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• Genomics of Kidney Transplantation

  We have an established consortium consisting of 5 clinical centers which do a total of >800 kidney transplants/year. We have developed a quality-controlled multicenter database with high quality data, and obtained DNA samples and clinical data on 962 recipients and 442 donors. Using our developed infrastructure, we propose to study whether genetic variants are, in part, responsible for the differing outcomes of transplant recipients treated with contemporary immunosuppressive protocols. Our central hypotheses are that the genetic variation is associated with a) kidney transplant outcome, and b) immunosuppressive drug disposition and toxicity. Our long-term goals are to determine whether it is possible to individualize immunosuppressive therapy, based on genetics. At the same time, our studies may elicit new information on pathways important in the immune response or in immunosuppressive drug efficacy, disposition, and toxicity.Our application consists of 3 cores (Genetics Core, Clinical Core, and Administrative Core). We will do a genome wide association study (GWAS). Significant single nucleotide polymorphisms (SNPs) will be identified using the GWAS.Project 1 has 2 specific aims.Aim 1: To identify recipient SNPs that are associated with kidney allograft outcomes, including acute rejection, chronic graft dysfunction, and graft failure. Aim 2: To identify living donor SNPs that are associated with kidney allograft outcomes. Project 2 has 4 specific aims. Aim 1: To identify SNPs that are associated with tacrolimus blood levels.Aim 2: To identify SNPs that are associated with early tacrolimus-related nephrotoxicity and immune suppressant-related new onset diabetes.Aim 3: To identify SNPs that are associated with mycophenolate-related toxicity. Aim 4: To establish the relationships between candidate recipient SNPs, enzyme activity and mRNA expression of the pharmacologic targets of mycophenolate and calcineurin inhibitors. The projects use the genotyping data, which were provided by the Genetics Core, and clinical information, which were collected and entered into the multicenter database by the Clinical Core. Further, biostatistical support (Clinical Core) and administrative oversight and support (Administrative Core) will facilitate data collection, data entry, and data analyses for both projects. The Administrative Core will also facilitate interaction between Sites, Cores, and Projects.Technical note: Regarding to the study design, all transplant recipients should be unrelated. Given the nature of transplantation, some donors may be related to recipients. The donor-recipient relationships are reported in the demographic file under the "related" column. As we did not collect full pedigree information for the related donor-recipient pairs, we have included a IBD file (calculated using PLINK) with the genotype data.

  Study phs001667

• RNA sequencing on colonic biopsies from inflammatory bowel disease patients treated with vehicle control, MEK inhibitor, or infliximab

  This dataset consists of RNA sequencing data (FASTQs) from intestinal mucosal biopsies from 9 IBD patients. All patients endoscopically active disease and were not receiving immunosuppressive or biologic therapies. All biopsies (6 per donor) were collected from a single inflamed site. Biopsies were cultured for 18 hours at an air-liquid interface in media containing either DMSO (vehicle control), PD-0325901 (0.5uM) or infliximab (10ug/ml; MSD) - two biopsies per condition. Sequencing was performed on a NovaSeq 6000 (100bp, PE reads). After 18 hours, biopsies were harvested and snap frozen. After lysis, RNA was extracted using an AllPrep DNA/RNA Mini Kit (Qiagen). Sequencing libraries were prepared from 10ng RNA using the SMARTer Stranded Total RNA-Seq Kit v2 - Pico Input Mammalian (Takara) following the manufacturer’s instructions. The quality and molarity of all libraries was assessed using a BioAnalyzer 2100 and the libraries were sequenced on a NovaSeq 6000 (100bp, PE reads).

  Dataset EGAD00001011333

• NHLBI Recipient Epidemiology Donor Evaluation Study (REDS)-III - Brazil Sickle Cell Disease Cohort (REDS-BSCDC)

  The Recipient Epidemiology and Donor Evaluation Study (REDS)-III program established a Brazilian Sickle Cell Disease (SCD) Cohort to identify molecular determinants of response to transfusions, alloimmunization and risk factors associated with HIV infection. The Brazil population presents a complex admixture of African, European, Asian and Indigenous heritage and will provide insights into genetic, demographic, social, and healthcare system determinates of SCD outcomes. The REDS-III Brazil SCD cohort began in the Fall of 2013 and aimed to: Establish a cohort of SCD patients with a comprehensive centralized electronic database of detailed clinical, laboratory and transfusion information, as well as establish a repository of blood samples to support biological studies relevant to SCD pathogenesis and transfusion complications; Characterize changes in markers of inflammation in response to transfusion by analyzing chemokine/cytokine panels in serial post transfusion specimens; Identify single nucleotide polymorphisms (SNPs) that contribute to the risk of red blood cell alloimmunization in SCD by performing a genome-wide association (GWA) study in transfused SCD patients; Characterize risk of HIV and HIV outcomes in the Brazilian SCD population and compare SCD outcomes among HIV sero-positive and sero-negative SCD patients.

