3901 results for "*geneti*"

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• Functional Significance of Prostate Cancer Risk-SNPs

  Prostate Cancer (PrCa), the most frequently diagnosed solid tumor in men in the U.S., results in ~192,000 new cases and ~27,000 deaths per year. Although the variation of PrCa incidence is likely to be the result of several factors, there is a large body of literature that strongly implicates a genetic etiology. Genome-wide association studies (GWAS) have emerged as the most widely used contemporary approach to identify genetic variants (in particular SNPs) that are associated with increased risk of human disease. For PrCa, at least five GWAS have now been performed yielding a substantial number of well-validated SNPs that are associated with an increased risk of PrCa, and that number continues to grow. A significant problem for many of the PrCa risk-SNPs identified so far, however, is that they do not lie within or near a known gene and they have no obvious functional properties. These findings suggest that many (if not most) of these risk-SNPs will be located in regulatory regions that control gene expression rather than in coding regions that may directly affect protein function. Therefore, in order to define the functional role of currently known risk-SNPs, the target genes must first be identified. A promising strategy to address this problem involves the use of expression quantitative trait loci (eQTL) analysis. Unfortunately, most of the publically available SNP-Transcript eQTL datasets utilize lymphoblastoid cells with only a handful using tissue from target organs. Although useful, these datasets alone are unlikely to be sufficient. Recent studies have demonstrated that gene expression and gene regulation occur in both a tissue-specific and tissue independent fashion and suggest that a complete repertoire of regulatory SNPs can only be uncovered in the context of cell type specificity. To date, such a tissue-specific dataset for normal prostate tissue does not exist. In this study, we have constructed a normal prostate tissue specific eQTL data set.

  Study phs000985

• eMERGE Network Phase III: HRC SNV and 1000 Genomes SV Imputed Array Data of 105,000 Participants

