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• NHLBI TOPMed: Outcome Modifying Genes in Sickle Cell Disease (OMG)

  Sickle cell disease (SCD) is caused by homozygosity for a single mutation of the beta hemoglobin gene. Despite the constancy of this genetic abnormality, the clinical course of patients with SCD is remarkably variable. SCD can affect the function and cause the failure of multiple organ systems through the pathophysiologic processes of vaso-occlusion and hemolysis. These pathophysiological processes are complex and expected to impact multiple organ systems in a variety of ways. This study, therefore, was designed to identify genetic factors that predispose SCD patients to develop specific end-organ complications and to experience more or less severe clinical courses. We enrolled > 700 patients with Hb SS, Hb S-beta0 thalassemia and HbSC being followed primarily at three southeastern U.S. regional institutions (Duke University Medical Center, University of North Carolina Medical Center, and Emory University Medical Center). Medical information obtained included the presence or absence of specific targeted outcomes (overall disease severity as well as specific types of end organ damage). Clinical data include medical status (history, physical, examination, and laboratory results) and information regarding potentially confounding environmental factors. Limited plasma samples are available for correlative studies (e.g. of cytokine levels, coagulation activation). Targeted SNP for candidate gene analysis as well as GWAS has been performed on most samples. Whole genome sequencing has been conducted through the TOPMed Consortium. The subjects in this analysis were collected as part of a larger study, "Outcome Modifying Genes in Sickle Cell Disease" (OMG-SCD) aimed at identifying genetic modifiers for sickle cell disease. More information about the study can be found in Elmariah et al. (2014), PMID: 24478166. Clinical and genetic data have been used to identify genetic characteristics predisposing patients with SCD to a more or less severe overall clinical course as well as to individual organ-specific complications. It is anticipated that identification of such genetic factors will reveal new therapeutic targets individualized to specific complications of SCD, leading to improved outcomes and increased life expectancy for patients with SCD.

  Study phs001608

• NHLBI TOPMed: Heart and Vascular Health Study (HVH)

  Objectives The Heart and Vascular Health Study (HVH) is a case-control study of risk factors for the development of myocardial infarction (MI), stroke, venous thrombosis (VT), and atrial fibrillation (AF). The study setting is Group Health, an integrated health care delivery system in Washington State. Only VT cases and early-onset AF cases are included as part of TOPMed. Background The HVH study originated in 1988 with the examination of risk factors for MI. Over the ensuing years, the study has been funded by a series of grants which have added case subjects with stroke, VT, and AF. Study aims focused on the associations of medication use with cardiovascular events, and starting in 1997, the study aims expanded to include genetic associations with cardiovascular disease. Participants recruited in 2009 or later who provided blood samples for genetic analysis were asked for consent to deposit genetic and phenotypic data in dbGaP. Design As part of the HVH study, case subjects were identified by searching for ICD-9 codes consistent with MI, stroke, VT, or AF, and medical records were reviewed to confirm the diagnosis. Control subjects were identified at random from the Group Health enrollment and were matched to MI cases. All subjects have an index date. For cases, the index date was assigned as the date that the cardiovascular event (MI, stroke, VT, or AF) came to clinical attention. For controls, the index date was a random date within the range of the case index dates. For both cases and controls, information was collected from the inpatient and outpatient medical record, by telephone interview with consenting survivors, and from the Group Health pharmacy and laboratory databases. Consenting participants provided a blood specimen. Subjects Only VT and early-onset AF cases from HVH are included in TOPMed. Within the HVH study, VT and AF cases were diagnosed in both inpatient and outpatient settings, and only incident cases are eligible for inclusion in TOPMed. Genetic Research Genetic factors underlying cardiovascular disease are studied using DNA isolated from the blood samples. Phenotype data for HVH study participants are available through dbGaP phs001013.

