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• Autozygosity pilot - QMUL

  The offspring of first cousin marriages have ~6% of their genome autozygous, i.e. homozygous identical by descent, or even more if there was further consanguinity in their ancestry. In the UK there are large populations with very high first cousin marriage rates of 20-50%. Sequencing the exomes of a sample of these individuals has the potential both to support genetic health programmes in these populations, and to provide genetic research information about rare loss of function mutations. This pilot study based on existing British-Pakistani cohort samples will identify homozygous individuals for almost all variants down to an allele frequency around 1%, plus individuals carrying hundreds of new homozygous rare loss-of-function variants, and will support development of community relations and ethics for a wider study currently being designed. The data deposited in the EGA consists of low coverage whole exome sequencing on these samples.

  Dataset EGAD00001001027

• Genomic Characterization CS-MATCH-0007 Arm N

  The CS-MATCH-0007 protocol is part of a collaboration between the Center for Cancer Genomics (CCG) and the Division of Cancer Treatment and Diagnosis (DCTD) to perform whole-exome sequencing, RNA sequencing and if possible, whole-genome, methylation and miRNA sequencing using pre-and post-treatment tumor biopsy specimens from patients enrolled on a treatment arm of the NCI-MATCH clinical trial (EAY131). The goal of this study is to identify the molecular basis for response and resistance to targeted therapies that are matched to specific genomic alterations found in their cancers. Arm N is one of the treatment sub-protocols within the NCI-MATCH Clinical Trial (EAY131) where patients with PTEN mutation, or deletion with PTEN expression on IHC, are treated with the drug GSK2636771. This subprotocol is one of the treatment arms included in the CS-MATCH-0007 protocol and will provide specimens for the program including DNA from tumor tissue and whole blood.

  Study phs002151

• Investigating_the_impact_of_MBD4_on_the_mutability_of_the_germline

  We will be testing the hypothesis that MBD4 PTV germline carriers also show an increased number of C toT germline mutations in their offspring. 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 EGAS00001002861

• ESGI_Identification_of_novel_genes_and_mechanisms_leading_to_Primary_Ciliary_Dyskinesia

  Approximately 80% of clinically clearly diagnosed patients suffering from primary ciliary dyskinesia (PCD) cannot be assigned to a specific gene defect. Despite extensive research on PCD and despite the increasing number of PCD genes and knowledge about their sites of action as e.g structural component or cytoplasmic pre-assembly factor, the biology of motile cilia and the pathomechanism leading to PCD is largely unknown. The aim of this study is to identify novel PCD related genes and processes relevant for motile cilia function.We will perform exome sequencing, aiming on the analysis of family trios. In these families, the diagnosis of PCD is secured, but the underlying gene defects has so far not been identified.

  Study EGAS00001000523

• eMERGE Network's Multi-Center Pilot of Pharmacogenetic Sequencing in Clinical Practice