  The Electronic Medical Records and Genomics (eMERGE) Network is a National Institutes of Health (NIH)-organized and funded consortium of U.S. medical research institutions. The primary goal of the eMERGE Network is to develop, disseminate, and apply approaches to research that combine biorepositories with electronic medical record (EMR) systems for genomic discovery and genomic medicine implementation research. eMERGE was announced in June 2007 and began its third phase in September 2015. eMERGE Phase III (June 2015 - June 2020) consists of 10 study sites, two central sequencing and genotyping facilities, and a coordinating center. Included in this study are: Human Reference Consortium (HRC) single nucleotide variants and 1000 Genomes structural variants imputed array data of 105,108 eMERGE participants from nine Phase III study sites and three Phase II study site collaborators. Corresponding demographics, body mass index measurements. Case/control status for the following phenotypes: Abdominal aortic aneurysm; Ace-Inhibitor/Cough; Attention Deficit Hyperactivity Disorder; Age-related macular disease; Appendicitis; Asthma; Atopic Dermatitis; Autism; Benign Prostatic Hyperplasia; Carotid artery disease as a Quantitative Measure; caMRSA; Cataract; Clostridium difficile colitis; Extreme Obesity; Chronic Kidney Disease; Chronic Kidney Disease and Type 2 Diabetes; Chronic Kidney Disease, Type 2 Diabetes and Hypertension; Colon Polyps; Cardiorespiratory Fitness; Dementia; Diverticulosis; Diabetic retinopathy; Gastroesophageal Reflux Disease; Glaucoma; Height; Heart failure; Hypothyroidism; Lipids; Ocular hypertension; Peripheral Arterial Disease; QRS duration; Red blood cell indices; Remission of Diabetes after ROUX-EN-Y gastric bypass surgery; Resistant hypertension; MACE while on Statins; Type 2 Diabetes; Venous Thromboembolism; White blood cell indices; and Zoster virus infection. Study sites and participants include: Boston Children's Hospital: 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. Children's Hospital of Pennsylvania (CHOP): The Center for Applied Genomics (CAG) at the Children's Hospital of Philadelphia (CHOP) is a high-throughput, highly automated genotyping and sequencing facility equipped with state-of-the-art genotyping and sequencing platforms. Children who are treated at the Children's Hospital Healthcare Network and their parents may be eligible to take part in a major initiative to collect more than 100,000 blood samples, covering a wide range of pediatric diseases. A large majority of participants consenting to prospective genomic analyses also consent to analysis of their de-identified electronic health records (EHRs). EHRs are longitudinal, with a mean duration of 6.5 years. Cincinnati Children's Hospital Medical Center/Boston's Children's Hospital (CCHMC/BCH): Cincinnati Children's Hospital Medical Center (CCHMC) is a pediatric institution dedicated to improving health and welfare of children and to the discovery and practical application of new genomic information to the ordinary care of children. CCHMC brings an extraordinary faculty to eMERGE III who are committed to gain a better understanding of the genesis of disease and to elucidate the mechanisms of diseases that afflict children, specifically pediatric disease phenotypes that will leverage the available eMERGE adult genomic data and electronic medical records (EMRs) to discover meaningful use results. Generation of EMR phenotype algorithms, informed by natural language processing, using heuristic and machine learning methods is ongoing. CCHMC has developed tools to evaluate adolescent return of results preferences, examined the ethical and legal obligations and potential to reanalyze results, and developed clinical decision support for phenotyping, test ordering, and returning sequencing results. The success of these eMERGE III studies is enhanced by the ongoing institutional investment made in the CCHMC Biobank, the comprehensive EMR (EPIC), the i2b2 de-identified medical record data warehouse, and hundreds of faculty and senior staff who make genomics or informatics an active focus of their research. Columbia University: Columbia University Medical Center/New York Presbyterian (CUMC/NYP) Hospital system is one of the nation's largest and most comprehensive hospital systems with over 2 million inpatient and outpatient yearly visits that serves a racially and ethnically diverse urban patient population. The Columbia University GENomic Integration with EHR (GENIE) research study contributed and shared phenotype and genotype data for individuals who were recruited as part of a diverse array of initiatives within the hospital, including Northern Manhattan Study (NOMAS), Pediatric Cardiac Genomic Consortium (PCGC), Caribbean Hispanics with Familial and Sporadic Late Onset Alzheimer's disease (AD), Alzheimer's Disease Sequencing Project (ADSP), and Genetics of Chronic Kidney Disease study. Some of these individuals had kidney or neurological problems, some were healthy adult volunteers with self-reported health status information from the medically underserved Northern Manhattan community, and others were pediatric patients with cardiac conditions. For the kidney disease cohort, patients with the diagnosis of Chronic Kidney Disease (CKD) and healthy controls were recruited to the Columbia University CKD biobank. For the NOMAS cohort, eligible participants were stroke-free, were 40 years old, and resided for at least 3 months in a Northern Manhattan household with a telephone. The PCGC study recruited parent-offspring trios with pediatric probands diagnosed with congenital heart defects (CHD). For the Caribbean Hispanics with Alzheimer's disease project, individuals from families affected by AD and with sporadic AD were recruited, along with unrelated controls. Samples for the ADSP study have been selected from well-characterized cohorts of individuals with AD diagnosis. Geisinger Health System: A research cohort of adult Geisinger Clinic patients was enrolled from community-based primary care clinics of the Geisinger Health System. Patients were eligible for enrollment if they were a primary care patient of a Geisinger Clinic physician and were scheduled for a non-emergent clinic visit. All participants provided written informed consent and HIPAA authorization. Consenting patients agreed to provide blood samples for broad biomedical research use, and permission to access data in their Geisinger electronic medical record for research. The enrollment rate was 90% of patients approached. The demographics of the cohort approximate those of the Geisinger Clinic outpatient population. Research blood samples were collected during an outpatient clinical phlebotomy encounter. Research blood samples are coded and stored in a central biorepository. Samples are linkable to clinical data in a de-identified manner for research via an IRB-approved data broker process. For genomic analysis, DNA is extracted from EDTA-anticoagulated whole blood. Partners Health Care (Harvard): The Partners HealthCare Biobank is a large research program designed to help researchers understand how people's health is affected