  Study phs001972

• Functional single-cell characterization of immune aplastic anemia shows convergence of NK and NK-like CD8+ T cells with disease-associated TCR signature

  Immune aplastic anemia (AA) is a life-threatening bone marrow (BM) failure disorder driven by an autoimmune T cell attack against the hematopoietic stem and progenitor cells (HSPCs). However, the autoantigen targets and the role of other immune cells are unknown. Here, by analyzing an international cohort of 156 AA patients with scRNA+TCRαβ-seq, TCRβ-seq, flow cytometry, and plasma cytokine profiling with comparisons to healthy controls and patients with other hematological disorders, we identify NK cells and CD8+ TEMRA cells expressing NK receptors with AA-associated TCRβ-seq motifs as the most dysregulated immune cell populations in AA BM. Functional co-culture experiments with scRNA-TCRαβ-seq readout utilizing primary HSPCs and immune cells provide evidence that NK cellscannot kill HSPCs alone, but sensitize them to CD8+ T cell-mediated killing. Furthermore, HSPCs induce strong activation of T cell clones with CD8+ TEMRA NK-like phenotype and AA-associated TCR motifs. Our results reveal the convergent evolution of innate and adaptive immune cells in AA, where NK cells support CD8+ T cell-mediated autoimmunity.

  Study EGAS00001007602

• RNA-sequencing of tumors from 45 patients with recurrent or metastatic gastric cancer treated with immune checkpoint inhibitors

  Genomic profiling can provide prognostic and predictive information to guide clinical care. Biomarkers that reliably predict patient response to chemotherapy and immune checkpoint inhibition in gastric cancer are lacking. In this work, we used our machine learning algorithm NTriPath to identify a gastric-cancer specific 32-gene signature. Using unsupervised clustering on expression levels of these 32 genes in tumors from 567 patients, we identified four molecular subtypes that were prognostic for survival. We then built a support vector machine with linear kernel and the binary classifier to generate a risk score that is prognostic for 5-year overall survival and validated the risk score using three independent datasets. We also found that the molecular subtypes predicted response to adjuvant 5-fluorouracil and platinum after gastrectomy and immune checkpoint inhibitors in patients with metastatic or recurrent disease. The 32-gene signature is a promising prognostic and predictive biomarker to guide the clinical care of gastric cancer patients and should be validated in a prospective manner. This EGA archive includes both St.Mary hospital cohort samples (n=28) and Yonsei immunotherapy patient samples (n=17).

  Study EGAS00001005588

• Spatial_transcriptome_analysis_of_Paediatric_Thymus

  Cell atlas of Paediatric Thymus Cell atlas of Paediatric Thymus - The Human Cell Atlas initiative is an ambitious global research effort which aims to describe every cell in the human body across all developmental stages to generate a reference map to accelerate progress in science and medicine particularly relating to human development and disease. The initiative is led by investigators based at the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard and funding support from the Wellcome and NIH. We aim to interrogate the cellular composition and molecular regulators underpinning a cells identity through; genetic and genomic analysis, expression analysis, non-identifiable video imaging and cell line and organoid production, as well as, computational algorithms to predict cellular developmental trajectories and cell-cell interactions. We will subsequently validate these findings in situ using spatial genomic and imaging technologies e.g. immunohistochemistry, RNAscope, in situ sequencing and spatial transcriptomic analyses. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001004281

• Functional single-cell characterization of immune aplastic anemia shows convergence of NK and NK-like CD8+ T cells with disease-associated TCR signature

  Immune aplastic anemia (AA) is a life-threatening bone marrow (BM) failure disorder driven by an autoimmune T cell attack against the hematopoietic stem and progenitor cells (HSPCs). However, the autoantigen targets and the role of other immune cells are unknown. Here, by analyzing an international cohort of 156 AA patients with scRNA+TCRαβ-seq, TCRβ-seq, flow cytometry, and plasma cytokine profiling with comparisons to healthy controls and patients with other hematological disorders, we identify NK cells and CD8+ TEMRA cells expressing NK receptors with AA-associated TCRβ-seq motifs as the most dysregulated immune cell populations in AA BM. Functional co-culture experiments with scRNA-TCRαβ-seq readout utilizing primary HSPCs and immune cells provide evidence that NK cellscannot kill HSPCs alone, but sensitize them to CD8+ T cell-mediated killing. Furthermore, HSPCs induce strong activation of T cell clones with CD8+ TEMRA NK-like phenotype and AA-associated TCR motifs. Our results reveal the convergent evolution of innate and adaptive immune cells in AA, where NK cells support CD8+ T cell-mediated autoimmunity.

