examine the cellular identities of SARS-CoV-2 infected cell types and identify the cellular responses to infection across these organs. This fundamental knowledge will help guide future treatment choices for COVID19. 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 EGAS00001004442

• Post_Mortem_Tissue_COVID19_spatial

  Single cell analysis of post mortem tissue samples from SARS-CoV2-infected patients We aim to directly identify the human cell types infected by SARS-CoV-2 and measure the cellular response to COVID19 infection across 20 different tissues from infected patient autopsies. We have examined the expression pattern of viral entry receptors across healthy human tissues to predict several candidate target cell types across the airway and heart. In addition, high prevalence of cardiac failure and abnormal renal function in COVID19 patients implicates heart and kidney involvement, but the pathogenesis of organ specific damage - whether via a direct cytopathic mechanism or an indirect inflammatory response - remains unknown . Currently, we lack confirmation of target cell types and cellular processes in infected tissues as autopsies are discouraged in most countries due to health and safety risks. Our collaborators Drs Michael Osborn and Brian Hanley (Imperial College) have outlined guidelines to perform post-mortem in COVID19 patients (Hanley et al., 2020) and have established a programme of autopsies for research to be performed in a high-risk facility at Westminster Public Mortuary. Here, we propose to identify infected cell types and aberrant molecular pathologies in this precious tissue resource using single cell and spatial genomics. We will prioritise three organ systems: the human airway, heart and the kidney. We will directly examine the cellular identities of SARS-CoV-2 infected cell types and identify the cellular responses to infection across these organs. This fundamental knowledge will help guide future treatment choices for COVID19. 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 EGAS00001004441

• Genomic Correlates of Response and Resistance to Immune Checkpoint Blockade in Solid Tumors

  Immune checkpoint inhibitors yield clinical benefit in many cancer types, but molecular predictors of response have not yet been robustly characterized. In this study, we pursued whole exome sequencing (WES) of pre-treatment tumors from patients treated with immune checkpoint therapies - including monoclonal antibodies targeting programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). Using these data, we aim to apply computational pipelines for mutation-calling, neoantigen prediction, and other analyses to validate pre-existing hypotheses regarding response to immune checkpoint therapies and discover new relationships with greater power. Further, by pursuing genomic characterization of tumors from patients with a variety of cancer types, we hope to describe molecular features of intrinsically sensitive or resistant tumors that are both context-specific and shared across cancer types.

  Study phs001565

• Genetics of Hypertension Associated Treatment (GenHAT) Study, Genomic Background of Blood Pressure Response to Treatment in African Americans

  The GenHAT study is an ancillary pharmacogenomics study to the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT was a randomized, double-blind, multi-center trial that enrolled 42,418 participants ≥55 years of age with hypertension and at least one additional risk factor for cardiovascular disease (CVD). Participants were randomized to treatment with one of four primary antihypertensive drugs: chlorthalidone (thiazide-like diuretic), amlodipine (CCB), lisinopril (ACE-i), or doxazosin (alpha-adrenergic blocker) in a ratio of 1.7:1:1:1, respectively. Participants were followed for treatment response and CVD outcomes. The original GenHAT study (N=39,114) evaluated the association of candidate hypertensive genetic variants with CVD outcomes for participants consenting to genetic research. The current GWAS study focuses on a subset of African American GenHAT participants (n=6908).  

  Study phs002716

• Tissue-specificity and co-expression analyses identify human long non-coding RNAs related to inherited retinal disease genes

  The role of long non-coding RNAs (lncRNAs) in biological and pathological processes is still poorly understood. In this study, we aimed to identify lncRNAs that potentially contribute to retinal biology and Inherited Retinal Disease (IRD) by using two complementary strategies, tissue-specificity and location in topologically associating domains (TADs) containing IRD genes on one hand, and co-expression analyses on the other, applied to human retinal omics datasets. This combined approach resulted in the selection of 11 Retina Enriched IRD-gene Related (REIR) lncRNAs, one of which is novel. In-depth in silico and experimental characterization of REIRs identified novel REIR isoforms and confirmed retina-predominant (often photoreceptor-specific) expression as well as predicted functional association with visual function. Long-read direct cDNA sequencing (ONT) of three post-mortem human retina samples was used to delineate the novel REIR isoforms.

  Study EGAS50000000963

• High coverage target resequencing of coding and regulatory regions of 38 Parkinson disease genes associated either to the Mendelian or the sporadic forms of the disease

  Coding sequences and putative regulatory sequences (retrieved from Ensembl and including up to 2500 bp of promoter sequence upstream the transcription start site) were re-sequenced to a mean depth of 49X on 38 genes associated to Parkinson's disease (RAB25, NUCKS1, RAB7L1, GBA, SYT11, ACMSD, STK39, MCCC1, STBD1, GAK, DGKQ, BST1, SCARB2, HLA-DRB5, GPNMB, FGF20, ITGA8, HIP1R, STX1B, SETD1A, SREBF1, MED13, RAI1, MAPT, RIT2, GIGYF2, HTRA2, EIF4G1, SNCA, LRRK2, VPS35, PINK1, DJ1, ATP13A2, UCHL1, PARK2, FBXO7, and PLA2G6). Sequencing was performed on 249 Parkinson's idiopathic cases and 145 unrelated controls of Spanish origin. All sequencing data was generated with an Illumina Hiseq2000 instrument after enrichment with a custom NimbleGen array. Raw reads were mapped to human reference genome hg19/GRCh37 using BWA aligner.

  Study EGAS00001000973

• Epigenetic profiling of colorectal cancer initiating cells (CC-ICs) to identify bivalently marked genes (H3K4me3 and H3K27me3 ChIP-seq), and investigation of changes in transcriptome following EZH2 inhibition using RNA-seq.

  Epigenetic regulation of transcription plays a crucial role in lineage commitment of embryonic stem cells. Promoters of key lineage-specific differentiation genes are found in a repressed bivalent state, having both activating H3K4me3 and repressive H3K27me3 histone marks, making them poised for transcription upon loss of H3K27me3 in response to environmental cues. Whether the tumour-initiating, self-renewing, cancer-initiating cells (C-ICs) have similar epigenetic regulatory mechanism that prevent lineage commitment is unknown. In order to investigate bivalently marked and repressed promoters, we used a patient-derived CC-IC enriched model to identify the changes in transcriptome following inhibition of EZH2, the H3K27 methyltransferase. We also performed ChIP-seq for H3K27me3 and H3K4me3 at baseline in order to identify repressed and bivalently marked promoters.

