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• Virginia PrIMeD Study

  The goal of this study was to determine whether screening children (2-16 yrs) in pediatric waiting rooms for genetic risk of type 1 diabetes (T1D) could be applied to diverse (by geography, genetic ancestry) communities, and for those at "high genetic risk," if barriers prevent subsequent screening for presence of islet autoantibodies. A total of 3,818 children were recruited from eight general pediatric and specialty clinics across Virginia. Clinical Research Coordinators were stationed at each clinic and obtained informed consent/assent, a brief medical history, and a saliva sample for DNA extraction and determination of their genetic risk using a T1D Genetic Risk Score (T1D GRS). Children were present in the clinic for a "healthy" visit, although children with and without a history of T1D were recruited into the study. Age, sex, self-reported ancestry/race, T1D history, and other medical history information was obtained. DNA was extracted from the saliva samples and genotyping with a T1D-focused array using 74 SNPs (including 26 SNPs in the HLA region) provided data to generate a T1D GRS for each individual. Of the 3,818 children recruited, there was a slight excess of males (1,959, 51.3%), a majority of white and Hispanic/Latino ancestry (82.8%), and 91 (2.4%) with prevalent T1D. A total of 542 (14.2%) had "high T1D genetic risk" (T1D GRS > 5). Although the T1D GRS included non-HLA genetic variants, 80% of those with "high genetic risk" would have been classified using only those SNPs in the HLA region alone. Of children with "high genetic risk" and without pre-existing T1D (n=494), 7.0% (34/494) consented for islet autoantibody screening. Among children with pre-existing T1D (n=91), 52% (n=48) also had a "high genetic risk." The HLA-focused T1D GRS was not significantly associated with age at onset of T1D. Of those at high genetic risk that consented for autoantibody testing (n=34) and completed the blood collection (n=28), two (2/28, 7.1%) tested positive for multiple autoantibodies and were at significant risk of developing T1D. Follow up of 55% of parents/guardians identified 2 (of 2,096, 0.095%) participants who developed T1D, one at "high genetic risk" and one with a first-degree relative with T1D. A major factor in obtaining islet autoantibody testing was concern over SARS-Cov-2 exposure and an independent non-scheduled blood collection.Individual-level data at each SNP (genotyped and imputed) for T1D genetic risk and affiliated data are provided in dbGaP.

  Study phs003609

• Pharmacogenomics of Mercaptopurine Intolerance in Children with Acute Lymphoblastic Leukemia (AALL03N1)

  Mercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to comprehensively identify the genetic basis of MP intolerance in children with ALL in AALL03N1. MP dose intensity was defined as prescribed dose divided by the planned protocol dose during maintenance therapy.  Germline variants in NUDT15 and TPMT were found to be strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.

  Study phs002846

• Genetic mechanisms of resistance to chemotherapy in breast cancer

  Resistance towards chemotherapy is one of the main causes of treatment failure and deathamong breast cancer patients.The main objective of this project is toidentify genetic mechanisms causing some breast cancer patients not torespond to a particluar type of chemotherapy (epirubicin) while otherpatients respond very well to the same treatment. In the project wewill perform genome / exome sequencing of a selection of breast cancerpatients (n=30). These patients are drawn from a cohort where allpatients have recieved treatment with epirubicin monotherapy before surgical removal of alocally advanced breast tumour, and where all patients have beensubjected to objective evaluation of the response to thetherapy. Subsequent to sequencing, we will analyse the data andcompare with the clinical data for each patient (object response totherapy). The main aim being to identify mutations that are associatedwith resistance to epirubicin. Identification of mutations with strongpredictive value, may have a direct impact on cancer treatment sinceit opens the possibility for genetic testing of a tumour, and desicionon which drug is likely to work best, prior to treatment start.

  Dataset EGAD00001000264

• Gabriella Miller Kids First Pediatric Research Program: An Integrated Clinical and Genomic Analysis of Treatment Failure in Pediatric Osteosarcoma

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in childhood cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. All of the WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Although the survival of children with relapsed osteosarcoma is very poor, little is known about the etiology of treatment failure in this disease. The purpose of this project is to perform whole genome sequencing on serial samples from patients with osteosarcoma obtained before treatment, after treatment, and at relapse/metastasis in order to identify the mutations and pathways that are drivers of drug resistance. If successful, our results may help identify patients at high risk for treatment failure and may yield new treatments for children who cannot currently be cured.

  Study phs001714

• Genome-Wide Association Studies in Upper Gastrointestinal Cancers (Asian)

  This project aims to conduct genome-wide association studies (GWAS) in two anatomically different upper gastrointestinal (UGI) cancer sites in two populations with distinctly different disease rates and genetic profiles. One population has very high rates for both esophageal squamous cell carcinomas (ESCCs) and gastric cancers (GCs) and is comprised of Asians (the "Asian UGI GWAS"), while the other population has low rates of ESCC and GC and includes non-Asians from the Americas, Europe, and Australia (the "Non-Asian UGI GWAS"). Study participants for the Asian UGI GWAS reported here (Illumina 660W Quad chip) were drawn from 2 studies, the Shanxi Upper Gastrointestinal Cancer Genetics Project (Shanxi) and the Linxian Nutrition Intervention Trial (NIT), a prospective cohort, and included a total of 1898 ESCCs, 1625 GCs, and 2100 controls. For the 2nd phase (8 TaqMan SNPs), additional subjects from Shanxi and NIT as well as subjects from the Shanghai Men's Health Study (SMHS), the Shanghai Women's Health Study (SWHS), and the Singapore Chinese Health Study (SCHS) were also included (217 ESCCs, 615 GCs, 1202 controls). Altogether 2115 ESCCs, 2240 GCs, and 3302 controls were genotyped in this study.