  Study EGAS00001007604

• The Egyptian Collaborative Cardiac Genomics (ECCO-GEN) Project: Defining a Healthy Volunteer Cohort

  The integration of comprehensive genomic and phenotypic data from diverse ethnic populations offers unprecedented opportunities towards advancements in precision medicine and novel diagnostic technologies. Current reference genomic databases are not representative of the global human population, making variant interpretation challenging, especially in underrepresented populations such as the North African population. To address this, the Egyptian Collaborative Cardiac Genomics (ECCO-GEN) Project launched a study comprising 1000 individuals free of cardiovascular disease (CVD). Here, we present the first 391 Egyptian healthy volunteers (EHVols) recruited to establish a pilot phenotyped control cohort. All individuals underwent detailed clinical investigation, including cardiac MRI, and were sequenced using a targeted panel of 174 genes with reported roles in inherited cardiac conditions (ICC). We identified 1,262 variants in 27 cardiomyopathy genes of which 15.1% were not captured in current global and regional genetic reference databases (here: gnomAD and Great Middle Eastern (GME) Variome). The ECCO-GEN project aims at defining the genetic landscape of an understudied population and providing individual-level genetic and phenotypic data to support future studies in CVD and population genetics.

  Study EGAS00001004434

• Patient-derived neuroblastoma model system OHC-NB1

  Accurate disease modeling presents a bottleneck against effective translation of novel neuroblastoma therapies into the clinic. Recently, considerable intra-tumor genetic heterogeneity has been observed in neuroblastoma, which calls for preclinical models that reflect this feature. Flexibility in a testing platform is also desirable to support assessment of different endpoints and tumor cell characteristics. We present the novel neuroblastoma model OHC-NB1, propagated from a bone marrow metastasis from a patient with INRG stage M, MYCN-amplified neuroblastoma at first diagnosis. To model different aspects of the disease, several preclinical models were developed from the bone marrow aspirate: a tissue plastic-adherent cell line, a 3-dimensional (3D) spheroid culture, and cell line-derived xenografts that were subcutaneously passaged in mice. Typical aspects of MYCN-amplified neuroblastoma, such as MYCN amplification in double minutes, 1p deletion, 17q gain, and a diploid karyotype, are present in OHC-NB1 and persist in all culture types. Whole exome sequencing revealed intra-tumor heterogeneity in the bone marrow metastasis reflected in the culture models. The set of OHC-NB1 cultures with a genetically heterogeneous MYCN-amplified neuroblastoma background provide a flexible preclinical testing system that recapitulates important features of metastatic neuroblastoma.

  Study EGAS00001003031

• Accurate detection of tumor-specific fusion genes reveals strongly immunogenic personal neo-antigens

  Fusion genes arising from cancer-associated somatic mutations are a potential rich source for highly immunogenic neo-antigens. However, their exploitation as targets for personalized cancer immunotherapy is currently limited by the lack of computational tools allowing transcriptome-wide identification of unique fusion genes in an accurate and sensitive manner. Here, we present EasyFuse, a computational pipeline, to detect individual and cancer-specific fusion genes in next-generation-sequencing transcriptome data obtained from human cancer samples. Using machine learning, EasyFuse predicts personal fusion genes with high precision and sensitivity and outperforms previously described approaches as qualified by an unprecedented ground-truth dataset of >1500 verification experiments in relevant patient samples. By testing immunogenicity with autologous blood lymphocytes from cancer patients we detected pre-established CD4+ and CD8+ T cell responses for 10 of 21 (48%), and for 1 of 30 (3%) of identified fusion genes, respectively. In conclusion, we demonstrate accurate detection of cancer-specific fusion genes. The high frequency of T cell responses detected in cancer patients support the relevance of private fusion genes as neo-antigens for personalized immunotherapies, especially for tumors with low point mutation burdens.