  eMERGE-PGx is a multi-site test of the concept that sequence information can be coupled to electronic medical records (EMRs) for use in healthcare. The promise of personalized medicine - health care guided by each individual's biological characteristics - is being fostered by increasingly powerful and economical methods to acquire clinically relevant biomarkers from large numbers of people. One therapeutic area that seems especially ripe for an early test of the personalized medicine concept is pharmacogenomics (PGx) - the idea that individual variation in drug response includes a genomic component. Drug response variation is an accepted feature of virtually all drug treatments, and contemporary molecular biologic tools continue to identify key genes mediating drug metabolism, transport, and targets. Importantly, common variation in these genes is an increasingly well-recognized contributor, sometimes with large effects, to variation in drug responses. As a result, recommendations for genotype-guided therapy are increasing. These evidence-based recommendations, if implemented in health care practice, could reduce adverse drug events and improve time to therapeutic response. Through eMERGE-PGx, we are developing strategies for the optimal implementation of genetic sequence data into the clinical environment with the ultimate goal of improving patient care. Site and participants include: Children's Hospital of Pennsylvania (CHOP): The Center for Applied Genomics (CAG) at the Children's Hospital of Philadelphia (CHOP) is a high-throughput, highly automated genotyping and sequencing facility equipped with state-of-the-art genotyping and sequencing platforms. Children who are treated at the Children's Hospital Healthcare Network and their parents may be eligible to take part in a major initiative to collect more than 100,000 blood samples, covering a wide range of pediatric diseases. The PGx population selected for sequencing with the PGRNseq panel at CHOP is 1,650 children from CAG's biorepository with well-documented drug-related severe adverse events (SAEs) or EHR-based drug response profiles. SAEs were extracted from EPIC records and from CHOP's Adverse Event (AE) database, which documents every AE at CHOP. These AEs are classified by a medical review panel according to the causal relationship with the suspected drug into 'doubtful', 'possible', and 'probable'. Individuals with events classified as probable, severe and objective, were selected for sequencing. The drugs more frequently associated with adverse events are antibiotics, antineoplastics, immunosuppressants and psychotropic drugs. This cohort constitutes 50% of the target population. The remaining subjects were selected using EHR-based algorithms that we have developed and validated at CAG for identifying patients not responding to ADHD medication (primarily atomoxetine) and patients refractory to antiepileptic treatment from responders. Cincinnati Children's Hospital Medical Center/Boston's Children's Hospital (CCHMC/BCH): 811 CCHMC samples were obtained from children, adolescents or young adults exposed to medication or at risk for needing medication of study interest. 55% of participants were exposed to one or more opioids and their DNA source was a CCHMC study-specific biobank; while 27% of participants were at risk for needing an opioid for surgical pain management and were newly recruited. The remainder of the cohort was exposed to methylphenidate and their DNA samples were obtained from a CCHMC study-specific biobank. The focus of Boston Children's Hospital eMERGE PGx project is on individuals with epilepsy. Samples were taken from a current pharmacogenomics study already in place through which DMET analysis was run and used as confirmation for PGRN-Seq results. A total of 109 samples were sent for PGRN-Seq analysis at University of Washington. The remaining 141 epilepsy samples were from Children's Hospital of Philadelphia and underwent testing with PGRN-Seq at CHOP. Geisinger Health System: A research cohort of adult Geisinger Clinic patients was enrolled from community-based primary care clinics of the Geisinger Health System. Patients were eligible for enrollment if they were a primary care patient of a Geisinger Clinic physician and were scheduled for a non-emergent clinic visit. All data are from Geisinger patients who consent to participate in the MyCode project. MyCode participants agree to provide biological samples for broad research use, including genomic analysis, and for linking of sample data to information in the participant's Geisinger health record. The consent also permits sharing of de-identified data for research purposes. Group Health(GH)/University of Washington (UW): Potential GH participants for the PGx project were enrolled in the eMERGE Network through the Northwest Institute of Genetic Medicine (NWIGM) biorepository, and provided the appropriate consent to receive clinically relevant genetic results (N~6300). Participants were eligible if aged 50 - 65 years old at the time of their enrollment into the NWIGM repository, living, enrolled in GH's integrated group practice, and had completed an online Health Risk Appraisal. The selection algorithm was based on several data sources from the EHR at Group Health: 1. Demographics - participants with self-reported race as Asian or African ancestry were prioritized and selected to enrich for non-European ancestry; 2. Diagnosis and procedure codes - participants were selected if found to have a history of hypertension, atrial fibrillation (AF,) or congestive heart failure (CHF). Participants with a history of arrhythmia were added if the entire selection algorithm did not generate 900 individuals. We also enriched for participants with EHR evidence of actionable indications related to PGRNSeq genes. Participants were selected if found to have an ICD9 code for malignant hyperthermia, hypertension, atrial fibrillation, congestive heart failure or long QT syndrome (LQTS); 3. Laboratory values - if a participant had any laboratory event of creatine kinase (CK) > 1000, and were dispensed statins within 6 months of the event, then they were selected; and 4. Medications - participants were excluded if ever on carbamazepine or had