  Study EGAS00001003003

• An exome sequencing approach to defining the genetic risk factors for Achilles tendinopathy

  Musculoskeletal soft tissue injuries are complex phenotypes. Case control association studies using the candidate gene approach have predominantly been used to identify risk loci for these injuries. However, the ability to identify all risk conferring variants using this approach alone is unlikely. Therefore, this study aimed to define the genetic profile of these injuries using whole exome sequencing and a customized analysis pipeline. The exomes of ten exemplar asymptomatic controls and ten exemplar cases with Achilles tendinopathy were individually sequenced using a platform that included the coverage of the untranslated regions and miRBase miRNA genes. These results provide a proof of concept for the use of a customized pipeline for the exploration of a larger genomic dataset. This approach, using previous research to guide a targeted analysis of the data has generated new genetic signatures in the biology of musculoskeletal soft tissue injuries.

  Study EGAS00001003234

• The impact of mutational clonality in predicting the response to anti-PD-L1/PD-L1 in advanced urothelial cancer

  The advent of immune checkpoint inhibitors (ICI) has radically changed the management and therapeutic treatment landscape for patients with cancer. It has been shown that the use of these inhibitors can result in long-term complete remissions even in cases with advanced stages of the disease. However, only a small fraction of patients respond to the treatment. A better understanding of which factors could drive this clinical benefit is fundamental to building more accurate predictive biomarkers and developing alternative therapeutic options for patients who are unlikely to benefit. In order to address this issue, we have generated and analyzed whole exome sequencing (WES) and RNA sequencing (RNASeq) data from a cohort of metastatic urothelial carcinoma patients (N = 27) treated with ICI such as anti-PD-(L)1 monoclonal antibodies.

  Study EGAS00001007086

• Characterisation of the genomic landscape of CRLF2-d ALL

  To determine the clinical and genetic landscape of CRLF2 deregulated acute lymphoblastic leukaemia (CRLF2-d ALL). We identified 172 patients with a CRLF2 rearrangement treated on either the UKALL2003 trial for children and adolescents (1-24 years) or the UKALLXII trial for adolescents and adults (15-59 years). Genomic technologies from conventional karyotyping, and FISH through to whole genome and exome sequencing were used to characterise the genomes of patients with CRLF2-d ALL. This is the largest study to date to investigate the genomic landscape of CRLF2-d ALL and define CRLF2-d as a unique subgroup of B-other ALL. We have confirmed the high incidence of CRLF2-d in Down syndrome-ALL and demonstrated the co-existence of CRLF2-d with other primary chromosomal rearrangements, suggesting that in these patients CRLF2-d can be a secondary genetic abnormality. Other defining features included enrichment of IKZF1, BTG1 and ADD3 deletions in IGH-CRLF2 patients and specific chromosomal gains seen at much higher frequencies than B-other ALL . We report recurrent established and new co-operating abnormalities and the novel involvement of USP9X and DDX3X in CRLF2-d ALL. It is clear from these data that CRLF2-d ALL is heterogenoeus, requiring a combination of genetic abnormalities in functionally relevent genes, to work alongside the deregulated expression of CRLF2 in order to initiate and drive leukaemogenesis in this subtype. Although the functional relevance of many of the abnormalities presented here are currently unknown, many are likely to activate alternate pathways or sensitize patients to current therapies.

  Dataset EGAD00001002007

• Characterisation of the genomic landscape of CRLF2-d ALL

  To determine the clinical and genetic landscape of CRLF2 deregulated acute lymphoblastic leukaemia (CRLF2-d ALL). We identified 172 patients with a CRLF2 rearrangement treated on either the UKALL2003 trial for children and adolescents (1-24 years) or the UKALLXII trial for adolescents and adults (15-59 years). Genomic technologies from conventional karyotyping, and FISH through to whole genome and exome sequencing were used to characterise the genomes of patients with CRLF2-d ALL. This is the largest study to date to investigate the genomic landscape of CRLF2-d ALL and define CRLF2-d as a unique subgroup of B-other ALL. We have confirmed the high incidence of CRLF2-d in Down syndrome-ALL and demonstrated the co-existence of CRLF2-d with other primary chromosomal rearrangements, suggesting that in these patients CRLF2-d can be a secondary genetic abnormality. Other defining features included enrichment of IKZF1, BTG1 and ADD3 deletions in IGH-CRLF2 patients and specific chromosomal gains seen at much higher frequencies than B-other ALL . We report recurrent established and new co-operating abnormalities and the novel involvement of USP9X and DDX3X in CRLF2-d ALL. It is clear from these data that CRLF2-d ALL is heterogenoeus, requiring a combination of genetic abnormalities in functionally relevent genes, to work alongside the deregulated expression of CRLF2 in order to initiate and drive leukaemogenesis in this subtype. Although the functional relevance of many of the abnormalities presented here are currently unknown, many are likely to activate alternate pathways or sensitize patients to current therapies.

  Dataset EGAD00001002008

• This DAC is to control access to data contained within dataset EGAS00001001147, for Myeloma XI clinical trial patients.

  Dac EGAC00001000307

• Zambian Genetic Variation DAC

  DAC to govern access to array genetic variation data from five populations in Zambia.

  Dac EGAC50000000258

• Liberate Cohorts

  This DAC will govern access to WES data associated with publications belonging to Liberate Cohorts

  Dac EGAC50000000455

• Identifying_Novel_Fusion_Genes_in_Myeloma

  To identify novel fusion genes in Myeloma samples

  Study EGAS00001000220

• Tetralogy of Fallot Exome Trios

  Exome sequencing of 30 parent-offspring trios to >50X mean depth, where the offspring has sporadic TOF, to identify potential causal de novo mutations. We will use the exome plus design for pulldown that incorporates ~6.8Mb of additional regulatory sequences in addition to the ~50Mb GENCODE exome.

  Dataset EGAD00001000344

• Bulk RNASeq of metastatic colorectal cancer organoids with ATOH1 knockout

  Bulk RNA sequencing was performed on mCRC organoids subjected to cetuximab treatment, comparing ATOH1 knockout and control conditions. The dataset is intended to elucidate the contribution of ATOH1-regulated secretory cell population to cetuximab persistence mechanisms.