  Study EGAS00001004877

• T2D-GENES Project 2: San Antonio Mexican American Family Studies

  The Type 2 Diabetes (T2D) Genetic Exploration by Next-generation sequencing in Ethnic Samples (T2D-GENES) Consortium is a collaborative international effort to identify genes influencing susceptibility to T2D in multiple ethnic groups using next generation sequencing. T2D-GENES Project 2 is a complex pedigree-based study designed to identify low frequency or rare variants influencing susceptibility to T2D, using whole genome sequence (WGS) information from 1,043 individuals in 20 Mexican American T2D-enriched pedigrees from San Antonio, Texas. The major objectives of this study are to identify low frequency or rare variants in and around known common variant signals for T2D, as well as to find novel low frequency or rare variants influencing susceptibility to T2D. The sampled individuals are obtained from two studies: the San Antonio Family Heart Study (SAFHS) and the San Antonio Family Diabetes/Gallbladder Study (SAFDGS), collectively referred to as the San Antonio Mexican American Family Studies (SAMAFS). The strategy is to sequence approximately 600 individuals at an average of 50x coverage across the entire genome, then impute genome wide genotypes for about 440 additional family members. The 600 sequenced individuals are specifically chosen for their value in imputing sequence information into other family members. By studying large pedigrees, we expect to find multiple individuals carrying each genetic variant, even if this variant is very rare in the population at large. Thus, a pedigree-based approach provides an excellent opportunity for identifying rare novel variants influencing risk of T2D and quantitative variation in T2D-related phenotypes. The whole genome sequencing has been done commercially by Complete Genomics, Inc. (CGI). The final data set includes whole genome sequence data for 607 individuals. After quality control, 585 sequenced individuals provide data for family based imputation, using Merlin linkage analysis software, into approximately 440 additional family members for whom chip based genotypes are available to indicate which parental haplotype is transmitted. Extensive phenotype data is provided for 1048 individuals. These include 5 sequenced individuals who do not belong to any of the 20 large pedigrees. Phenotype information was collected between 1991 and 2011 in the two contributing longitudinal studies. SAFHS participants may have information from up to 5 visits, and SAFDGS participants may have up to 4 visits. The clinical variables reported are coordinated with T2D-GENES Project 1 (multi-ethnic exome sequencing) and include T2D status and age at diagnosis, glycemic traits (fasting and 2 hour glucose and insulin), blood pressure, blood lipids (total cholesterol, HDL cholesterol, calculated LDL cholesterol and triglycerides), clinical chemistry (cystatin c, glutamic acid decarboxylase antibody titer (GadAb), creatinine, adiponectin and leptin). Glycated hemoglobin (HbA1c) was not measured for these individuals and insulin C-peptide is not included in this data set. Additional phenotype data include the medication status at each visit, classified in four categories as any current use of diabetes, hypertension or lipid-lowering medications, and, for females, current use of female hormones. Anthropometric measurements include age, sex, height, weight, hip circumference, waist circumference and derived ratios. Each phenotype variable has an initial summary column containing the most recent non-missing measurement for each individual, followed by the five potential time points for each individual, the number of non-missing measurements, and the age and year for the most recent non-missing measurement. For historical reasons, the order in which variables are presented on the dbGaP web site differs from their order in the data download file. When reading the comment fields for each variable, please note that commas are omitted to support data exchange in .csv format.

  Study phs000462

• Resuscitation Outcomes Consortium (ROC) Amiodarone, Lidocaine or Neither for Out-Of-Hospital Cardiac Arrest Due to Ventricular Fibrillation or Ventricular Tachycardia (ALPS)(ROC-ALPS-BioLINCC)

  Accessing Data Please refer to “Authorized Access” below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP. Objective To compare the effects of amiodarone, lidocaine, and placebo on survival to hospital discharge after out-of-hospital cardiac arrest due to shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. Background Ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) are common causes of out-of-hospital cardiac arrest, but are considered the most responsive to shock and therefore the most treatable. Nonetheless, most defibrillation attempts do not result in sustained return of spontaneous circulation, and VF or VT may persist or recur after shock. There is also evidence that longer durations of VF or VT are associated with decreases in the likelihood of resuscitation. Amiodarone and lidocaine are commonly used to promote successful defibrillation of shock-refractory VF or VT and prevent recurrences. Previous trials have shown amiodarone to be more effective than placebo or lidocaine for return of spontaneous circulation and survival at hospital admittance. This study sought to further extend the research and examine whether amiodarone would improve survival to hospital discharge and neurologic outcomes, as compared to placebo or lidocaine. Participants 3,026 eligible participants were enrolled, with 974 assigned to amiodarone, 993 assigned to lidocaine, and 1,059 assigned to placebo. An additional 1,627 participants that received a study intervention, but did not meet eligibility criteria, were included in analysis of the intention-to-treat population. Design The study interventions (amiodarone, lidocaine, and saline) were packaged in indistinguishable sealed kits and randomly distributed in to Emergency Medical Services (EMS) providers in a 1:1:1 ratio, stratified by participating site and agency. Each kit contained three syringes, and each syringe held 3 ml of colorless fluid containing 150 mg of amiodarone, 60 mg of lidocaine, or normal saline. Participants with out-of-hospital cardiac arrest were treated in accordance with local EMS protocols, in compliance with American Heart Association (AHA) guidelines. If VF or VT persisted or recurred after one or more shocks, eligible participants received a vasopressor and the masked kit containing amiodarone, lidocaine, or placebo. Approximating current clinical practice, the initial dose consisted of two syringes administered by rapid bolus. If the estimated body weight of the patient was less than 100 lbs., then one syringe was used. If VF or VT persisted, standard resuscitation measures, additional shocks, and an additional syringe of the study drug were administered. At that point the trial interventions were completed and standard interventions for advanced life support were employed. Upon arrival at the hospital, providers were notified of the patient's enrollment in the trial and encouraged to provide usual care in accordance with AHA guidelines, including open-label amiodarone or lidocaine if necessary. Components of hospital care were monitored but not standardized by the trial protocol. Participants, providers, and trial personnel were blinded to the trial drug assignments, with the exception of treating physicians if emergency un-blinding was required for care. Data from pre-hospital patient care records, CPR process measures, and hospital medical records were collected. The primary outcome of the trial was survival to hospital discharge, and the secondary outcome was survival with favorable neurologic status at discharge, defined as a score on the modified Rankin scale of 3 or less. Conclusions Neither amiodarone nor lidocaine resulted in a significantly higher rate of survival to hospital discharge or favorable neurologic outcome, as compared to placebo, among participants with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia.