a current regimen of warfarin. Essentia Institute of Rural Health, Marshfield Clinic, Pennsylvania State University (Marshfield): For this study, 750 subjects were selected and enrolled into PGx based on Vanderbilt's algorithm designed to enrich for patients who are most likely to receive one of three common drugs (Clopidogrel, Warfarin or Simvastatin) in the next 2-3 years. These patients were sent a letter of invitation and description of the PGx project. Follow-up phone calls were made, and interested subjects came in for a one time meeting to discuss the project and go through the informed consent with the research coordinator. If they were interested they signed the consent and HIPAA forms and gave blood. Subjects were chosen and enrolled into PGx independently of previous biobank participation. Mayo Clinic: The Right Drug, Right Dose, Right Time - Using Genomic Data to Individualize Treatment (The RIGHT Protocol) enrolled 1013 patients to test the hypothesis that prescribers could deliver genome-guided drug therapy at the point-of-care by using pharmacogenomic data preemptively integrated in the electronic medical record. Complete details regarding the study population have been previously described (Bielinski et al., 2014). Icahn School of Medicine at Mount Sinai School (Mt Sinai): Our study site is the Primary Care Associates (PCA) practice group of the Mount Sinai Faculty Practice Associates (FPA) of the Mount Sinai Medical Center in New York City. This practice has 12 physician providers. All patient encounters are documented and managed with EpicCare ambulatory electronic medical record. Active PCA Patients eligible for enrollment fulfilled the following criteria: a) age 50 or older receiving clinical care at Mount Sinai FPA PCA practice with at least one practice encounter within 18 months prior to commencement of enrollment; b) no history or current use of clopidogrel, warfarin, or simvastatin. Eligible patients were invited to participate through de novo recruitment by letter sent by their provider. Interested patients were screened for eligibility and enrolled to participate in the eMERGE PGX study on site by a dedicated research coordinator. In addition to de novo enrollment from clinical practice, patients of FPA PCA who had previously enrolled in Mount Sinai's BioMe Biobank program AND fulfilled eligibility criteria as stated under a) and b) were identified by chart review and samples sequenced at CIDR using PGRNseq platform (N=300). PGRNseq data from 291 samples passed stringent quality control and are included in the current data set. Furthermore, 56 of these patients carrying known and validated 'actionable' variants affecting prescribing of clopidogrel, warfarin, and/or simvastatin were enrolled in the eMERGE PGX study following invitation through recontacting by the Principal Investigator of the BioMe Program. Northwestern University: Participants for this study were recruited from the General Internal Medicine (GIM) clinic at Northwestern Medical Group (NMG). Patients were selected for invitation to participate if they had been seen a minimum of two times over the last four years, having a high likelihood to receive a prescription for warfarin, Plavix, or a statin, and are seeing a physician who has agreed to allow their patients to be contacted for the study. We utilized an algorithm developed at Vanderbilt and tailored to our population which uses our EHR to estimate the probability that individuals will receive a prescription for warfarin, Plavix, or a statin in the next three years. Participants were sent a letter explaining the study prior to their GIM appointment and offered participation at the time of their visit. Participants were consented on-site and blood drawn after consent was obtained. The GIM clinic consists of 39 primary care physicians who provide approximately 80,000 patient encounters per year. As with any large primary care clinic, a significant proportion of patients in GIM clinic suffer from a variety of chronic health conditions, such as diabetes, hypertension, and coronary artery disease. Over 50,000 individuals have been seen by GIM doctors in the past 5 years; 11,562 of these patients have evidence of a statin prescription in the EHR, 3,436 have evidence of a warfarin prescription, and 1,872 have evidence of a Plavix prescription. Vanderbilt University: The more than 1000 participants enrolled into Vanderbilt's eMERGE PGx study were newly recruited from the Cardiology and Internal Medicine Clinics and the Hillsboro Medical Group within Vanderbilt University Medical Center (VUMC). Patients were selected based on a predictive algorithm estimating the patient's likelihood of receiving Clopidogrel, Warfarin, and/or Simvastatin. The algorithm identifies primarily older middle-aged patients, and the mean age of the study group is 74. The cohort is approximately 45% female with 75% of subjects self-identified as EA and 24% as AA. Subjects were consented in person by study personnel following a routine clinic visit and an introduction to the study staff by their doctor. VUMC is a comprehensive health care facility dedicated to patient care, research, and the education of health care professionals. Translational research into the causes and treatment of disease as well as studying fundamental biological properties is the primary focus of discovery at Vanderbilt. Clinical research is conducted in Vanderbilt University Hospital, the Nashville Veterans Administration Hospital, Meharry General Hospital and in their associated outpatient clinics. These hospitals and clinics, all associated with the Vanderbilt system, each have full time Vanderbilt faculty and medical housestaff and provide clinical care and participate in research programs. The Vanderbilt Clinic is comprised of more than 95 adult outpatient specialty practices and received over 1.5 million ambulatory visits in 2012-13. The Vanderbilt Heart and Vascular Institute offers a comprehensive heart program offering diagnosis, medical treatment, minimally invasive therapies, surgical intervention and disease management, tailored to each individual's unique needs. All programs within the Vanderbilt Clinic have survival figures that surpass the national average.