  Study phs000993

• Genetics and Functional Studies of Autosomal Recessive Neurological Disorders

  Neurological conditions account for over 6% of the global disease burden. There are more than 600 neurological disorders, and cognitive dysfunction, also referred to as intellectual disability (ID), occupies a prominent position in this list. Cognitive dysfunction arises from the failure of neuronal cells to organize into a complex network and remodel this network in response to learning and experience. It is manifested by deficits in adaptive behaviors in everyday social and practical skills. Due to its high prevalence and the lifetime cost of care per individual, in the range of $1-2 million in United Sates (CDC), it presents a significant health burden. Genetic and functional studies of the genes and protein determinants of ID have helped to elucidate the molecular pathways of human brain development in health and disease. However, the identity of a large number of essential molecular and cellular components still remain elusive. The objectives of our study are to expand the genetic repertoire of causal ID genes and characterize their role in neuronal structure and cognitive function. The rationale is that identification and functional elucidation of causative gene variants that lead to cognitive dysfunction will be essential for understanding brain function and for developing improved diagnostic tools and efficacious preventive and therapeutic agents for neurological disorders, including ID. There are 3 aims of our comprehensive research program: 1) Ascertain and clinically phenotype members of extended families segregating autosomal recessive intellectual disability (ARID); 2) identify new ARID genes and gene products; and 3) determine the functions of prioritized novel ARID genes using multifaceted approaches, including analysis of spatiotemporal expression patterns in mouse brain, targeting in cultured rat hippocampal neurons, effects on cell morphology and synapse abundance, synaptic transmission and plasticity in neuronal cells by electrophysiology and live-cell imaging assays. The project will advantageously combine human clinical assessment, genetic and functional analyses relevant to brain development and function. Impact: Execution of the proposed studies will generate new knowledge that is clinically relevant, with high potential to impact ID molecular diagnosis, prognoses, and identify novel therapeutic targets to slow progression, delay onset, and possibly devising precision medicine approaches for ID.

  Study phs003298

• Genome-Wide Association Study of Genetic Susceptibility for Graft-vs-Host Disease Cohort 1

  Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curative therapy for many advanced hematologic malignancies. Allo-HSCT is associated with significant morbidities and mortality, mainly because of the graft-versus-host disease (GVHD) caused by donor T cells recognizing antigens present in recipient tissues, and initiating an alloimmune response resulting in damage to many organs including the skin, gastrointestinal (GI) tract, and liver in recipient. More than half of all Allo-HSCT recipients develop different degrees of GVHD (grades I-IV). About 20% of recipients develop severe GVHD (grades III-IV) that is associated with a very high morbidity and mortality. The most important factor determining the severity of GVHD is the genetic disparities between donors and recipients, as is reflected in human leukocyte antigen (HLA) haplotypes that are routinely checked for donor selection. Even when donors and recipients are HLA-identical, many recipients develop severe GVHD. As a result, non-HLA antigens are important determinants of acute GVHD. An interesting and unique aspect of GVHD is that it is the consequence of an interaction between antigens present in one individual with the immune system of another individual. As a result, genotypes of both donor and recipient, and their interactions affect the pathogenesis of GVHD. To determine the genetic risk factors for GVHD, in the first aim (discovery phase), we will conduct Genome-Wide Association Studies (GWAS) in 3,000 patients who underwent Allo-HSCT and in their respective donors (6000 DNA samples) that are provided to us by the Center for International Blood and Marrow Transplant Research (CIBMTR), a research collaboration between the NMDP and Medical College of Wisconsin. In the second aim, we will validate the association between high risk genotypes detected in the first aim and severe GVHD in 1,750 donors and 1,750 recipients of Allo-HSCT, and perform the joint analysis with the discovery samples. In the third aim, we will investigate the functional effect of SNPs detected and validated to be significantly correlated with the severity of acute GVHD in mixed lymphocyte reaction (MLR), as an ex vivo surrogate for an alloimmune response.

  Study phs002185

• NRG-GY017: Atezolizumab before and/or with Chemoradiotherapy in Immune System Activation in Patients with Node Positive Stage IB2, II, IIIB, or IVA Cervical Cancer