  Study phs003784

• Single nuclei ATAC-Seq data from the human ganglionic eminences

  Data generated through single nuclei ATAC sequencing on whole ganglionic eminences from 3 human fetuses (two of 16 and one of 17 gestational weeks). Tissue was acquired from the MRC-Wellcome Trust Human Developmental Biology Resource with ethical approval. snATAC-Seq libraries were prepared from ~8,000 nuclei per sample using Chromium Next GEM Single Cell ATAC (v1.1) reagents (10X Genomics). Quality control of libraries was performed using the Agilent 5200 Fragment Analyzer before sequencing on an Illumina NovaSeq 6000 to a depth of at least 617 million read pairs per library. Raw sequencing data were converted into FASTQ files. For a full description of data generation, please see Cameron et al, Schizophrenia Bulletin 2024, https://doi.org/10.1093/schbul/sbae083. Please note that 10X generated BAM files, rather than FASTQ files, have been uploded. FASTQ files can be regenerated using the 10X Genomics bamtofastq tool. https://support.10xgenomics.com/docs/bamtofastq

  Dataset EGAD50000000601

• Single-cell RNA-sequencing of rhabdomyosarcoma tumour tissue (2025-09-30)

  This study investigates high-risk rhabdomyosarcoma (RMS) using multiple single-cell and spatial genomic technologies. We generated and analysed single-cell and single-nucleus RNA-sequencing, chromatin accessibility, and spatial transcriptomics data from primary tumours and validation samples. These datasets characterise cellular diversity within rhabdomyosarcoma and identify cell states associated with aggressive disease. The data support research into tumour biology, risk stratification, and therapeutic target discovery. This repository houses the single-cell RNA sequencing of RMS tumours data. . This dataset contains all the data available for this study on 2025-09-30.

  Dataset EGAD00001015713

• CcRCC_metabolic_heterogeneity

  Heterogeneity is a hallmark of clear cell renal cell carcinoma (ccRCC). In this study, hyperpolarized [1-13C]pyruvate MRI (HP-13C-MRI) was used to probe metabolic heterogeneity non-invasively in 6 ccRCC patients from which 58 tumor and healthy tissues biopsies were acquired postoperatively. MRI parameters were correlated with 146 metabolite concentrations and the expression of 2523 metabolic genes across 34 metabolic pathways. Using metabologram projections and pathway consensus scoring, several metabolic pathways were correlated with the metabolic MRI, including glycolysis, pentose phosphate pathway, and the TCA cycle. A simple thresholding approach applied to the imaging metrics was sufficient to provide meaningful metabolic pathway information. We also show that tissue metabolic heterogeneity increases in regions with higher pyruvate-to-lactate conversion on imaging. These results provide validation of the biological relevance of HP-13C-MRI and support the possibility of its clinical use to improve disease characterization, stratification, targeting of biopsies, and providing novel methods to monitor treatment response.

  Dataset EGAD00001015780

• National Cancer Institute (NCI) Adding Hispanics to Ongoing GWAS in Colorectal Cancer