  Study phs000906

• Genome-wide cell-free DNA termini in patients with cancer

  The structure, fragmentation patterns and terminal sequences of cell-free DNA (cfDNA) are altered by nucleases and biological mechanisms in the blood of cancer patients. The cfDNA fragment-end composition recovered from low coverage WGS (<1 fold coverage) using a bespoke software (FrEIA) is aberrant in the plasma from cancer patient (n = 418, 655 samples) compared to controls (n = 117). As a standalone test FrEIA allows detection down to ~0.2% tumor fraction in vitro and in silico at 95% specificity, leading to a sensitivity of ~71% for detecting lung cancer (14/22 stage I-II, 27/38 stage III, 92/127 stage IV) and ~68% for detecting esophageal adenocarcinoma (26/44 stage II, 46/62 stage III). Additional cfDNA biological patterns can be combined with FrEIA increasing the diagnostic potential of low coverage WGS at minimal cost (mean AUROC = 0.96). Integrating multiple cfDNA biological signal augments the diagnostic performance of liquid biopsy.

  Study EGAS00001006142

• Comparison of Custom Capture for Targeted Next Generation DNA Sequencing

  Targeted, capture-based DNA sequencing is an economical way to sequence a customized region of the genome. Several targeted sequencing kits are available, but the efficacies of these kits have not been compared. We appraised four targeted DNA technologies for next generation sequencing, considering on-target sequencing, uniformity, and single nucleotide variation and copy number variation discovery. The technologies which utilized sonication to fragment genomic material showed impressive uniformity of capture. The other two had shorter preparation times, but sacrificed uniformity. One of those technologies, which needs transposase to fragment genomic material, has a weakness that requires all samples be pooled and the final one, which uses restriction enzyme digestion, is limited depending on restriction enzymes digest sites. Naturally, all technologies showed some concordance for calling SNVs, the kits that used restriction enzymes or transposase missed several SNVs, due, in large part, to lack of coverage. All technologies showed high integrity for copy number variant calling when compared to SNP arrays. This study aids laboratories in their decision of the proper technology to use for their intended applications.

  Study phs000811

• Characterization of Immune Evasion in Merkel Cell Carcinoma

  Merkel cell carcinoma (MCC) is a rare, neuroendocrine skin carcinoma that is caused by the Merkel cell polyomavirus (MCPyV) in 80% of cases and by ultraviolet (UV) damage in 20% of cases. MCC should theoretically elicit a strong cytotoxic T cell response due to the high neoantigen and viral antigen burden in MCPyV- and MCPyV+ MCC, respectively. However, MCC often escapes immune recognition and is associated with very poor prognosis at advanced stages. To systemically identify mechanisms of immune evasion in MCC, we established 11 robust MCC lines from either primary tumors or patient-derived xenografts (7 MCPyV+ and 4 MCPyV-). We then characterized these tumors and cell lines by whole exome sequencing (WES), RNA-sequencing, scRNA-sequencing, ATAC-seq, and whole genome bisulfite sequencing (WGBS). We also studied MCC transcriptional subtypes, utilizing bulk and scRNA-sequencing datasets of patient-derived tumors and cell lines to investigate profiles of neuroendocrine gene expression. The genes linked below define either a neuroendocrine or a non-neuroendocrine phenotype presence within MCC tumors.

  Study phs002260

• Infiltrative and drug-resistant slow-cycling cells support metabolic heterogeneity in glioblastoma

  Metabolic reprogramming has been described in rapidly growing tumors, which are thought to mostly contain fast-cycling cells (FCCs) that have impaired mitochondrial function and rely on aerobic glycolysis. Here, we characterize the metabolic landscape of glioblastoma (GBM) and explore metabolic specificities as targetable vulnerabilities. Our studies highlight the metabolic heterogeneity in GBM, in which FCCs harness aerobic glycolysis, and slow-cycling cells (SCCs) preferentially utilize mitochondrial oxidative phosphorylation for their functions. SCCs display enhanced invasion and chemoresistance, suggesting their important role in tumor recurrence. SCCs also demonstrate increased lipid contents that are specifically metabolized under glucose-deprived conditions. Increased fatty acid transport in SCCs is targetable by pharmacological inhibition or genomic deletion of FABP7, both of which sensitize SCCs to metabolic stress. Furthermore, FABP7 inhibition, whether alone or in combination with glycolysis inhibition, leads to overall increased survival. Our studies reveal the existence of GBM cell subpopulations with distinct metabolic requirements and suggest that FABP7 is central to lipid metabolism in SCCs and that targeting FABP7-related metabolic pathways is a viable therapeutic strategy.