  Dataset EGAD50000002060

• WES dataset

  Associated with Molecular biomarkers in progression from refractory celiac disease to the lethal cancer variety enteropathy associated T cell lymphoma (EATL) Study. Whole Exome Sequencing (WES) of 63 samples. WES analysis done to detect mutations and copy number aberration predictive for progression from RCD to EATL.

  Dataset EGAD50000001164

• To determine the genomic profile of Triple Negative Breast Cancer patient-derived xenografts (PDX cohort)

  Specific BRCA and immune configurations determine optimal response to platinum-based chemotherapy in triple negative breast and ovarian carcinomas (PDX_WGS)

  Study EGAS00001005995

• Gene expression profile of mesothelial cells from peritoneal adhesion biopsies

  RNA-sequencing analysis was carried out on mesothelial cells isolated from peritoneal adhesion biopsies and compared to control human peritoneal mesothelial cells to identify a mesothelial-to-mesenchymal transition (MMT)-related gene signature in patients.

  Dataset EGAD00001008324

• 2017_ AML WGS analysis result

  This data is belong to 2017 AML genome data which is aligned to human reference(human_g1k_v37.fasta). There are 10 paired tumor/normal samples from SNUH. All samples has passed QC and recalibration steps while aligning to reference.

  Dataset EGAD00001003599

• 2017_ AML prospective data analysis result

  This data is belong to 2017 AML prospective data which is aligned to human reference(human_g1k_v37.fasta). There are 10 paired tumor/normal samples from SNUH. All samples has passed QC and recalibration steps while aligning to reference.

  Dataset EGAD00001003598

• 2014 AML WES analysis result

  This data is belong to 2014 AML patients' exome data which is aligned to human reference(human_g1k_v37.fasta). There are 51 paired tumor/normal samples from SNUH. All samples has passed QC and recalibration steps while aligning to reference.

  Dataset EGAD00001003932

• Ovarian cancer/normal cell lines

  We performed whole genome sequencing of nine OC patient-derived cell lines and one normal cell line (HOSEpiC) to analyze if the cell lines harbor OC-typical genomic aberrations absent in normal cells and to relate genomic features to drug sensitivities.

  Dataset EGAD00001003146

• RNA bam files of Renal Cell Carcinoma patients

  the dataset contains RNA bam files of Renal Cell Carcinoma patients, which belongs to "An Empirical Approach Leveraging Tumorgrafts to Dissect the Tumor Microenvironment in Renal Cell Carcinoma Identifies Missing Link to Prognostic Inflammatory Factors"

  Dataset EGAD00001003895

• Whole Genome Sequencing of 18 sequential samples from 3 CLL patients

  Whole Genome Sequencing to track subclonal heterogeneity in 18 samples from 3 Chronic Lymphocytic Leukemia patients subjected to repeated cycles of therapy. NOTE: There are only 12 BAM files available to download. The other 6 files are missing.

  Dataset EGAD00001000972

• Transposome Bisulfite Sequencing

  DNA belonging to 16 tumour/normal samples were treated with bisulfite, then up to 5 different bisulfite PCRs were performed in each one of the samples. Amplicons form the same sample were pooled and submitted to sequencing on a MiSeq platform.

  Dataset EGAD00001001028

• NHLBI TOPMed: The Jackson Heart Study (JHS)

  Since there is a greater prevalence of cardiovascular disease among African Americans, the purpose of the Jackson Heart Study (JHS) is to explore the reasons for this disparity and to uncover new approaches to reduce it. The JHS is a large, community-based, observational study whose 5306 participants were recruited from among the non-institutionalized African-American adults from urban and rural areas of the three counties (Hinds, Madison, and Rankin) that make up the Jackson, MS, metropolitan statistical area (MSA). Jackson is the capital of Mississippi, the state with the largest percentage (36.3%) of African Americans in the United States. The JHS design included participants from the Jackson ARIC study who had originally been recruited through random selection from a drivers' license registry. Approximately six months before the JHS was to begin, an amendment to the federal Driver's Privacy Protection Act was passed that changed the level of consent for public release of personal information from driver's license lists from an "opt out" to an "opt in" basis. The Mississippi Highway Patrol was no longer able to release a complete listing of all persons with driver's licenses or state identification cards, which prevented its use in the JHS. New JHS participants were chosen randomly from the Accudata America commercial listing, which provides householder name, address, zip code, phone number (if available), age group in decades, and family components. The Accudata list was deemed to provide the most complete count of households for individuals aged 55 years and older in the Jackson MSA. A structured volunteer sample was also included in which demographic cells for recruitment were designed to mirror the eligible population. Enrollment was opened to volunteers who met census-derived age, sex, and socioeconomic status (SES) eligibility criteria for the Jackson MSA. In addition, a family component was included in the JHS. The sampling frame for the family study was a participant in any one of the ARlC, random, or volunteer samples whose family size met eligibility requirements. Eligibility included having at least two full siblings and four first degree relatives (parents, siblings, children over the age of 21) who lived in the Jackson MSA and who were willing to participate in the study. No upper age limit was placed on the family sample. Known contact information was obtained during the baseline clinic examination from the index family member with a verbal pedigree format to identify name(s), age(s), address (es), and telephone number(s). Recruitment was limited to persons 35-84 years old except in the family cohort, where those 21 years old and above were eligible. Only persons who otherwise met study criteria but were deemed to be physically or mentally incompetent by trained recruiters were excluded from study eligibility.1 1 Wyatt SB, Diekelmann N, Henderson F, Andrew ME, Billingsley G, Felder SH et al. A community-driven model of research participation: the Jackson Heart Study Participant Recruitment and Retention Study. Ethn Dis 2003; 13(4):438-455 (PMID: 14632263).