  Locally advanced cervical cancer remains an area of high therapeutic unmet need, with ~50% of patients developing disease recurrence despite treatment with chemotherapy combined with radiation. Combination of immune checkpoint blockade with chemoradiation has been explored in this setting, but optimal sequencing of these modalities is unknown. To address this question, we developed and conducted the NCI sponsored trial “Anti PD-L1 (Atezolizumab) as an Immune Primer and Concurrently with Extended Field Chemoradiotherapy for Node Positive Locally Advanced Cervical Cancer”, randomizing patients to atezolizumab administration prior to and concurrent with chemoradiation therapy (CRT) vs. concurrent with CRT (NRG-GY017; N=40, ClinicalTrials.gov Identifier: NCT03738228). Patients were randomized to atezolizumab neoadjuvant and concurrent (Arm A) or concurrent with CRT (Arm B). The study closed to successful accrual of 36 evaluable patients in June 2020. Out of 40 patients consented patients, 4 were never treated. The reasons for that are: 2 were screen failures, 1 withdrew consent, and 1 was not treated due to physician preference. The study incorporated comprehensive collection of pre- and on-treatment tumor biopsies as well as multitime point blood collections. T cell receptor (TCR) sequencing was performed on the tumors as well as pre- and on-treatment peripheral blood, and the data are included with dbGaP submission. Among the 36 eligible and treated patients, there were 30 (17 on Arm A and 13 on Arm B) with pre- and on-treatment peripheral TCR sequencing data. Twenty-five patients (14 in Arm A and 11 in Arm B) had additional tumor TCR sequencing data available, which enabled tracking of tumor-associated TCR clones in peripheral blood. We demonstrate that neoadjuvant atezolizumab administration results in peripheral expansion of higher proportion of tumor-associated TCR clones in Arm A than in Arm B and is associated with favorable 2-year disease-free survival (DFS). No new safety signals were identified. These findings support further evaluation of the neoadjuvant IO and CRT sequencing strategy in locally advanced cervical cancer.

  Study phs003833

• Contextual and Health Behavior Effects on Epigenetic Aging Among Africans in the Family and Community Health Studies

  The Family and Community Health Studies (FACHS) is a longitudinal examination of health and health related behaviors in African American families. The original study cohort consisted of 867 African American parent-child dyads from Georgia and Iowa who were ascertained in cooperation with local school districts. The key inclusion criteria for participating in the study were the presence of an adolescent in the 5th grade (approximately 10-11 years old) who self-identified as African American (i.e., the Target) and the participation of a primary caretaker (PC) for the Target. The clinical and biological data included in this collection are from the Target (i.e., FACHS-T) portion of these studies of these African American parent-child dyads. The initial wave of behavioral assessments of the FACHS-T subjects was conducted in 1997-98 (Wave 1), with seven subsequent ascertainments, Wave 2 (1999–2000), Wave 3 (2002–2003), Wave 4 (2005–2006), Wave 5 (2007–2009), Wave 6 (2010–2011), Wave 7 (2014–2016) and Wave 8 (2019-2021). Full interviews were obtained at each wave of the study with the exact content of the wave varying as a function of developmental age. These interviews of the FACHS-T subjects collected a wide variety of data including the following: perceived discrimination; socioeconomic status; substance use exposure; common internalizing and externalizing disorders such as depression, substance use, and conduct disorder; school efficacy; peer support and perceived parenting practices. Biological sampling of the FACHS-T subjects was conducted at three time points. Saliva DNA was collected at Wave 5 while full phlebotomy was conducted at Waves 7 and 8. The genome wide methylation data listed below is derived from the whole blood DNA samples collected at Wave 8 and Wave 9. The genome wide genotyping data was determined using DNA from the Wave 7 samples. The clinical and biological data available herein are those from 309 FACHS-T subjects who participated in both Wave 7 and Wave 8, and who consented for deposition of their data in dbGAP.

  Study phs003723

• Kids First: Whole Genome Sequencing in Recessive Structural Brain Defects

  Almost 5% of all live births in the US (1:20 births) display an inborn defect, including both structural and functional/metabolic abnormalities. These are among the most common causes of Infant mortality in the developed world and underlie nearly half of hospitalizations in the first 3 years of life. Of the 35 major defects observable at birth from the International Clearinghouse for Birth Defects Surveillance Program (www.icbdsr.org, external link), about half involve the nervous system. Many of these result in lifelong neurodevelopmental disorders. Structural Brain Defects (SBDs) result from errors in development of the central nervous system, including defects in the forebrain, midbrain and hindbrain. Many SBDs arise as the consequence of a single gene bi-allelic mutation, and for this reason, occur more commonly in populations or communities with elevated consanguinity.Our lab has identified dozens of novel SBD genes using WES/WGS in consanguineous SBD families. Importantly, the genes that we and others have identified in these unique families are then used to advance diagnosis in pediatric SBDs around the world. We have built an enormous cohort of SBD families, including newly recruited families not yet studied genetically, and previous families that were negative for cause following WES analysis. Here we propose to collaborate with the Gabriella Miller Kids First Pediatric Research Program (X01) to have sequencing performed in individuals from a total of 200 families with genetically undiagnosed SBDs. The Gleeson Lab team of researchers is dedicated to the field of SBDs, with an outstanding track record of high-impact science, and a collaborative approach to discovery. We have 150 newly recruited families that we propose to study by WES by sequencing blood-derived DNA from two affected patients, or the parents and one affected patient. We also have 50 families in which WES was negative, which we propose to study in a multi-omics approach combining WGS from blood-derived DNA. We anticipate that this study will lead to the identification of many new molecular causes of SBDs, as well as uncover new genotype-phenotype correlations and new disease mechanisms, paving the way for future breakthroughs in detection, treatment and prevention.