  Study EGAS00001003251

• Wisconsin Longitudinal Study on Aging

  The Wisconsin Longitudinal Study (WLS) is a long-term study of a random sample of men and women, who graduated from Wisconsin high schools in 1957, and their siblings. The WLS panel started out with a panel of 10,317 members from the class of 1957. Over time a second panel of 8,734 randomly selected siblings of the original graduate panel were recruited for the study. Of these combined panel members, 9,027 survived and contributed saliva for genetic analysis. Survey data were collected from the original respondents or their parents in 1957, 1964, 1975, 1992, 2004, and 2011, and from a selected sibling in 1977, 1994, 2005, and 2011. WLS data provide a detailed record of educational, social, psychological, economic, mental and physical health characteristics of a relatively homogeneous population that is almost entirely of Northern and Western European ancestry. Saliva was first collected in 2007-2008 by mail. Additional samples were collected in the course of home interviews that began in March 2010.

  Study phs001157

• Targeted de-methylation of the FOXP3-TSDR

  CD4+ regulatory T cells (Tregs) are key mediators of immunological tolerance and promising effector cells for immuno-suppressive adoptive cellular therapy to fight autoimmunity and chronic inflammation. Their functional stability is critical for their clinical utility and has been correlated to the demethylated state of the TSDR/CNS2 enhancer element in the Treg lineage transcription factor FOXP3. However, proof for a causal contribution of the TSDR de-methylation to FOXP3 stability and Treg induction is so far lacking. We here established a powerful transient-transfection CRISPR-Cas9-based epigenetic-editing method for the selective de-methylation of the TSDR within the endogenous chromatin environment of a living cell. The induced de-methylated state was stable over weeks in clonal T cell proliferation cultures even after expression of the editing complex had ceased. Epigenetic editing of the TSDR resulted in FOXP3 expression, even in its physiological isoform distribution, proving a causal role for the de-methylated TSDR in FOXP3 regulation. However, successful FOXP3 induction was not associated with a switch towards a functional Treg phenotype, in contrast to what has been reported from FOXP3 overexpression approaches. Thus, TSDR de-methylation is required, but not sufficient for a stable Treg phenotype induction. Therefore, targeted demethylation of the TSDR may be a critical addition to published in vitro Treg induction protocols which so far lack FOXP3 stability.

  Study EGAS00001004867

• Genome analysis of oesophageal cancer and Barrett's oesophagus

  The median survival of oesophageal cancer this year is only 13 to 19 months after diagnosis and more than 90% will die from their disease. Therefore better treatment options are needed. The likelihood of cure for early screen-detected cancers is much higher. Barrett's oesophagus is a pre-cancerous lesion associated with a 30-40 fold increased risk of developing cancer. In an attempt to detect cancer early many patients with Barrett's are enrolled into surveillance programs involving regular endoscopies. A major problem with this approach is that the prevalence of BO in the population is estimated to be around 2%, but most patients with BO will never develop cancer. We are undertaking genomic and/or transcriptomic analysis of oesophageal tumours, Barrett's oesophagus and matched normal samples. The aim is to identify oesophageal-related genomic and transcriptomic alterations, which may reveal mutational process occurring, suggest biomarkers of tumour progression and treatment and identify novel treatment strategies.

  Study EGAS00001002864

• Diabetes Multi-Omic Investigation of Drug Response (DIAMOND)

  The Diabetes Multi-omic Investigation of Drug Response (DIAMOND) cohort is a population-based cohort of individuals with type-2 diabetes (T2D) who receive their care through a large health system serving southeast Michigan and metropolitan Detroit. The cohort represents the diversity of the population from which it was created. Because of their health plan membership, participants have a rich dataset of longitudinal clinical health information related to their care. The intent of the DIAMOND study is to use genomic profiling, drug exposure information, and electronic health record (EHR) derived outcome data to identify genetic predictors of treatment response. Genome-wide genotyping was performed using the AxiomTM Precision Medicine Research Array (ThermoFisher Scientific Inc.).