  Study phs000964

• Environmental Influences on Child Health Outcomes (ECHO) - PATHWAYS - Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE)

  Pregnant women are exposed daily to multiple chemical and non-chemical stressors, including air pollutants, phthalates, and psychosocial stress. The Developmental Origins of Health and Disease model (DOHaD) states that exposure to these stressors in pregnancy affects fetal development in a manner that impacts offspring health across the life course. Yet epidemiologic data in these areas is limited, particularly with U.S. samples. It is also poorly understood whether these exposures prenatally affect childhood neurodevelopment and airway health in an independent or combined manner, and likely moderators of effects, such as the sex of the child, are infrequently addressed. We propose to unify three diverse extant pregnancy cohorts: TIDES (N=717, 2010-12), GAPPS (N=1133, 2012-16), and CANDLE (N=1385, 2007-11), for a combined sample size of 3235 mother-child dyads in the PATHWAYS study. PATHWAYS will investigate how chemical (air pollutants and phthalates) and non-chemical (psychosocial stress) exposures during pregnancy are related to placental gene expression (transcriptome) and childhood neurodevelopment and airway health (at ages 4-6, 8-9, and 10-11 years). Each cohort has rich resources of prenatal data and banked specimens (urine, blood, and placenta) that will be harmonized for the PATHWAYS study and will contribute to the ECHO consortium. We will develop a national model with high spatiotemporal resolution of key air pollutants and assess urinary markers of maternal exposure. A composite measure will capture multilevel maternal psychosocial stress across pregnancy, and urinary phthalate and blood stress hormone [Corticotropin-releasing hormone (CRH)] levels in the second and third trimesters will provide individual assessment of those exposures in potential critical periods. We will characterize the placental transcriptome using RNA sequencing (RNA-Seq) and will assess neurodevelopment and airway health prospectively into middle childhood. PATHWAYS will examine how these prenatal exposures are related to the placental transcriptome and child health outcomes in main effect and interactive models, with emphasis on sex-specific associations. For both neurodevelopment and airway health, we propose to measure both phenotypic precursors of health outcomes (i.e. fluid cognition, lung function growth), which yield dimensional tests of proposed associations, as well as clinically meaningful and policy relevant outcomes (i.e. asthma, mental health). Our study is powered to assess interactive effects of chemical and non-chemical stressors and will be the first study to characterize how prenatal environmental exposures relate to placental transcriptome pathways in relation to childhood health outcomes. This represents a significant scientific advance in testing DOHaD hypotheses. Major contributions to the ECHO Consortium include: 1) the development of a state of the art national model of air pollution, 2) a large, diverse pregnancy cohort with extensive biorepositories and extant prenatal and postnatal biomarkers, placental transcriptome, psychosocial and environmental data, and 3) an experienced, interdisciplinary team that will contribute meaningfully to the ECHO program of work.The sequencing data in this submission pertains only to the 794 subjects from the CANDLE study for whom placental tissue transcriptomics was performed.

  Study phs003619

• Lipid Research Clinics - Prevalence Study (LRC-PS-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. Objectives: The LRC Program began in 1971 under the sponsorship of the National Heart, Lung, and Blood Institute, National Institutes of Health. Part of this program was the Lipid Research Clinics Prevalence Study, a standardized series of cross-sectional surveys of various North American populations designed to determine the prevalence of dyslipidemias and to describe the distributions of lipids and lipoproteins in major ethnic and social groups. In addition to contributing to the aggregate analysis, each independent population-based study was designed with capabilities for separate analyses of lipid and lipoprotein distributions. The participating populations were not selected to be a probability sample representative of the North American population per se, but by virtue of their size and economic and geographical diversity, they provide a useful cross-sectional group. The Family Study was the third phase of the Lipids Research Clinics North American Population Studies. The Family Study was designed to obtain knowledge of the distribution of lipids and lipoproteins among family members and of the association of familial and genetic attributes to dyslipoproteinemias. Background: An association between serum cholesterol and coronary heart disease is well established. A system was developed for classifying hyperlipoproteinemias into six types of patterns, as a basis for characterizing lipoprotein disorders. The Lipid Research Clinics was thus created to improve the detection of and clinical management of hyperlipoproteinemias. The three primary objectives were: 1) to acquire data on the prevalence of different types of hyperlipoproteinemia in various age and ethnic groups, with special emphasis on the nature and frequency of genetic forms; 2) to collect reliable data on the prevalence and incidence of atherosclerosis in different types of hyperlipoproteinemia; and 3) to conduct an intervention trial to determine if lowering plasma lipid levels would reduce the risk of CHD. Participants: There were 60,495 participants. Conclusions: Data from this study confirm findings from earlier studies in developed countries, showing age-related differences in plasma lipid levels. However, for overall distributions, the LRC data showed slightly lower cholesterol and markedly higher trigylceride values than those previously reported for North America. Some variation in plasma lipid values was evident among the clinic populations. The large number of participants within most subgroups permitted a variety of analytic and comparative studies. For example, data from the large pediatric population revealed a drop in plasma cholesterol levels in adolescent males and females. Males aged 20-50 years had higher cholesterol levels than females in the same age group, and higher trigylceride levels between ages 20-70 years. Numbers were also significient for meaningful comparisons between lipid distributions of females who were taking sex hormones and those who were not; in females taking sex hormones, cholesterol and triglyceride levels were higher for subjects younger than 45 years, but slightly lower after age 45, than lipid levels in females not taking hormones (Circulation 1979; 60(2):427-439).

  Study phs003995

• Overcoming Clinical Resistance to EZH2 Inhibition Using Rational Epigenetic Combination Therapy

  Essential epigenetic dependencies have become evident in many cancers. Based on functional antagonism between BAF/SWI/SNF and PRC2 in SMARCB1-deficient sarcomas, we and colleagues recently completed the clinical trial of the EZH2 inhibitor tazemetostat, leading to its FDA approval. However, the principles of tumor response to epigenetic therapy in general and tazemetostat in particular remain unknown. Using functional genomics of patient tumors and diverse experimental models, we defined molecular mechanisms of tazemetostat resistance. We found distinct classes of acquired mutations that converge on the RB1/E2F axis, decoupling EZH2-dependent differentiation and cell cycle control. This allows tumor cells to escape tazemetostat-induced G1 arrest despite EZH2 inhibition and suggests a general mechanism for effective EZH2 therapy. Using RNA-sequencing of patient tumor specimens, we identified specific genes as markers of a deficient RB1/E2F axis, which we propose as prospective biomarkers for therapy stratification. This offers a paradigm for rational epigenetic combination therapy suitable for immediate translation to clinical trials.This study was performed on archived tumor tissue collected as part of the above clinical trial at Memorial Sloan Kettering Cancer Center. Patient tumors were classified into "Response" or "Progression" groups based on RECIST 1.1 criteria. "Response" included tumors exhibiting a complete response, partial response, or stable disease. All other tumors were classified under the "Progression" group. Archived frozen tumor samples were weighed and up to 20-30mg were homogenized in RLT buffer, followed by extraction using the AllPrep DNA/RNA Mini Kit (QIAGEN catalog 80204) according to the manufacturer's instructions. RNA was eluted in 13 μL nuclease-free water. After RiboGreen quantification and quality control by Agilent BioAnalyzer, 1 μg of total RNA with DV200 percentages varying from 78% to 100% underwent ribosomal depletion and library preparation using the TruSeq Stranded Total RNA LT Kit (Illumina catalog RS-122-1202) according to instructions provided by the manufacturer with 8 cycles of PCR. Samples were barcoded and sequenced using NovaSeq 6000 in a PE150 mode, with the NovaSeq 6000 S4 Reagent Kit (Illumina). On average, 84 million paired reads were generated per sample and 70% of the data mapped to mRNA. For analysis, read adaptors were trimmed and quality filtered using 'trim_galore' and mapped to GRCh38/hg19 reference genome using STAR v2.7.9 with default parameters.

