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• Host genotyping data from Dutch adult bacterial meningitis patients and linked bacterial genome sequences

  Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. This study includes 1146 samples of host genotyping data (genotyped and imputed) from Illumina Omni arrays. Samples were collected from adults (>16 yrs) patients with CSF confirmed bacterial meningitis in the Netherlands between 2006 and 2015. Metadata includes patient outcome, species of bacteria, and for 467 samples a link to an ENA run with the associated bacterial genome (S. pneumoniae only).

  Study EGAS00001005993

• NHLBI GO-ESP Family Studies: Pulmonary Arterial Hypertension

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. Pulmonary arterial hypertension (PAH) is a progressive disease characterized by widespread occlusion of the smallest arteries of the lungs. Pulmonary vascular obstruction leads to increased pulmonary vascular resistance, which subsequently causes heart failure with mean survival of 3 years. PAH occurs at all ages and affects women more than twice as frequently as men. Sporadic Idiopathic pulmonary arterial hypertension (IPAH), comprises 94% of what was formerly known as primary pulmonary hypertension, and is clinically and pathologically indistinguishable from familial PAH (FPAH). Most FPAH is due to mutation in BMPR2, including more than 120 families in the US. Our goal here is to find other genes that are a basis for FPAH, so we selected for exome sequencing 5 families among 40 who do not have mutation in BMPR2, or other known genes (ACVRL1, SMAD8, ENG) that rarely are the basis for FPAH.

  Study phs000354

• Population Architecture Using Genomics and Epidemiology (PAGE): Epidemiologic Architecture for Genes Linked to Environment (EAGLE) - BioVU Cancer Project

  As part of Population Architecture using Genomics and Epidemiology PAGE study (Phase I), the Epidemiologic Architecture using Genomics and Epidemiology (EAGLE I) project accessed both epidemiologic- and clinic-based collections. The epidemiologic-based collection of EAGLE I included the National Health and Nutritional Examination Surveys (NHANES), ascertained between 1991-1994 (NHANES III), 1999-2002, and 2007-2008. NHANES is a population-based cross-sectional survey now conducted every year in the United States to assess the health status of Americans at the time of ascertainment and to assess trends over the years of survey. Genetic NHANES consists of 19,613 DNA samples linked to thousands of variables including demographics, health and lifestyle variables, physical examination variables, laboratory variables, and exposures. NHANES is diverse with almost one-half of the samples (46.4%) coming from self-reported Mexican Americans and non-Hispanic blacks. In contrast to NHANES, BioVU is a clinic-based collection of >150,000 DNA samples from Vanderbilt University Medical Center linked to de-identified electronic medical records (EMRs). Approximately 12% of BioVU's overall DNA sample collection is from African American, Hispanic, and Asian patients. The overall goals of PAGE I and EAGLE I were broad and several-fold: Replicate genome-wide association study (GWAS)- identified variants in European Americans; Identify population-specific and trans-population genotype-phenotype associations; Identify genetic and environmental modifiers of these associations. NHANES is an excellent resource for the study of quantitative traits associated with common human diseases. However, given that the age range of NHANES spans childhood to late adulthood and not all diseases are surveyed, NHANES is less useful for the study of adult-onset diseases such as major cancers. Therefore, under American Recovery and Reinvestment Act (ARRA) funding, EAGLE as part of PAGE I defined eight major cancers sites for genetic analysis in BioVU, Vanderbilt's biorepository linked to de-identified EMRs. The eight major cancers defined for this study included melanoma, breast, ovarian, prostate, colorectal, lung, endometrial, and Non-Hodgkin's lymphoma (NHL). Cancer cases were defined using a combination of ICD-9 codes and tumor registry entries. Controls include BioVU participants without cancer and encompassing the age and gender distributions of cancer cases. Targeted genotyping of GWAS-identified variants for these diseases (124 SNPs) and ancestry informative markers (128 AIMs) was performed by the Center for Human Genetics Research Vanderbilt DNA Resources Core. After quality control, a total of 116 cancer-associated SNPs and 122 AIMs were available for downstream analyses.