  Study phs003350

• ATAC-seq

  ATAC-seq data for 26 CLL samples (7 controls, 19 tumor) of the CancerEpiSys-PRECiSe project.

  Dataset EGAD00001005967

• MutWP1: CRUK Grand Challenge Mutographs of Cancer: kidney (2019-03-26)

  This dataset contains all the data available for this study on 2019-03-26.

  Dataset EGAD00001004867

• Genetic defects in familial renal disorders

  Several different genes cause, when mutated, increased urinary phosphate excretion and hypophosphatemia leading to rickets/osteomalacia; however, the majority of phosphate-wasting disorders has not yet been defined at the molecular level. Identification of phosphate-regulating genes has provided important novel insights into the mechanism contributing to phosphate homeostasis, which remains incompletely understood. We therefore pursue exome-wide nucleotide sequence analysis to define the underlying mutations, which is expected to provide novel insights into the regulation of this important mineral. Virtually nothing is known about the genetic mutations that cause non-syndromic structural abnormalities involving the urinary tract, which represent about 50% of the causes of end-stage renal disease (ESRD). The completion of the human genome project and the technological advances that allow low cost whole exome sequencing have now made it feasible to readily search for the cause of different inherited disorders in humans, particularly if clinical information and genomic DNA is available from larger kindreds with multiple affected members that can be used for mapping the disease-causing genetic locus. Furthermore, catalogs were generated that document the expression profiles of numerous genes during embryonic, fetal, and postnatal development, thereby supporting the exploration of kidney involvement in animal models of different diseases and in human genetic syndromes. We therefore plan to define the mechanisms leading to inherited disorders of the urogenital tract and the kidneys by establishing the causative genetic defects through a combination of genetic mapping and whole exome sequencing. Hajdu-Cheney Syndrome (HCS) is a rare autosomal-dominant skeletal disorder characterized by severe osteoporosis, acroosteolysis of the distal phalanges, renal cysts and other abnormalities. Our goal is to identify the genetic cause of HCS using exome sequencing. Opsismodysplasia is a very rare recessive spondylometaphyseal dysplasia characterized by delayed epiphyseal ossification, shortness of bones and sometimes low serum phosphate levels. Discovery of the causing mutation will give us insights into the pathogenesis of this often lethal disease.

  Study phs000477

• Healthy_ageing_thymus

  Single cell RNA sequencing of immune and non-immune cells from healthy ageing thymus Thymus is a primary lymphoid organ that creates an environment for the T lymphocyte precursors differentiation into the naive T cells, which involves TCR gene rearrangement, negative and positive selection. Despite thymus critical function for the recognition of the pathogens it starts to atrophy very early in life. Thymic Epithelial Space (TES), where thymocyte education occurs, starts to decline rapidly just after birth, while with the onset of puberty thymus is also progressively replaced with adipose tissue. This leads to a reduced naive T cell output,which decreases an organism's ability to recognize pathogens. In our lab, we have already collected and characterized cell type composition and gene regulatory networks of the fetal tand adult human thymus (Park et al, Science 2020). In the current project we plan to expand the number of paediatric and adult samples in the study with the aim to understand how the process of thymic involution happens. We will use single-cell transcriptomics to zoom on changes that occur in immune and non-immune cell types in different phases of thymic involution with the hope to understand which gene expression changes are causal for the thymic involution process and how naïve T cell production can be increased in elderly. 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 EGAS00001004311

• Validation of a Haloplex platform for targeted re-sequencing of the exons of 25 genes

  We recently used the Agilent SureSelect platform to re-sequence a set of genes known to be mutated in human AML. The results from 10 AML DNA samples were very satisfactory, but the effort required was significant. Thus, we decided to re-sequence the same genes using the Haloplax system for target enrichment in 48 AML samples. We planned to do this using MiSeq and have data from a pilot of 3 samples. The data is promising but coverage appears pathcy so far. However, in order to get a better understanding of the data we will need deeper sequencing. We will need two lanes of HiSeq to get the same degree coverage as Sureselect. his 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/

  Dataset EGAD00001000603

• Profiling the unique protective properties of intracranial arterial endothelial cells