  Study phs002590

• Gabriella Miller Kids First Pediatric Research Program in Pediatric T-Cell Acute Lymphoblastic Leukemia

  The outcome for patients with relapsed T-ALL is dismal with 3-year event free survival of AALL0434 was a Children's Oncology Group-initiated phase 3 randomized clinical trial comparing Capizzi-style escalating methotrexate plus pegaspargase (CMTX) vs. high dose methotrexate (HDMTX), with/without six 5-day courses of nelarabine. Survival on this study was superior to any prior trial for de novo T-ALL, changing the standard of care. Yet, a substantial minority (~15%) of patients had relapsed or refractory (r/r) disease. Through the TARGET initiative, RNA sequencing (RNA-Seq), DNA copy number analysis, and whole-exome sequencing (WES) were performed on 264 T-ALL patients treated on AALL0434, demonstrating recurrent alterations could be grouped into 10 different potentially targetable functional pathways. This analysis was not powered to examine associations between genetic lesions with outcome, because too few patients with r/r disease were included. This project is dedicated to testing the hypothesis that comprehensive genomic profiling of the entire AALL0434 cohort will identify recurrent genetic alterations that can be segregated into biologically relevant deregulated pathways that can be combined with MRD to identify patients at risk for poor outcomes before they relapse and provide rationale for treatment with alternative therapies. In addition, a number of small recent studies demonstrated that many of the biologically relevant alterations in T-ALL occur in non-coding regions of the genome, but no large studies have performed whole genome sequencing (WGS) in T-ALL. This project also tests the hypothesis that WGS of a large cohort of patients with T-ALL will identify novel lesions in coding and non-coding regions that will be highly impactful in the understanding of T-ALL pathogenesis.These hypotheses are tested by performing comprehensive genomic profiling (WGS, WES, RNA-Seq, and copy number analysis) of the entire AALL0434 cohort with available samples with the following specific aims: (1) identify recurrent genetic alterations that predict poor outcome in T-ALL; (2) identify novel alterations, including non-coding alterations in T-ALL; and (3) identify germline genetic variants that predispose to T-ALL and to increased toxicity to chemotherapy.

  Study phs002276

• UK10K NEURO GURLING

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. This sample set consists of DNA from multiply affected schizophrenia families. The families have been diagnosed using the SADS-L clinical instrument which gives diagnoses at the probable level of the research diagnostic criteria (RDC). In addition all diagnoses are available using DSMIIIR criteria. These criteria are widely accepted as being valid and reliable for the diagnosis of schizophrenia. All families have been collected to ensure that they are uni-lineal for transmission of schizophrenia, i.e. they have only one affected parent with schizophrenia, or a relative of only one transmitting or obligate carrier parent with schizophrenia. Families with bi-lineal transmission of schizophrenia (i.e. with both parents being affected) were not sampled for this study. All families have multiple cases of schizophrenia and related disorders. The families have been selected to ensure there are no cases of bipolar disorder within them and that they do not contain bipolar disorder in any relatives on either side of the family.For further information on this cohort please contact Hugh Gurling (h.gurling@ucl.ac.uk).

  Study EGAS00001000225

• Genomic analysis of patient-derived xenograft models reveals intratumor-heterogeneity in endometrial cancer and can predict tumor growth inhibition with talazoparib