  Study phs000559

• NHLBI TOPMed: The Genetics and Epidemiology of Asthma in Barbados

  Asthma is a complex disease where the interplay between genetic factors and environmental exposures influences susceptibility and disease prognosis. Asthmatics of African descent tend to have more severe asthma and more severe clinical symptoms than individuals of European ancestry. The baseline prevalence of asthma in Barbados is high (~20%), and from admixture analyses, we have determined that the proportion of African ancestry among Barbadian founders is similar to U.S. African Americans, rendering this a unique population to disentangle the genetic basis for asthma disparities among African ancestry populations in general. We therefore performed whole genome sequencing on 1,100 individuals from the Barbados Genetics of Asthma Study (BAGS), in order to generate additional discovery of rare and structural variants that may control risk to asthma.

  Study phs001143

• RNA-seq study of longitudinal blood cell samples from children at risk of type 1 diabetes

  The appearance of type 1 diabetes (T1D)-associated autoantibodies is the first and only measurable parameter to predict progression toward T1D in genetically susceptible individuals. However, autoantibodies indicate an active autoimmune reaction, wherein the immune tolerance is already broken. Therefore, there is a clear and urgent need for new biomarkers that predict the onset of the autoimmune reaction preceding auto-antibody positivity or reflect progressive b-cell destruction. Here we report the mRNA sequencing–based analysis of 306 samples including fractionated samples of CD4+ and CD8+ T cells as well as CD4, CD8 cell fractions and unfractionated PBMC samples longitudinally collected from seven children who developed beta-cell autoimmunity (Case subjects) at a young age and matched control subjects.

  Study EGAS00001004071

• Risk Assessment of Cerebrovascular Events (RACE) Study

  This study includes 1,220 cases with young onset stroke (stroke before age 60 years) who are participants of the larger RACE study. Risk Assessment of Cerebrovascular Events (RACE) is an on-going existing case-control study of stroke now involving over 5000 imaging confirmed cases of stroke and 5000 controls, recruited from seven centers in Pakistan. The study is aimed to investigate the genetic, biomarker and lifestyle determinants of stroke and its subtypes. Cases are eligible for inclusion in the study if they: (i) are aged at least 18 years; (ii) present with a sudden onset of neurological deficit respecting a vascular territory with sustained deficit at 24 hours verified by medical attention within 72 hours after onset (onset is defined by when the patient was last seen normal and not when found with deficit); and (iii) the diagnosis is supported by CT/MRI; and (iv) present with a Modified Rankin Score < 2 prior to the stroke. Findings from patient's history, 12-lead ECG and CT or MRI of the brain. The mandatory procedures for inclusion in this investigation are: (i) clinical verification of cerebrovascular event within 72 hours of onset; (ii) neuroimaging CT (non-contrast) or MRI (MRI is not a mandatory investigation but recorded whenever ordered by the attending physician); and (iii) 12-lead ECG. All other ancillary investigations ordered by the attending physician are recorded as well. The TOAST classification method is used to classify ischemic stroke based on aetiology whereas the Oxfordshire classification is used to classify stroke neuro-anatomically. Control participants for this subset of young onset stroke were individuals enrolled in the Pakistan Risk of Myocardial Infarction Study (PROMIS), a case-control study of acute MI based in Pakistan. RACE capitalizes on the genetic data (including information on GWAS) that has already been collected from the healthy participants enrolled in PROMIS. RACE and PROMIS share similar methodology of recruitment. Participants from both these investigations are derived from similar catchment areas, hence providing an attractive opportunity for RACE to utilize PROMIS controls as common controls for genetic investigations. Controls in PROMIS were recruited following procedures and inclusion criteria as adopted for RACE cases. In order to minimize any potential selection biases, PROMIS controls selected for this stroke substudy were frequency matched to RACE cases based on age and gender and were recruited in the following order of priority: (1) non-blood related or blood related visitors of patients of the out-patient department; (2) non-blood related visitors of stroke patients; (3) patients of the out-patient department presenting with minor complaints (e.g. back pain, minor gastric complaints). Control subjects from the PROMIS study were genotyped at the Wellcome Trust Sanger Institute on the Illumina 660W Quad array. The Center for Non-Communicable Diseases, Pakistan, serves as the coordinating center for both RACE and PROMIS. More information on these research investigations can be found at www.cncdpk.com. This young onset stroke component to the RACE study was funded through the Gene Environment Association Studies initiative (GENEVA, www.genevastudy.org as one of three studies designed to assess the genetics of young onset stroke and modification of genetic effects by smoking. GENEVA is part of the trans-NIH Genes, Environment, and Health Initiative (GEI). Genotyping of 1,220 young onset stroke cases was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to stroke through large-scale genome-wide association studies of cases and controls recruited within Pakistan. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000456