by their genes, lifestyle, and environment. This large research data and sample repository provides access to high-quality, consented blood samples to help foster research, advance our understanding of the causes of common diseases, and advance the practice of medicine. For the Partners research community (Massachusetts General Hospital and Brigham and Women's Hospital), the Biobank provides: Banked samples (plasma, serum, and DNA) collected from consented patients Blood samples that were discarded after clinical testing in the Crimson Cores maintained in the Brigham and Women's Hospital and Massachusetts General Hospital Pathology Departments Sample handling and preparation services Link to the biobank data to the Partners Research Patient Data Registry (RPDR) a research instance of our electronic clinical chart Data access through our research portal. To date, over 60,000 Partners patients have given their consent to enroll, give a blood sample, receive research results and agreed to be re-contacted for additional research studies. The Biobank has enabled Partners investigators to compete for nationally recognized grants in personalized medicine such as a clinical electronic Medical Records and Genomics network (eMERGE) site and the national All of US program. The Biobank currently supports over 120 Partners investigators and over 100 million dollars in NIH research. Kaiser Permanente Washington with the University of Washington and the Fred Hutchinson Cancer Research Center: KPWA participants were enrolled in the eMERGE Network through the Northwest Institute of Genetic Medicine (NWIGM) biorepository, and provided the appropriate consent to receive clinically relevant genetic results (N~8,073.) NWIGM is based at the University of Washington and co-managed by the University of Washington and KPWA. The purpose of the NWIGM biorepository is to build infrastructure and resources to carry out a broad range of future genetic research. KPWA members enrolled in the biorepository are asked to provide informed consent to providing a DNA sample for storage in the NWIGM biorepository. The consent is purposefully broad to serve the dual purpose of reducing the burden on researchers who wish to use this biorepository and the IRB committees who will be responsible for reviewing these requests in the future. Participants were eligible if aged 50 - 65 years old at the time of their enrollment into the NWIGM repository, living, enrolled in KPWA's integrated group practice, and had completed an online Health Risk Appraisal. The selection algorithm was based on several data sources from the EHR at KPWA. 1) Demographics - participants with self-reported race as Asian ancestry were prioritized and selected to enrich for non-European ancestry. The KPWA eMERGE cohort includes n=1,245 members of Asian ancestry. 2) Participants were also selected for a history of colorectal cancer (n=1,002), in order to allow us to enrich germline pathogenic variants. Essentia Institute of Rural Health, Marshfield Clinic, Pennsylvania State University (Marshfield): The Marshfield Clinic Personalized Medicine Research Project is a population-based biobank in central Wisconsin with more than 20,000 adult subjects who provided written, informed consent to access their medical records and provided a blood sample from which DNA was extracted and plasma and serum stored. In addition to an average of 30 years of medical history data, a questionnaire about environmental exposures, including a detailed food frequency questionnaire, is available to facilitate gene/environment studies. Mayo Clinic: The Mayo Vascular Disease Biorepository is a disease-specific biobank for vascular diseases including peripheral arterial disease (PAD). PAD patients were identified from individuals referred to the non-invasive vascular laboratory for lower extremity arterial evaluation. Since 1997, laboratory findings have been recorded into an electronic database employing an in-house software package for data archiving and retrieval;this data becomes part of the Mayo EMR. Patients referred to the center with suspected PAD undergo a comprehensive non-invasive evaluation including the ankle-brachial index (ABI) - the ratio of blood pressure measured in the upper arms divided by blood pressure measured at the ankles. Controls subjects are identified from patients referred to the Cardiovascular Health Clinic for stress ECG. The prevalence of PAD in patients with normal exercise capacity who do not have inducible ischemia on the stress ECG , was <1%. Data regarding risk factors for atherosclerosis such as diabetes, dyslipidemia, hypertension, and smoking are ascertained from the EMR. Case control study of venous thromboembolism (PI John Heit) Controls from a case control study of pancreatic cancer (PI Gloria Petersen) Mayo Clinic Biobank. Icahn School of Medicine at Mount Sinai School (Mt. Sinai): The Institute for Personalized Medicine (IPM) Biobank Project is a consented, EMR-linked medical care setting biorepository of the Mount Sinai Medical Center (MSMC) drawing from a population of over 70,000 inpatients and 800,000 outpatient visits annually. MSMC serves diverse local communities of upper Manhattan, including Central Harlem (86% African American), East Harlem (88% Hispanic Latino), and Upper East Side (88% Caucasian/white) with broad health disparities. IPM Biobank populations include 28% African American (AA), 38% Hispanic Latino (HL) predominantly of Caribbean origin, 23% Caucasian/White (CW). IPM Biobank disease burden is reflective of health disparities with broad public health impact: average body mass index of 28.9 and frequencies of hypertension (55%), hypercholesterolemia (32%), diabetes (30%), coronary artery disease (25%), chronic kidney disease (23%), among others. Biobank operations are fully integrated in clinical care processes, including direct recruitment from clinical sites, waiting areas and phlebotomy stations by dedicated Biobank recruiters independent of clinical care providers, prior to or following a clinician standard of care visit. Recruitment currently occurs at a broad spectrum of over 30 clinical care sites. Northwestern University: The NUgene Project is a repository with longitudinal medical information from participating patients at affiliated hospitals and outpatient clinics from the Northwestern University Medical Center. Participants'DNA samples are coupled with data from a self-reported questionnaire and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 2 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators. Vanderbilt University Medical Center: BioVU, Vanderbilt's DNA databank, was designed as an enabling resource for exploration of the relationships among genetic variation, disease susceptibility, and variable drug responses. BioVU acquires DNA from discarded blood samples collected from routine patient care. The biobank is linked to de-identified clinical data extracted from Vanderbilt's EMR, which forms the basis for phenotype definitions used in genotype-phenotype correlations. BioVU is currently the largest single site DNA collection world-wide, at >235,000 samples as of spring 2017.