  Background: Endometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprised of four molecular subtypes with differing etiology, prognoses, and response to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. Pre-clinical models that faithfully represent the molecular subtypes of EC are urgently needed, we sought to develop and characterize a panel of novel EC patient-derived xenograft (PDX) models. Methods: Here, we report whole exome or whole genome sequencing of 11 PDX models and the matched primary tumor. Analysis of multiple PDX lineages and passages was performed to study tumor heterogeneity across lineages and/or passages. Based on recent reports of frequent defects in the homologous recombination (HR) pathway in EC, we assessed mutational signatures and HR deficiency scores and correlated these with in vivo responses to the PARP inhibitor (PARPi) talazoparib in six PDXs representing the copy number high/p53-mutant and mismatch-repair deficient molecular subtypes of EC. Results: PDX models were successfully generated with similar histomorphology from all four molecular subtypes of EC and uterine carcinosarcomas. We also observed a wide range of inter-tumor and intra-tumor heterogeneity across different PDX lineages, however one arm of most PDX models recapitulated the molecular landscape of the primary tumor without major genomic drift. An in vivo response to talazoparib was detected in four copy number high models. Two models (carcinosarcomas) showed a response consistent with stable disease and two models (one copy number high serous EC and another carcinosarcoma) showed significant tumor growth inhibition, albeit one consistent with progressive disease, however all lacked the HR deficiency genomic signature. Conclusions: EC PDX models represent the four molecular subtypes of disease and can capture intra-tumoral heterogeneity of the original primary tumor. PDXs of the copy number high molecular subtype showed sensitivity to PARPi, however, deeper and more durable responses will likely require combination of PARPi with other agents.

  Study EGAS00001004666

• ICGC Breast Cancer Project, RNA seq

  A comprehensive characterisation and analysis of human breast cancers through genome-wide approaches through transcriptomics.

  Dataset EGAD00001001323

• APCIM_Nanostring_HD

  Expression of immune related genes in 12 healthy donors. Expression assessed by analyzing whole blood-derived RNA samples using a Nanostring nCounter Immunology V2 panel (579 genes)

  Dataset EGAD00010002554

• PREGO

  Core set of the PREGO biobank containing experimental genotypes at 209,706 autosomal sites measured on Affymetrix PMRA Axiom array plates for a group of 3,234 individuals from Western France.

  Dataset EGAD00010002661

• MM GWAS dataset

  This is a meta-analysis of myeloma datasets, both with and without the UK Biobank cohort included.

  Dataset EGAD50000000422

• WGBS of stepwise-edited melanoma model

  This dataset contains WGBS of a stepwise-edited, human melanoma model including in vitro samples and corresponding xenografts.

  Dataset EGAD50000001317

• RNA-Seq - Characterization of a Breast Patient-derived Tumor Organoid biobank from an underserved population of patients

  RNA-seq datasets of patient and patient-derived organoids

  Study EGAS50000000683

• Nanopore sequencing of AML and control samples

  Three AML samples from patients with mutations in DNMT3A, IDH2, TET2, and a control sample of whole genome amplified DNA.

  Dataset EGAD50000001692

• Exome sequencing for LySeqST

  Exome sequencing of 120 lymphoma samples and 13 normal samples for LySeqST: A targeted sequencing assay for robust genomic classification of diffuse large B-cell lymphoma.

  Dataset EGAD50000002289

• Reference epigenome KNIH005 WGBS data generated from KEP study

  A KNIH005 Whole-Genome Bisulfite Sequencing(WGBS) paired end data for islet cells

  Dataset EGAD00001002753

• Reference epigenome ADMSC02_smRNA-Seq data generated from KEP study

  A ADMSC02_smRNA-Seq single end data for adipose-derived mesenchymal stroaml cells

  Dataset EGAD00001003868

• 10K Project Metagenomic

  This dataset includes metagenomic sequencing of faecal samples from 7,190 Israeli individuals. Single-end sequencing was performed using a NovaSeq sequencing platform (Illumina).

  Dataset EGAD00001010925

• Reference epigenome KNIH003 WGBS data generated from KEP study

  A KNIH003 Whole-Genome Bisulfite Sequencing(WGBS) paired end data for islet cells

  Dataset EGAD00001002751

• Reference epigenome ADMSC03_smRNA-Seq data generated from KEP study

  A ADMSC03_smRNA-Seq single end data for adipose-derived mesenchymal stroaml cells

  Dataset EGAD00001003869

• Reference epigenome KNIH004 WGBS data generated from KEP study

  A KNIH004 Whole-Genome Bisulfite Sequencing(WGBS) paired end data for islet cells

  Dataset EGAD00001002752

• Reference epigenome DB31_N_Alpha_smRNA-Seq data generated from KEP study

  A DB31_N_Alpha_smRNA-Seq single end data for alpha cells(PSA-NCAM(-), pancreas)

  Dataset EGAD00001003494