  Cardiovascular disorders, like atherosclerosis and hypertension, are increasingly known to be associated with vascular cognitive impairment (VCI). In particular, intracranial atherosclerosis is one of the main causes of VCI, although plaque development occurs later in time and is structurally different compared to atherosclerosis in extracranial arteries. Recent data suggest that endothelial cells (ECs) that line the intracranial arteries may exert anti-atherosclerotic effects due to yet unidentified pathways. To gain insights into underlying mechanisms, we isolated post-mortem endothelial cells from both the intracranial basilar artery (BA) and the extracranial common carotid artery (CCA) from the same individual (total of 15 individuals) with laser capture microdissection. RNA sequencing revealed a distinct molecular signature of the two endothelial cell populations of which the most prominent ones were validated by means of qPCR. Our data reveal for the first time that intracranial artery ECs exert an immune quiescent phenotype. Secondly, genes known to be involved in the response of ECs to damage (inflammation, differentiation, adhesion, proliferation, permeability and oxidative stress) are differentially expressed in intracranial ECs compared to extracranial ECs. Finally, Desmoplakin (DSP) and Hop Homeobox (HOPX), two genes expressed at a higher level in intracranial ECs, and Sodium Voltage-Gated Channel Beta Subunit 3 (SCN3B), a gene expressed at a lower level in intracranial ECs compared to extracranial ECs, were shown to be responsive to shear stress and/or hypoxia. With our data we present a set of intracranial-specific endothelial genes that may contribute to its protective phenotype, thereby supporting proper perfusion and consequently may preserve cognitive function. Deciphering the molecular regulation of the vascular bed in the brain may lead to the identification of novel potential intervention strategies to halt vascular associated disorders, such as atherosclerosis and vascular cognitive dysfunction.

  Study EGAS00001004479

• The Prediction and Prevention of Preeclampsia

  The Prediction and Prevention of Preeclampsia (PREDO) is a prospective birth cohort study of Finnish women who were pregnant between 2005 and 2010 and their children. The PREDO study cohort was set up to identify novel risk factors and biomarkers in pregnant women associated with the development of preeclampsia and intrauterine growth restriction (IUGR). Two groups of pregnant women were enrolled during the first trimester of their pregnancy: first, pregnant women with a known clinical risk factor status for preeclampsia and IUGR (N=1079; 969 of these women had at least one and 110 had none of the known risk factors for preeclampsia and IUGR), and second, pregnant women who volunteered to participate regardless of their risk factor status for preeclampsia and IUGR (N=3698). Both samples were monitored during pregnancy with four clinical visits and bi-weekly self-reports. The post-delivery follow-up has taken place at approximately 2 weeks, 6 months, and 3.5 years after the delivery. The most recent follow-up started in 2016 and is ongoing. In the high-risk sample, cord blood samples were collected and genome-wide genotyping has been conducted with Illumina OmniExpressExome 1.2 and genome-wide methylation status has been analysed with Illumina 450k HM array.

  Study EGAS00001001898

• Ecological Stressors, PTSD, and Drug Use in Detroit: The Detroit Neighborhood Health Study (DNHS)

  The Detroit Neighborhood Health Study (DNHS) is a prospective, representative longitudinal cohort study of predominantly African American adults living in Detroit, Michigan. The overall goal of the DNHS is to identify how genetic variation, lifetime experience of stressful and traumatic events, and features of the neighborhood environment predict psychopathology and behavior. Cohort participants were selected with a dual-frame probability design, using telephone numbers obtained from the U.S. Postal Service Delivery Sequence Files as well as a listed-assisted random-digit-dial frame. Individuals without listed landlines or telephones and individuals with only a cell phone listed were invited to participate through a postal mail effort. Participants completed a 40 minute, structured telephone interview annually between 2008-2012 to assess perceptions of participants' neighborhoods, mental and physical health status, social support, exposure to traumatic events, and alcohol and tobacco use; each participant was compensated $25USD. All survey participants were offered the opportunity to provide a specimen (venipuncture, blood spot, or saliva) for immune and inflammatory marker testing as well as genetic testing of DNA. Participants received an additional $25USD if they elected to give a sample. Informed consent was obtained at the beginning of each interview and again at specimen collection. The Institutional Review Board of the University of Michigan reviewed and approved the study protocol. The DNHS submission to dbGaP includes phenotype data from all five survey waves (n=856), all available GWAS data for participants who completed wave 4 (n=507), and methylation data for wave 1, wave 2, wave 4, and wave 5 participants (n = 456).