  Study phs001584

• Whole-Genome and Exome Sequencing in clear-cell Renal Cell Carcinoma (ccRCC)

  Study to evaluate the molecular genetics of ccRCC through integrative analyses of tumors and tumorgrafts using multiple platforms in clinically annotated samples. Genome and exome data for patients giving consent to have the information available on a public, secure, database is being submitted.

  Study phs000491

• Genetic Analysis of Parkinson's Disease

  A portion of the sample includes multiplex PD families recruited as part of a previously funded study (R01NS037167; PI: Tatiana Foroud). Families were ascertained initially through a living affected sibling pair. Subsequently, ascertainment was loosened to include PD probands having a positive family history of PD in a first degree relative, who was not required to be part of the study. All individuals completed an in-person evaluation at one of the > 65 Parkinson Study Group sites participating in this study. Individuals completed a detailed evaluation that included the Unified Parkinson Disease Rating Scale (UPDRS), Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS) and a diagnostic checklist that implemented the UK PD Brain Bank inclusion and exclusion criteria. An autopsy program was established in this study and brain tissue for confirmation of diagnosis and further experimental study are available from over 100 participants. Autopsy confirmation of the PD diagnosis was nearly 100% for those who met UK PD Brain Bank criteria. In addition, because this was a cross sectional study and family members were often seen very early in disease course, among those who did not meet UK PD Brain Bank criteria but had a subsequent autopsy, a significant subset (>1/3) had autopsy confirmation of PD. The second source of samples is from the NINDS Human Genetics DNA and Cell Line Repository located at the Coriell Institute. Currently DNA from 4,509 PD patients is available from the Coriell Institute. We restricted the selected sample to include only Caucasians and ensured there was no overlap with samples contributed by the PROGENI Study.

  Study phs001004

• The African American Breast Cancer Epidemiology and Risk (AMBER) Consortium Study