  Study phs003188

• DAC to control the access to the RRBS raw data of the glioblastom progression study (GBMatch).

  Dac EGAC00001000689

• Longitudinal peripheral blood DNA methylation profiling of endoscopic response to tofacitinib in moderate-to-severe ulcerative colitis patients

  Study EGAS00001006968

• EGFR TARGETING IN GASTRO-ESOPHAGEAL CANCER

  WES ON GASTRO-ESOPHAGEAL TUMORS TO IDENTIFY BIOMARKERS OF RESPONSE TO EGFR INHIBITION

  Dac EGAC50000000562

• Olink CRS DAC

  DAC to regulate access to Olink targeted proteomics data in Chronic rhinosinusitis (CRS) patient cohort.

  Dac EGAC50000000547

• Lipomatous tumors with 12q amplification

  The project concerns whole genome sequencing (short-read and long-read) and RNA-sequencing of lipomatous tumors with 12q-amplification. A subset of lipomatous tumors is driven by amplification of genes mapping to chromosome arm 12q, including the MDM2 gene. The goals of the study were to compare expression levels of genes mapping to 12q in tumors with amplification in rod-shaped or circularized chromosomes as well as to assess and compare the structural variants in those tumors. In total, 20 samples were analyzed, and the data were correlated with genomic data on bulk and single cell DNA from the same tumors. The fastq files from the tumors were uploaded to EGA.

  Dataset EGAD50000000087

• The Incidence of Thromboembolic Events in Patients with Antibodies to Heparin-PF4 after Cardiac Bypass

  The purpose of this study is to determine how often heart surgery patients who receive heparin develop an immune response (heparin-induced thrombocytopenia) that leads to clots forming in different parts of the body. These clots usually occur in the legs (deep venous thrombosis or DVT) or lungs (pulmonary embolism or PE) or cause heart attacks (myocardial infarction or MI) and strokes.

  Study phs000606

• DDX50 Cooperates With STAU1 to Effect Stabilization of Pro-Differentiation RNAs

  This study was undertaken to determine the role of DDX50 in epidermal homeostasis. Primary neonatal foreskin keratinocytes were obtained from discarded surgical samples at a California hospital. Samples were anonymous and not selected. DDX50, which was associated with STAU1, was found to promote epidermal differentiation and transcript stability using the methods of RNA-seq, CLIP-seq and DMS-MaP-seq.

  Study phs003766

• Tumor-resident T-cell regulate responses to checkpoint blockade immunotherapies

  In cancer models, CD103+CD8 TRM cells are implicated in the response to anti-PD-1 immunotherapy, and a subset of CD4 TRM cells expressing the integrin CD49a is required for response to anti-CTLA-4 immunotherapy. We performed single-cell RNA sequencing on tumour-infiltrating T lymphocytes (TILs) isolated from colon carcinoma et unsupervised analyses reveal several TRM populations.

  Study EGAS50000000826

• Genetic and Epigenetic Screens in Primary Human T Cells Link Candidate Causal Autoimmune Variants to T Cell Networks

  We aimed to define the target genes and pathways in which autoimmune disease-associated genetic variants operate. We performed single cell-CRISPR-interference screens in primary human T cells and bulk RNA-seq on T cells containing CRISPRi and single gRNAs to assess how T cell regulatory regions containing autoimmune-associated genetic variants affect nearby gene expression and cellular programs.

  Study phs004072

• Single-cell multi-omics reveals clonal evolution and T-cell dynamics underlying differential responses to ibrutinib in Waldenström macroglobulinemia.

  To elucidate the molecular basis underlying differential response and resistance to ibrutinib in Waldenström’s macroglobulinemia (WM), we conducted a prospective phase II trial (NCT02604511) of ibrutinib monotherapy in treatment-naïve patients. Seventy-four sequential bone marrow (BM) aspirates from 17 patients, collected from baseline through 48 treatment cycles, were profiled using single-cell RNA and V(D)J sequencing.

  Study EGAS50000001596

• Inherited genetic predisposition to childhood acute lymphoblastic leukemia investigated using a genome wide association study.

  This series consists of summary data generated from a genome-wide association study (GWAS) investigating inherited genetic risk to childhood acute lymphoblastic leukemia (ALL). The GWAS comprised 784 cases recruited to the Medical Research Council UK ALL-2003 and ALL-97/99 trials and 7,385 controls. The data describe SNPtest association statistics from the case-control analysis.

  Study EGAS00001002809

• Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence (RNA-seq)

  Understanding how prostate cancer cells adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenetic plasticity towards pro-survival signaling, and uncovered circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel clinical lead for therapeutic development.

  Study EGAS00001006016

• Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence (ChIP-seq)

  Understanding how prostate cancer cells adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenetic plasticity towards pro-survival signaling, and uncovered circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel clinical lead for therapeutic development.

  Study EGAS00001006017

• Massive parallel RNA sequencing of highly purified mesenchymal cells derived from bone marrow specimens of 3 Diamond-Blackfan anemia cases

  Highly purified mesenchymal cells (CD45-/7AAD-/CD235a-/CD31-/CD271+/CD105+) were prospectively FACS-isolated from bone marrow specimens of 3 Diamond-Blackfan anemia (DBA) cases. This data set, comprising 3 DBA cases, is used as complement to 45 low-risk myelodysplastic syndrome (LRMDS) and 4 Shwachman-Diamond syndrome (SDS) cases to demonstrate aberrant inflammatory signaling as a common mechanism in pre-leukemia syndromes to induce genotoxic stress in hematopoietic stem cells. In addition, this data set is used to determine different overlapping gene expression signatures in pre-leukemia syndromes compared to gene expression profiles of highly purified mesenchymal cells of healthy donors.