  Genome-wide association studies (GWAS) of colorectal cancer (CRC) have been instrumental in identifying a number of common susceptibility loci in Non Hispanic (NH)-White populations, and a NCI priority is to extend GWAS findings to other populations to address racial/ethnic disparities in cancer susceptibility. Currently, GWA studies of CRC in NH-Whites, Japanese and African-Americans are ongoing. We propose a complementary study to address this critical research area in Hispanics. Hispanics represent the fastest growing ethnic population in the U.S. and have been largely understudied in terms of genetic susceptibility to cancer. There are noted differences in incidence, survival and mortality in CRC by ethnic/racial groups. Hispanics often present with CRC at a younger age and have a significantly greater incidence of stage IV tumors or metastatic disease compared to NH-Whites. We propose to conduct a large, cost-efficient, population-based GWAS in Hispanics by building upon existing NIH-funded resources, the Colon Cancer Family Registry (Colon CFR) and the Multiethnic Cohort Study (MEC). We plan to recruit 2,500 Hispanic men and women diagnosed with CRC between 01/2008 to present using cancer registries in California, physican referrals and familial referrals. Risk factor/diet questionnaires, pathology reports, Oragene saliva samples (for genotyping), optional blood samples (for genotyping and biometric analysis) and tumor blocks (for MSI testing) will be collected using methodologies developed in the Colon CFR/MEC. Cases of CRC in the MEC (currently 473; anticipated 600 at end) will also be included. Population-based Hispanic individuals without a diagnosis of CRC participating in other GWA studies in the MEC (n=3,900, U01HG004726, Haiman) will be used as controls. We will genotype all 3,100 cases using the Illumina 1M array and use available genotype and epidemiologic data collected on 3,900 controls. Our statistical analyses will include: single-SNP and haplotype effects, gene-environment interactions and heterogeneity by MSI, tumor subtype and family history of CRC. We will replicate findings in a second-stage using CRC cases and controls from Mexico (1,000 cases and 1,000 controls, EU FP7 funding, CHIBCHA, Carvajal-Carmona/Tomlinson). We will also examine heterogeneity of the risk estimates by ethnicity/race by leveraging GWA data on NH-Whites (2,142 cases, 1,909 controls, U01 CA122839, Casey), (4,000 cases, 6,000 NH-White controls, UK-CHIBCHA, Tomlinson), Colombians (2,000 cases and 2,000 controls, CHIBCHA), Japanese (1,000 cases and 1,000 controls) and African-Americans (1,500 cases and 1,500 controls, R01CA126895, Le Marchand). We will genotype replicated significant SNPs in our main and combined analysis in several Hispanic populations (note: studies funded by EU or NIH for data collection but not GWAS), including 800 Puerto Ricans, 2,000 Brazilians, 2,000 Argentineans and 3,000 Spanish/Portuguese, to assess generalizability of findings. We will examine the differences in inflammatory gene transcription dynamics in leukocytes (from blood sample collection) by fatigue level (as assessed from study questionnaire data). This study will have a high impact by addressing the key question of racial/ethnic disparities related to genetic susceptibility to CRC, will provide translational guidelines on biological mechanisms during the cancer survivorship period to increase quality of life among cancer survivors, and will enable further growth and investment into research among Hispanics by providing a resource of genetic data and biospecimens, which is lacking.

  Study phs001193

• 3/7 Psychiatric Genomics Consortium: Finding Actionable Variation

  The goal of this study was to generate new therapeutic hypotheses by targeted sequencing of 161 genes most likely to harbor schizophrenia (SCZ) causal variants in multi-ancestry schizophrenia case-control cohorts. The gene panel was intended to contain putative SCZ risk genes, from within which, the majority of new discoveries from additional WES/WGS would come. To this end, we integrated current knowledge of the genetic architecture of SCZ (results from The Schizophrenia Exome Sequencing Meta-Analysis Consortium, or SCHEMA) and gene membership in gene sets that have been implicated in SCZ using a Bayesian framework. A total of 23,352 individuals selected to be non-overlapping with SCHEMA, as well as other previous and ongoing sequencing efforts in the field, were identified from over 20 individual study sites. Sequencing of the exonic regions of 161 prioritized genes was performed on the Ion Torrent platform in between June 2018 and April 2019. Sequencing plates were matched with respect to ancestry and case/control composition whenever possible. The average sequencing depth across all samples was 224x. Single sample calling was performed using Torrent Variant Caller v5.8.0, which is specially optimized to exploit the underlying flow signal information generated by the Ion Torrent sequencing. The schizophrenia case-control status was obtained from each original study site.

  Study phs003138

• Ischemic Stroke Genetics Study (ISGS)

  The third leading cause of death in the United States, stroke is an acute neurological event leading to death of neural tissues. Although the majority of strokes are ischemic strokes, meaning there is oxygen deprivation to the brain, almost 20% of strokes are hemorrhagic, resulting from bleeding into the brain. Stroke is a complex disorder and likely multigenic in nature, resulting from a combination of genetic and environmental factors. These well characterized risk factors that contribute to the incidence of stroke include hypertension, cardiac disease, sickle cell disease, hyperhomocysteinemia, family history of stroke and smoking. ISGS aim is to perform a prospective genetic association study of ischemic stroke focusing on the hemostatic system. ISGS is a 5-center case-control study of first-ever ischemic stroke cases and concurrent controls individually matched for age, sex and recruitment site. This data includes that from subjects both banked in the NINDS repository with biologicals publicly available, and those whose samples are not banked/not available. Important links to apply for individual-level data Data Use Certification Requirements (DUC) Apply here for controlled access to individual level data Participant Protection Policy FAQ --> This study utilized the NINDS Repository Cerebrovascular/Stroke Study, and neurologically normal controls from the sample population which are banked in the National Institute of Neurological Disorders and Stroke (NINDS Repository) collection for a first stage whole genome analysis.