  Study phs000560

• Comprehensive molecular and clinicopathological profiling of glioma

  Various molecular profiles are needed to classify malignant brain tumors, including gliomas, based on the latest classification criteria of the World Health Organization, and their poor prognosis necessitates new therapeutic targets. The Todai OncoPanel 2 RNA Panel (TOP2-RNA) is a custom-target RNA-sequencing (RNA-seq) using the junction capture method to maximize the sensitivity of detecting 455 fusion gene transcripts and analyze the expression profiles of 1,390 genes. This study aimed to classify gliomas and identify their molecular targets using TOP2-RNA. A total of 124 frozen samples of malignant gliomas were subjected to TOP2-RNA for classification based on their molecular profiles and the identification of molecular targets.

  Study JGAS000671

• CancerLocator: Non-Invasive Cancer Diagnosis and Tissue-of-Origin Prediction Using Methylation Profiles of Cell-Free DNA

  Background: The detection and characterization of cell-free DNA in plasma is one of the most promising new areas in cancer diagnosis. Liquid biopsy, unlike traditional tissue biopsy, has the potential to diagnose a variety of different malignancies. Results: Here we propose a probabilistic method, CancerLocator, which exploits the diagnostic potential of cell-free DNA by determining not only the presence but also the location of tumors. CancerLocator simultaneously infers the proportions and the tissue-of-origin of tumor-derived cell-free DNA in a blood sample using genome-wide DNA methylation data. We comprehensively evaluate CancerLocator with simulations and real data, and compare its performance with that of two established multi-class classification methods. We show that the predicted tumor burdens are highly consistent with the true values. In addition, when the proportion of tumor-derived DNAs in the cell-free DNAs is low, the two popular machine learning methods completely fail for cancer diagnosis, while CancerLocator successfully overcomes the challenge. CancerLocator also achieves promising results on patient plasma samples, despite the fact that the DNA methylation data from these samples has very low sequencing coverage. Conclusions: CfDNA methylation may be developed as an important approach for non-invasive early cancer diagnosis.

  Study EGAS00001002211

• The Gene Partnership (TGP) - eMERGE Data

  The Gene Partnership (TGP) is a prospective longitudinal registry at Boston Children's Hospital (BCH) to study the genetic and environmental contributions to childhood health and disease, collect genetic information on a large number of children who have been phenotyped, and implement the Informed Cohort and the Informed Cohort Oversight Board (ICOB). The term "The Gene Partnership" reflects a partnership between researchers and participants. Children seen at BCH are offered enrollment, as are their parents and siblings. DNA is collected on all enrollees. BCH has a comprehensive EMR system, and virtually all inpatient and outpatient data are captured electronically. Clinical data in the BCH EMR is loaded in the i2b2 data warehouse which is available to investigators. Cases, phenotypes, and covariates are ascertained using the i2b2 database. Participants at BCH in TGP have consented to receive any research result and/or incidental finding that arises from studies using TGP that is approved by the Informed Cohort Oversight Board (ICOB) and is in accordance with the participants' preferences; results are returned through the Personally Controlled Health Record (PCHR). BCH and Cincinnati Children's Hospital Medical Center (CCHMC) have partnered as the Pediatric Alliance for Genomic and Electronic Medical Record (EMR) Research (PAGER) site for the eMERGE Phase II network for pediatric institutions, and the cohort for eMERGE at BCH is TGP.

  Study phs000495

• Relaxed selection during a recent human expansion

  To better understand and quantify the effect of a recent expansion process on the amount and pattern of mutation load, we screened the ascending genealogies of 3916 individuals from the CARTaGENE cohort (Awadalla et al. 2013) that were linked to the BALSAC genealogical database (http://balsac.uqac.ca/). Using stringent criteria on the quality of genealogical information, we selected (front) individuals whose ancestors were as close as possible to the front of the colonization of Quebec, and (core) individuals whose ancestors were as far as possible from the front. We then sequenced these 102 individuals at very high coverage (mean 89.5X, range 67X-128X) for 106.5 Mb of exomic and UTR regions and contrasted their genomic diversity to detect if sites with various degrees of conservation and deleteriousness had been differentially impacted by selection.

  Study EGAS00001001957