• De_novo_mutations_in_cell_free_foetal_DNA__cffDNA_

  This project is to develop and validate a method to detect de novo mutations in a foetal genome through deep sequencing of cell-free DNA from the plasma of pregnant women.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 EGAS00001000322

• Characterization of Prostate Cancer Organoids

  Using models from the LuCaP series as well as those generated at the National Cancer Institute, we have established organoids for in vitro mechanistic testing, including drug screening and genetic manipulation. The major findings from these continuing studies is the durability of organoids for maintaining complex subpopulation and intratumoral heterogeneity and the parallels between in vitro testing and patient outcomes. Existing data from prior releases includes whole-genome sequencing, whole-exome sequencing, single-cell and bulk RNA-seq, single-cell ATAC-seq, and SNP array. New data in this release is ChIP-seq data from three models and RNA-seq data from one model.

  Study phs001587

• Epigenome wide DNA methylation assay of gingivo-buccal oral squamous cell carcinoma using single base resolution high throughput array

  Gingivo-buccal oral squamous cell carcinoma (OSCC-GB) is the most common cancer among men in India and is associated with high mortality. Although OSCC-GB is known to be quite different from tongue cancer in its genomic presentation and its clinical behavior, it is treated identically as tongue cancer. Predictive markers of prognosis and therapy that are specific to OSCC-GB are, therefore, required. To achieve this, we have carried out epigenomic (n=87) profiling of paired tumor-normal tissues collected from OSCC-GB patients from India and genome-wide DNA methylation assays were performed. DNA was isolated using DNeasy Blood and Tissue Kit (Qiagen). The purity and concentration was estimated using NanoDrop 2000 (Thermo Fisher Scientific). Approximately 500 ng genomic DNA from each sample was used for sodium bisulfite conversion using the EZ DNA methylation Gold Kit (Zymo Research, USA). Genome-wide DNA methylation was assayed using iScan (Illumina), for paired tumour and adjacent normal samples of 25 patients using the Infinium Human Methylation450 BeadChip and of 62 patients using the Infinium MethylationEPIC BeadChip.

  Study EGAS00001003896

• Clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancers defined by genomic analysis

  Ductal Carcinoma In Situ (DCIS) is the most common form of pre-invasive breast cancer and despite treatment a small fraction (5-10%) of DCIS patients present with invasive disease many years later. A fundamental biologic question is whether the invasive disease recurring in the same breast is established by tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial pure DCIS lesion and paired invasive recurrent tumors in 95 patients together with single cell DNA sequencing in a subset of cases. Our data shows that in 75% the invasive recurrence was clonally related to the initial DCIS, suggesting that the tumor cells were not eliminated during the initial treatment with surgery +/- radiotherapy. Surprisingly however, 18% were clonally unrelated to the DCIS, representing new independent lineages, and 7% of cases were ambiguous. Our findings show that although DCIS is often the precursor of invasive recurrence, a significant fraction of invasive recurrences are unrelated to the initial DCIS. This knowledge is essential for accurate risk evaluation of DCIS treatment de-escalation strategies and the identification of predictive biomarkers.

  Study EGAS00001005784