  Dataset EGAD00001002661

• Massive parallel RNA sequencing of highly purified mesenchymal cells derived from bone marrow specimens of 4 Shwachman-Diamond syndrome cases

  Highly purified mesenchymal cells (CD45-/7AAD-/CD235a-/CD31-/CD271+/CD105+) were prospectively FACS-isolated from bone marrow specimens of 4 Shwachman-Diamond syndrome (SDS) cases. This data set, comprising 4 SDS cases, is used as complement to 45 low-risk myelodysplastic syndrome (LRMDS) and 3 Diamond-Blackfan anemia (DBA) cases to demonstrate aberrant inflammatory signaling as a common mechanism in pre-leukemia syndromes to induce genotoxic stress in hematopoietic stem cells. In addition this data set is used to determine different overlapping gene expression signatures in pre-leukemia syndromes compared to gene expression profiles of highly purified mesenchymal cells of healthy donors.

  Dataset EGAD00001002660

• Use of Deep Sequencing to Dectect Clonal Mutations In Sun Exposed Skin Epidermis PART2

  This study aims to define the landscape of somatic mutations in sun exposed human skin by deep sequencing, analyse their frequency and use the data to infer the effect of mutations on proliferating cell behaviour. The frequency of each mutation will reflect the size of the clone of cells in the tissue sample. By analyzing small samples, clones with as few as 100 cells will be detectable. Allele frequency distributions for each mutation will be used to infer cell fate using published methods (Klein et al. 2010). This study will shed unprecedented light on the early clonal events that lead to the emergence of cancer.

  Dataset EGAD00001000825

• Mapping regulatory variation in sensory neurons using IPS lines from the HIPSCI project

  Sensory neurons are nerve cells that are activated by sensory input such as heat, light and convey information to the brain. Although a key cell type in complex organisms, human sensory neurons are challenging to study because they are impossible to obtain from living donors. We have collaborated with the Neucentis Pharmaceutical Research Unit to differentiate sensory neuron like cells from human induced pluripotent stem cells derived as part of the Human Induced Pluripotent Stem Cells Initiative. We will sequence RNA from 100 IPS lines derived from healthy individuals and perform RNA-seq on the differentiated cells to identify noncoding variants that alter gene expression in human sensory neurons.

  Dataset EGAD00001003145

• Use of Deep Sequencing to Dectect Clonal Mutations In Sun Exposed Skin Epidermis

  This study aims to define the landscape of somatic mutations in sun exposed human skin by deep sequencing, analyse their frequency and use the data to infer the effect of mutations on proliferating cell behaviour. The frequency of each mutation will reflect the size of the clone of cells in the tissue sample. By analyzing small samples, clones with as few as 100 cells will be detectable. Allele frequency distributions for each mutation will be used to infer cell fate using published methods (Klein et al. 2010). This study will shed unprecedented light on the early clonal events that lead to the emergence of cancer.

  Dataset EGAD00001001090

• Collaborative Study of Genes, Nutrients and Metabolites (CSGNM)

  While many genetic and metabolic studies focus on understanding disease states, this genome wide association study (GWAS) was designed to understand the influence of genetic variants on circulating metabolites and factors in normal, healthy individuals. Over 2500 healthy, ethnically Irish college students attending Trinity College Dublin completed a health and diet questionnaire and provided a non-fasting blood sample to be used for genetic and metabolic analysis. The questionnaire was designed to collect information on age, sex, height, weight, medical conditions, smoking, dietary habits, and consumption of alcohol, fortified foods, and supplements. Extracted DNA was genotyped using the Illumina HumanOmni1-Quad Beadchip. Metabolites were measured using a number of methods and focused on those relevant to the folate/vitamin B12 pathway.

  Study phs000789

• Episodic Ataxia Syndrome: Longitudinal Study

  Individuals with episodic ataxia experience recurrent attacks of dizziness and incoordination; between attacks patients are typically normal. The majority of cases are likely caused by an inherited genetic mutation. However, in some patients we are unable to identify the mutation. So far, 2 genes have been identified which cause different types of episodic ataxia. Ultimately, when the actual mutation is identified the protein product of the gene can be studied and specific medications can be designed. During this study, we will clinically evaluate patients with EA and follow them over time to help us better characterize the disease. We will also obtain blood samples to test for the known genetic mutations. In the future, we plan to coordinate trials of medications for the treatment of these disorders.

  Study phs000521

• DNA Replication Timing Alterations in Genetic Diseases

  This study contains a collection of lymphoblastoid cell line (LCL) and induced pluripotent stem cell (iPSC) whole genome sequencing from individuals with an without a diagnosed genetic disease. Several types of genetic diseases are included such as translocations, repeat expansions, and heritable or spontaneous mutations of genes. We used the whole genome sequencing to generate DNA replication timing profiles for these individuals and compared the profiles of diseased individuals to presumed healthy samples. We aimed to identify replication timing alteration linked to a specific genetic disease and therefore elucidate trans-acting factors of DNA replication timing. We found that replication timing was highly consistent across almost all diseased samples. Only one genetic disease, a mutation in MCM10, demonstrated an altered profile of replication timing.

  Study phs002597

• Next Generation Mendelian Genetics: Malignant Hyperthermia

  Malignant hyperthermia (MH) is a genetic disorder that causes a profound metabolic derangement following exposure to certain anesthetics. While approximately half of all cases are associated with ryanodine receptor-1 gene (RYR1) mutations, many cases have an unknown genetic cause. We sought to identify rare variants in novel MH candidate genes by sequencing the protein-coding regions of the genomes of individuals whose disease was either ruled in or out by the gold-standard diagnostic test. We also carefully selected individuals from well-characterized families to use gene-sharing information and maximize efficiency in the study design. Exome sequencing has helped identify the causes of over a dozen Mendelian disorders, has high power at low sample sizes, and is cost-efficient compared to whole-genome sequencing.

  Study phs000405

• Hyperdiploid Acute Lymphoblastic Leukemia RNA-Seq

  Few genetic drivers of children with hyperdiploid precursor B-cell acute lymphoblastic leukemia (ALL) have been identified to date. In an effort to detect novel genomic rearrangements that could be promoting leukemogenesis in this subset of patients, we sequenced ribosomal RNA-depleted transcriptomes isolated from 5 hyperdiploid acute lymphoblastic leukemia samples. In addition to looking for novel genomic rearrangements, we also sought to identify transcripts that could be created as a result of a novel posttranscriptional process. Surprisingly, we identified transcripts created as the result of exon circularization. The results of our studies are present in the paper "Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types" published in PLoS ONE (PMID: 22319583).