  Study phs000361

• dbGaP Collection: Open Translational Science in Schizophrenia (OPTICS)

  Schizophrenia is a chronic, severe, disabling brain disorder that affects approximately 1% of the population worldwide. Epidemiologic studies have clearly demonstrated that genetics play a strong role in etiology, but the inheritance is very complex. Innovative analytic approaches and creative ways of combining disparate data sets will be necessary for making breakthroughs in identifying causal pathways and ultimately new drug targets. This dbGaP Collection consists of all genetic studies of schizophrenia available in dbGaP that have been consented for general research use. The goal is to facilitate identification of datasets with related scientific content in order to expedite the application process and ascertainment of datasets of interest for increased scientific discovery. The Open Translational Science in Schizophrenia (OPTICS) Project, was launched by Janssen Research & Development, LLC, part of the Janssen Pharmaceutical Companies of Johnson & Johnson, with a group of leading research organizations including the National Institutes of Health, Yale University School of Medicine, Rutgers University and the Harvard T.H. Chan School of Public Health, to create a new forum for collaborative analysis of Janssen's schizophrenia clinical trial data and other publicly available data about schizophrenia with the goal of creating new models for conducting research. The OPTICS project is one part of a larger effort at Janssen and other Johnson & Johnson research companies to share clinical trials data to enhance public health and advance science and medicine. Qualified investigators and physicians may apply for access to anonymized clinical trials data from Janssen, for more information please visit https://sites.google.com/site/opticsschizophrenia/.

  Study phs000887

• NHLBI TOPMed - NHGRI CCDG: Groningen Genetics of Atrial Fibrillation (GGAF) Study

  Atrial fibrillation (also called AFib or AF) is a quivering or irregular heartbeat (arrhythmia) that can lead to blood clots, stroke, heart failure and other heart-related complications. The Groningen Genetics of Atrial Fibrillation (GGAF) cohort is a cohort composed from 5 different sources of individuals with atrial fibrillation (AF) and age and sex-matched controls. Written informed consent was provided from all participating individuals, and all 5 studies were approved by the ethical committee at the University Medical Center (www.atrialfibrillationresearch.nl) and Maastricht University. All samples selected for TOPMed WGS are from individuals with atrial fibrillation.

  Study phs001725

• Organ_maturation_in_preparation_for_birth__Peds_RFA__to_develop_a_tissue__resource_and_a_single_cell_atlas_of_organ_development_and_maturation_for__dissemination_among_the_scientific_and_clinical_community__RNA

  Knowledge about abnormal organ development is important to understand pathology and to develop novel treatment approaches for individuals with congenital and acquired disease. Most of our current understanding is based on examination of tissues from the embryo and early foetus, collected from women undergoing termination of pregnancy in the first trimester (third) of pregnancy. There is very little known about normal and abnormal organ development from a developmental perspective during the crucial last two-thirds of pregnancy when much remodelling of foetal tissues occurs. This study will generate a single-cell atlas of late-foetal lungs, blood, heart, bone and immune organs.

  Study EGAS00001008256

• NHLBI TOPMed: The Genetic Epidemiology of Asthma in Costa Rica

  This administrative supplement to the project, "The Genetic Epidemiology of Asthma in Costa Rica" (R37 HL066289) is in response to NOT-HL-14-029 to perform whole genome sequencing (WGS) on existing NHLBI populations. We focus on asthma because of its public health significance. Asthma affects 26 million U.S. children and adults, remains a major cause of morbidity (one-half million hospitalizations a year) and is the most common cause of school and work days lost. Asthma-related costs are estimated to be over $12.7 billion annually. The Asthma Probands for both the extended pedigrees and the trios utilized in this study were selected on the basis of a physician diagnosis of asthma; a history of recurrent asthma attacks or at least 2 respiratory symptoms; and either airway hyperresponsiveness to methacholine or significant response to bronchodilator (Albuterol) administration. These criteria are identical to the criteria used in the Childhood Asthma Management Program (CAMP). The three primary goals of this project are to: (1) identify common and rare genetic variants that determine asthma and its associated phenotypes (height, weight, IgE level, lung function, bronchodilator response, steroid treatment response) through whole genome sequencing (WGS); (2) perform novel family based association analysis of our WGS data to identify novel genes for asthma; and (3) integrate epigenomic and transcriptomic data with our WGS data and determine the epistatic interactions present using systems genomics approaches. Identification of the molecular determinants of asthma remains an important priority in translational science. Genome-wide association studies (GWAS) have been successful in this regard, identifying at least 10 novel susceptibility genes for asthma. However, as with most complex traits, the variants identified by GWAS explain only a fraction of the estimated heritability of this disorder. Herein, we propose a novel family-based study design and state-of-the-art genome sequencing techniques to map a set of sequence variants for asthma and its associated phenotypes and assess the interrelationships of the identified genes and variants using systems genomics methods. We have assembled a team of investigators highly-skilled and expert in whole genome sequencing (Drs. Michael Cho and Benjamin Raby), genetic association analysis (Drs. Scott T. Weiss, Jessica Lasky-Su and Christoph Lange), integrative genomics (Drs. Raby, Kelan Tantisira, Augusto Litonjua and Dawn DeMeo), and systems genomics (Drs. Weiss, Amitabh Sharma, Lange and Raby) to address this important problem with both a novel study design and data set.

  Study phs000988

• Autozygosity pilot - Born in Bradford (2014-11-20)

  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 cohort samples from the Born In Bradford study 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 consist of low coverage whole exome sequencing on these samples.Data Access is controlled by the Wellcome Trust Sanger Institute DAC and the Born In Bradford Executive Group. This dataset contains all the data available for this study on 2014-11-20.

  Dataset EGAD00001001079