  Study phs000102

• 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

• Alzheimer's Disease Genetics Consortium (ADGC) Genome Wide Association Study -NIA Alzheimer's Disease Centers Cohort

  The National Institute on Aging (NIA) Alzheimer's Disease Centers (ADCs) cohort includes subjects ascertained and evaluated by the clinical and neuropathology cores of the 29 NIA-funded ADCs. Data collection is coordinated by the National Alzheimer's Coordinating Center (NACC). NACC coordinates collection of phenotype data from the 29 ADCs, cleans all data, coordinates implementation of definitions of AD cases and controls, and coordinates collection of samples. The ADC cohort consists of autopsy-confirmed and clinically-confirmed AD cases, and cognitively normal elders (CNEs) with complete neuropathology data who were older than 60 years at age of death, and living CNEs evaluated using the Uniform dataset (UDS) protocol who were documented to not have mild cognitive impairment (MCI) and were between 60 and 100 years of age at assessment. ADCs sent frozen tissue from autopsied subjects and DNA samples from some autopsied subjects and from living subjects to the National Cell Repository for Alzheimer's Disease (NCRAD). DNA was prepared by NCRAD for genotyping and sent to the genotyping site at Children's Hospital of Philadelphia. ADC samples were genotyped and analyzed in separate batches. [Reprinted from AC Naj et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nature Genetics 43, 436-441 (2011). doi:10.1038/ng.801. PMID: 21460841.]

  Study phs000372

• Whole genome sequencing of matched primary and metastatic acral melanomas

  Next generation sequencing has enabled systematic discovery of mutational spectra in cancer samples. Here we used whole genome sequencing to characterise somatic mutations and structural variation in a primary acral melanoma and its lymph node metastasis. Our data show that the somatic mutational rates in this acral melanoma sample pair was more comparable to the rate reported in cancer genomes not associated with mutagenic exposure than in the genome of a melanoma cell line or the transcriptome of melanoma short-term cultures. Despite the perception that acral skin is sun-protected, the dominant mutational signature in these samples is compatible with damage due to ultraviolet light exposure. A nonsense mutation in ERCC5 discovered in both the primary and metastatic tumours, could also have contributed to the mutational signature through accumulation of unrepaired dipyrimidine lesions. However, evidence of transcription-coupled repair was suggested by the lower mutational rate in the transcribed regions and expressed genes. The primary and the metastasis are highly similar at the level of global gene copy number alterations, loss of heterozygosity and single nucleotide variation (SNV). Furthermore, the majority of the SNVs in the primary tumour were propagated in the metastasis and one non-synonymous coding SNV and one splice site mutation appeared to arise de novo in the metastatic lesion.

  Study EGAS00001000169

• Analysis_of_genomic_integrity_of_disease_corrected_human_induced_pluripotent_stem_cells_by_exome_sequencing

  Induced pluripotent stem (iPS) cells hold great promise for autologous cell transplantation. In order to apply this therapy to monogenic disorder, disease-causing mutations must be corrected prior to transplantation. We generated iPS cells from patients with alpha-1 antitrypsin deficiency, which is caused by homozygous non-synonymous mutation in the SERPINA1 gene. In vitro differentiation of patient-derived iPS cells to hepatocytes showed recapitulation of the disease phenotype. We corrected the mutations by gene targeting using zinc finger nuclease (ZFN) and piggyBac transposon technologies. Our mutation correction is highly accurate. There is no exogenous sequence left behind at the targeted site. The corrected iPS cell-derived hepatocytes were indistinguishable from healthy hepatocyte, suggesting that the corrected gene was fully functional. The genomic integrity was also analyzed by CGH and SNP array, showing no genomic alterations. These are important points to ensure clinical safety as well as functional restoration of the corrected gene. One remaining question is if these corrected iPS cells are clinically safe at the single base-pair level. Recent publications suggested that cancer-related mutations are significantly accumulated during iPS cell propagation. We aim to assess the clinical safety of the corrected iPS cells by using exome sequencing. Outcome from this project would bring iPS cell technology one step closer to clinical applications.