  Study phs000522

• Multimodal Profiling of 500,000 Memory T Cells from a Tuberculosis Cohort Identifies Cell State Associations with Demographics, Environment, and Disease

  We conducted CITE-seq to measure whole transcriptome gene expression and surface expression of 31 proteins. We assayed >500K memory T cells from 259 donors from a tuberculosis progression cohort (128 cases: former progressors and 131 controls: non-progresssors/latent infection) >4 years post-infection after returning to immune steady state. We defined 31 memory T cell states influenced by age, sex, genetic ancestry, and season. After correcting for these covariates, we found that one cell state (C-12), resembling the T helper cells Th17s, were depleted in cases compared to controls. When sorted ex vivo, this state responds to polyclonal or Mycobacterium tuberculosis (Mtb) peptide antigen stimulation with interleukin-17 (IL-17) or interferon gamma (IFNg).

  Study phs002467

• Single Cell Genomic Analysis of Lymphoma

  Our study aimed to define the extent of heterogeneity between anatomically separated tumor manifestations in follicular lymphoma at single-cell resolution. We subjected single-cell suspensions derived from nodal, synchronously-acquired fine needle aspirations from two distinct tumor sites to high-throughput microfluidics-based single-cell RNA sequencing. By comparing the relative composition of the tumor subpopulations between the two tumor sites, we found that some patients can exhibit site-to-site differences. While the overall composition of the tumor microenvironment did not differ significantly between sites, we did detect a specific correlation between site-to-site tumor heterogeneity and T follicular helper cell abundance. Our study demonstrates the significant limitations of a solitary biopsy in defining the full scope of a patient's disease.

  Study phs002188

• Filtering and Annotation of Variants That Are Rare (FAVR)

  The project developed a suite of new methods (FAVR) designed to assist the shortlisting of genetic variants under a rare variant-phenotype/disease model. The methods were designed to work with commonly used massively parallel sequencing analysis pipelines, such as the GATK or ANNOVAR, and have been made publically available as a suite of software tools (https://github.com/bjpop/favr). The FAVR methods use signatures in comparator sequence alignment files to facilitate the filtering of mapping artifacts and common genetic variants, and annotation of genetic variants based on evidence of co-occurrence in individuals. As relevant, FAVR methods can also be used to filter out artifacts derived from imbalanced paired-end sequencing. Pope et al., BMC Bioinformatics, accepted Dec 2012.

  Study phs000601

• Whole exome sequencing in multiplex cleft families from a consortium

  Building upon our previous linkage and association studies, we will use whole exome sequencing studies of second and third degree affected relatives drawn from multiplex families. Our specific aims are: 1) To conduct whole exome sequencing on affected members (2° and 3° relatives) drawn from multiplex cleft families from a consortium to identify novel genes causing non-syndromic oral clefts; 2) To confirm and test the role of rare variants in these novel genes through confirmatory Sanger sequencing, plus linkage information using additional members available in these multiplex families. This whole exome sequencing approach will combine evidence from linkage studies and large scale sequencing to identify novel genes causing oral clefts in multiplex cleft families.

  Study phs000459

• Center for Common Disease Genomics (CCDG) - Cardiovascular: BioImage Cohort

  The genetic basis of cardiovascular disease in individuals of non-European ancestry remains largely unknown. Availability of ethnically diverse study populations is essential to fully investigate the underlying causes of disease. The BioImage Study enrolled adults aged 55-80 in a prospective observational study. Subjects had no prior history of cardiovascular disease, but were identified to be at intermediate to high risk for atherosclerotic cardiovascular events (PMID: 25790876). The recruiting target was a cohort with similar demographics to the US population in terms of race and ethnicity. Produced as part of the NHGRI Centers for Common Disease Genomics, this study contains whole genome sequence data and variant calls from 922 African American participants of the BioImage Study.

  Study phs002325

• Low Density Genotyping from the Fragile Families and Child Wellbeing Study

  The Fragile Families and Child Wellbeing Study (FFCWS) is based on a stratified, multistage sample of 4898 children born in large U.S. cities (population over 200,000) between 1998 and 2000, where births to unmarried mothers were oversampled by a ratio of 3 to 1. This sampling strategy resulted in the inclusion of a large number of Black, Hispanic, and low-income families. The project “Low Density Genotyping from the Fragile Families & Child Wellbeing Study” uses saliva collected from a subset of FFCWS children at Year 9 and from teens at Year 15 to examine genetic variation using a genome-wide assay (Illumina PsychChip). In addition to the genotype data, a limited set of self reported and anthropomorphic measures are included.

  Study phs002417

• NHLBI TOPMed - NHGRI CCDG: The Vanderbilt University BioVU Atrial Fibrillation Genetics Study

  Atrial fibrillation (also called AFib or AF) is a quivering or irregular heartbeat (arrhythmia) that can lead to blood clots, stroke, heart failure and other heart-related complications. At least 2.7 million Americans are living with AFib. Individuals with early onset atrial fibrillation (AF) are included in this study of cases from the BioVU sample repository. BioVU is Vanderbilt's biobank of DNA extracted from leftover and otherwise discarded clinical blood specimens. BioVU operates as a consented biorepository; all individuals must sign the BioVU consent form in order to donate future specimens. BioVU subjects are de-identified and linked to the Synthetic Derivative enabling researchers to access genetic data/DNA material as well as dense, longitudinal electronic medical record (EMR) information.

  Study phs001624

• Cross-site Concordance Evaluation of Tumor DNA and RNA Sequencing Platforms of CIMAC-CIDC Network

  The Cancer Immune Monitoring and Analysis Centers (CIMACs) and the Cancer Immunologic Data Commons (CIDC)  has engaged in efforts to harmonize Whole-exome (WES) and RNA-sequencing (RNA-seq) data from three different experimental platforms (MD Anderson, NCI MoCha lab, and Broad Institute) and are using a series of developed pipelines to process the early trial samples. To evaluate the consistency of tumor WES and RNA-seq profiling platforms across different centers, the CIMACs-CIDC conducted a systematic harmonization study. DNA and RNA were centrally extracted from fresh frozen (FF) and formalin-fixed paraffin-embedded (FFPE) non-small cell lung carcinoma (NSCLC) tumors and distributed to three centers for WES and RNA-seq profiling

  Study phs002295

• HuBMAP: A 3-D Tissue Map of the Human Lymphatic System

  The major goal of the 3-D Tissue Map of the Human Lymphatic System is to use microscopic and biomolecular procedures to facilitate co-registration pipelines and common 3D reconstruction algorithms. Tissue collected from human spleen, thymus and lymph node will be spatially resolved at the single cell level both within and across individuals. The approach employed involves sequencing of transcriptomes of dissociated cells and mapping to histological sections using CO-Detection by indEXing (CODEX) and /or Imaging mass spectroscopy, two highly multiplexed methods employing antibody-tagged target epitopes. Additionally, light sheet fluorescent microscopy is used to provide a higher level context for structural localization on a larger volume. The molecular data provided by this project is obtained through single-cell RNA-seq.