  Study EGAS00001000055

• Structural variant analysis of homologous recombination-deficient genomes

  Homologous recombination (HR) deficiency causes DNA breaks and cytogenetic aberrations. Paradoxically, the types of DNA rearrangements specifically associated with HR-deficient cancers only minimally impact chromosomal structure. Addressing this, we combined a genome graph analysis of short-read whole genome sequencing (WGS) profiles across thousands of tumors with deep linked-read (LR) WGS of 46 BRCA1 or BRCA2 mutant breast cancers to discover a distinct class of HR deficiency-enriched rearrangements called reciprocal pairs. LR WGS showed that reciprocal pairs with identical rearrangement orientations gave rise to one of two distinct chromosomal outcomes, distinguishable only with long molecule data. While one (cis) outcome corresponded to the copy and pasting of a small segment to a distant site, a second (trans) outcome was a quasi-balanced translocation or multi-megabase inversion with substantial (10kb) duplications at each junction. The full spectrum of reciprocal pair outcomes could be explained by an HR-independent replication restart repair mechanism. LR WGS additionally identified single-strand annealing (SSA) as a BRCA2-deficiency specific repair pathway in human cancers. Replication restart- and SSA-associated SVs improved BRCA1- vs. BRCA2- deficiency classification and identified metastatic cancer cases with favorable chemotherapy responses. Our data reveal classes of BRCA1- and BRCA2-deficiency specific rearrangements as drivers of cytogenetic aberrations in HR deficient cells.

  Study EGAS00001007186

• Prevention and Early Treatment of Acute Lung Injury (PETAL) Acetaminophen in Sepsis: Targeted Therapy to Enhance Recovery (ASTER) (PETAL ASTER-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. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL ASTER include plasma, urine and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis participants compared with placebo.Background: Acetaminophen (paracetamol) has many effects that can be beneficial in sepsis treatment, including analgesia, antipyresis, cyclooxygenase-2 inhibition, as well as a potent and specific hemoprotein reduction that can block hemoglobin-induced oxidation of lipids and other substrates. The majority of sepsis participants experience elevated circulating cell-free hemoglobin levels, which is associated with development of organ dysfunction including acute respiratory distress syndrome (ARDS) and death.Acetaminophen has been found in observational studies to be associated with improved survival in critically ill sepsis participants with elevated plasma cell-free hemoglobin, and small clinical trials have had positive sepsis participant outcomes such as reduced plasma biomarkers of lipid peroxidation and improved kidney function. However, a large, randomized trial of acetaminophen administration for treatment of fever in participants with suspected infection did not show a mortality benefit. The NHLBI PETAL Network initiated ASTER as a larger phase trial to examine the utility of plasma cell-free hemoglobin level as a biomarker for future sepsis trials and whether acetaminophen would increase the number of days alive and free of organ support for participants with sepsis and respiratory or circulatory organ dysfunction. Participants: A total of 447 participants were enrolled and randomized, 227 to the acetaminophen arm and 220 to the placebo arm. Data from 40 participants who were randomized to the Vitamin C arm, which was stopped early (see Design section below), is also included.Design: ASTER was a phase 2b multicenter, randomized, double-blind trial. The study originally had a 3-arm platform trial in which participants were randomized 1:1:1 to treatment with intravenous acetaminophen, vitamin C, or a common placebo. The vitamin C arm of the trial was stopped after enrolling 79 participants due to external clinical trial data for vitamin C.Participants randomized to the acetaminophen arm received acetaminophen at the dose of 1 g in 100 mL diluent (or 15 mg/kg if actual body weight was Conclusions: Intravenous acetaminophen was considered to be safe but did not significantly improve days alive and free of organ support in critically ill sepsis participants. There was no significant interaction between cell-free hemoglobin levels and acetaminophen.

  Study phs003900

• RNASeq of Plasmacytoid Dendritic Cells in Head and Neck Squamous Cell Cancer Patients

  Plasmacytoid dendritic cells (pDC) are a subset of dendritic cells with unique immunophenotypic properties and functions. While their role in antiviral immunity through production of type I interferons is well-established, their contributions to anti-tumor immunity are less clear. While some evidence demonstrates that pDC in the tumor microenvironment (TME) may drive CD4+ T cell to become Foxp3+ T regulatory cells, little is understood about the relationship of pDC with cytotoxic CD8+ T cell, the key player in antitumor immune responses. In this study, we perform comprehensive immunophenotyping and functional analysis of pDC from the TME and draining lymph nodes of patients with head and neck squamous cell carcinoma (HNSCC) and identify a novel pDC subset characterized by expression of the TNF receptor superfamily member CD134 (OX40). We show that OX40 expression is expressed on intratumoral pDC in both humans and mice in a tumor-model specific fashion and that this subset of pDC enhances tumor associated-antigen (TAA)-specific CD8+ T cell responses. Through transcriptomic profiling of OX40-expressing pDC from the TME, we further characterize gene signatures unique to this pDC subset that support its role as an important immunostimulatory immune population in the TME.

  Study phs001824