  Study phs002268

• DNA Repair Capacity for Lung Disease Risk Assessment

  A focus of this work was to address the extent to which susceptibility for lung cancer varies by gene-environment-phenotype interactions involving DNA repair capacity and differences in risk from environmental stressors. GWAS from a subset of subjects from the Lovelace Smokers Cohort and New Mexico Lung Cancer cohort were used to derive polygenic risk scores for DNA repair pathways (nucleotide excision, base excision, single strand break, non-homologous, homologous recombination). Logistic regression analysis was used to examine the association between polygenic risk score and lung cancer status. Polygenic risk scores were grouped by quartiles. Only diminished base excision repair was associated with increased risk for lung cancer at the 25-50% quartile and approached significance at the 50-75% quartile.

  Study phs004063

• APOBEC Mutagenesis, Kataegis, Chromothripsis in EGFR-Mutant Osimertinib-Resistant Lung Adenocarcinomas

  Expanding on studies investigating apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutagenesis in histological transformation of epidermal growth factor receptor (EGFR)-mutant lung cancers, it has been hypothesized that mutational signature analysis may help better understand acquired resistance to targeted therapies. Using mutational signature analysis in Receptor Tyrosine Kinase (RTK) driven lung adenocarcinomas, more specifically EGFR mutant lung cancer, APOBEC dominant mutational signatures were noted more frequently in subclonal post Tyrosine Kinase Inhibitor (TKI) treatment biospecimen samples and in the presence of large-scale genomic rearrangements. This is hypothesized to be due to the pressure of treatment with TKIs; a fact that should be further explored and can be potentially manipulated in order to overcome drug resistance.

  Study phs003812

• The PRIME-AIR Study: Positive End-Expiratory Pressure, Recruitment, Incentive Spirometry, Muscle Relaxant Optimization, Preoperative Education, Postoperative Early Ambulation, Individualized, and Reinforced

  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.The PRIME-AIR study ("Positive end-expiratory pressure, Recruitment, Incentive spirometry, Muscle relaxant optimization, preoperative Education, postoperative early Ambulation, Individualized, and Reinforced") was a prospective multi-center randomized controlled pragmatic trial, with a blinded assessor, to compare post-operative pulmonary complications (PPCs) in patients with an individualized anesthetic-centered intervention (including individualized mechanical ventilation positive end-expiratory pressure (PEEP) management to maximize respiratory system compliance and minimize driving pressures, a neuromuscular agent and subsequent reversal, and post-operative lung expansion and early mobilization) versus usual care.

  Study phs003926

• Longitudinal analysis of bone marrow heterogeneity reveals the co-evolution of malignant B cells and their T-cell niche supporting follicular lymphoma persistence

  Follicular Lymphoma (FL) is an indolent lymphoid malignancy characterized by cycles of remission and relapse, reflecting the inability of current therapies to fully eradicate tumor cells. Our hypothesis is that rare cancer precursor/persister cells (CPCs) evade treatment by homing to a protective tumor microenvironment, particularly within the bone marrow (BM), and/or by adopting specific cellular states, and form a rare reservoir of residual cells seeding lymphoma recurrence. To adress this, we collected paired BM samples at diagnosis and one year post-therapy from a clinical trial (FLIRT trial, NCT02303119) and applied multi-modal single-cell analysis to dissect the transcriptomics determinants of rare drug-tolerant persister cells and their surrounding T-cell niche.

  Study EGAS50000001295

• Construction of endoscopic biopsy banking for understanding the intestinal environment in colorectal diseases and exploratory studies using these banking systems.

  Colorectal cancer is the most common type of cancer in Japan. Although some colorectal cancers have a genetic background, most colorectal cancers are sporadic. Known risk factors for colorectal cancer include smoking, obesity, lack of exercise, and red and processed meat. Furthermore, although it has been suggested that changes in the intestinal environment due to changes in diet and lifestyle may be involved in the increased incidence of colorectal cancer in Japan, the molecular mechanism has not yet been fully elucidated. The main objective of this study is to elucidate the changes in the intestinal environment that cause colorectal tumors, and also to contribute to the establishment of colorectal mucosal tissue banking in Japan.

  Study JGAS000655

• Single cell RNAseq data of human neurons, Bouwen et al Nat Comm 2025

  Brain tumor patients often suffer from epilepsy, but the underlying neuronal changes leading to this neurological symptom are not well understood. This study examined the transcriptomic profiles of human cortical neurons collected from brain tumor patients with or without seizures. The goals of the study were to identify the molecular identities of the recorded neurons and confirm that they are layer 2/3 pyramidal neurons rather than neuron-like tumor cells; and to compare the differential gene expression profiles between patients with and without epilepsy. For each patient, cortical neurons were rapidly isolated from surgically resected tissue and prepared using the Smart-seq2 protocol. Samples from 12 patients were sequenced on an Illumina HiSeq 2500 platform to generate their transcriptomic profiles.

  Study EGAS50000001369

• Research on the identification of cancer stem cells for peidatric and adult malignancies.

  In recent years, "cancer stem cells" have been reported to exist in many cancers. Many reports have shown that they are the main cause of cancer recurrence. The aim of this study is to test whether cancer stem cells can be identified using patient samples. We will perform omics analysis of rare pediatric cancers by integrating genomics, transcriptomics, proteomics and metabolomics, including somatic and germline mutations, to deepen our understanding of the biological characteristics of the target disease. Based on the knowledge gained and clinical information from patients, we will conduct preclinical pharmacological studies using mouse models and in vitro models to investigate the therapeutic effects of novel therapeutic agents and novel therapeutic strategies such as cellular therapies.

  Study JGAS000623