  The AMBER Consortium Study was formed to pool interview data, questionnaire data, and biological samples from epidemiological studies of breast cancer in African-American women to discover the potential causes of early-onset and aggressive breast cancer in African-American women. AMBER is funded through a Program Project grant from the National Cancer Institute. Genetic data submitted to dbGaP come from participants in the Carolina Breast Cancer Study, Women's Circle of Health Study, and Black Women's Health Study. The P01 consists of four scientific projects; the aims include follow-up on previous GWAS findings for breast cancer susceptibility in AA women as well as investigation of SNPs in candidate genes in biologically plausible pathways. These SNPs were genotyped using DNA from 3130 African-American women with breast cancer and 3700 controls. Descriptions of the original studies that provided the data and samples for this collaborative study are given below. The Carolina Breast Cancer Study (CBCS): a North Carolina population-based case-control study of breast cancer, conducted in three phases. The current study phase, phase 3 (years 2008-2014), includes women residents in 44 counties. CBCS phases 1 and 2 were conducted in 24 counties. Breast cancer cases are identified using Rapid Case Ascertainment in cooperation with the NC Central Cancer Registry. Controls were identified for phases 1 and 2 only (1993-1996 and 1996-2001), using Division of Motor Vehicles lists for women under age 65 and Health Care Financing Administration lists for women 65 and older. Randomized recruitment was used to oversample AA women and women under age 50. In-depth interviews are conducted by study nurses in participants' homes to obtain information on potential risk factors for breast cancer. DNA samples have been obtained from most participants. Overall response rates for Phases 1 and 2 were 74% for AA cases and 54% for AA controls. Phase 3, conducted in 44 counties from 2008-2014, includes cases only. The response rate for AA cases in Phase 3 was 70.5%. The Women's Circle of Health Study (WCHS): a multi-site case-control study in New York City (NYC) and New Jersey (NJ) aimed at evaluating risk factors for early and aggressive breast cancer in women of AA and EA ancestry. Recruitment in NYC took place between January 2002 and December 2008 and involved hospital-based ascertainment of cases, while controls were identified through random digit dialing (RDD). Recruitment at the NJ site started in March 2006 and is ongoing. Phase I of the study ended in April 2012 and covered seven counties in NJ. WCHS2 includes two additional counties. Cases in NJ were identified from 2006 to 2012 by the NJ State Cancer Registry using rapid case ascertainment. Controls were initially recruited though RDD (2006 to 2010) and later through community-based efforts (2009-2012). In-person interviews ascertained data on established and suspected risk factors for breast cancer. DNA samples were obtained. Among eligible AA women, 75% in NY and 54% in NJ completed an interview and provided a biologic specimen. Black Women's Health Study (BWHS): an ongoing prospective cohort study of health and illness among U.S. black women, with a focus on cancer. The study began in 1995 when 59,000 AA women 21-69 years of age from across the United States completed a 14-page postal health questionnaire. The median age at entry was 38, and participants were residents of 17 states in mainland U.S.: Northeast, 28%; South, 30%; Midwest, 23%; West, 19%. The baseline questionnaire elicited information on a wide range of variables, including demographic factors, use of medical care, family history of breast cancer, reproductive and medical history, cigarette and alcohol use, weight, height, waist and hip circumference, medication use, diet, and exercise. Biennial follow-up questionnaires ascertain new cases of breast cancer and other illnesses and update covariate information. Medical record and cancer registry data are sought for all participants who report a diagnosis of breast cancer. As of 2014, approximately 80% of the baseline cohort have completed follow-up. DNA samples were obtained from about 50% of participants. BWHS data for the AMBER consortium were prepared as a nested case-control study, with controls frequency-matched to cases on year of birth, geographic region, and most recent questionnaire completed prior to the end of the at-risk period.

  Study phs000669

• Kids First and INCLUDE: Down Syndrome, Heart Defects, and Acute Lymphoblastic Leukemia

  This project is a collaboration with the trans-NIH INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project, which seeks to improve health and quality-of-life for individuals with Down syndrome, and NHLBI's TransOmics for Precision Medicine (TOPMed) program, which seeks to apply omics technologies to improve scientific understanding of the fundamental biological processes that underlie heart, lung, blood, and sleep (HLBS) disorders. The data is also available at the INCLUDE Data Hub. Down syndrome (DS), which occurs due to trisomy 21, is one of the strongest risk factors for both congenital heart disease (CHD) and acute leukemia. For instance, children with DS have a 2000-fold increased risk of atrioventricular septal defects (AVSD) and a 20-fold increased risk of acute lymphoblastic leukemia (ALL). An important and innovative aspect of the Kids First program is understanding the overlap between structural birth defects and childhood cancer. Notably, the background of DS predisposes children to both of these phenotypes, however, the genomic architecture of risk remains largely undiscovered. In this joint Kids First/TOPMed/INCLUDE project, we are currently including >2,000 samples for whole-genome sequencing, including: 1) paired germline-tumor samples from children with DS-ALL; and 2) samples from families with DS-CHD. This work will advance our understanding of the developmental pathways that may lead to both structural birth defects and childhood cancer. The objectives of this study are to determine the genetic variants underlying AVSD and ALL risk in children with DS. Therefore, the aims of our study are: 1) compare whole-genome sequencing (WGS) data between children with documented DS-AVSD and children with DS who have structurally normal hearts to identify genetic variants that perturb heart development; and 2) compare WGS data between children with documented DS-ALL and children (from Aim 1) with DS who do not have a known history of ALL. We will also examine associations between germline mutations and somatic genomic features. This study will address the fundamental question of why children with DS have an elevated risk of AVSD and ALL. Insights into the genes that drive DS-AVSD and DS-ALL may have implications for improved genetic counseling, surveillance, clinical management, and treatment strategies for these children. Additionally, our findings may inform targeted therapies or interventions for children without DS who are at risk for structural birth defects and cancer. Additional Pediatric Cardiac Genetics Consortium (PCGC) data from children affected with Down syndrome and congenital heart disease are accessible through two separate dbGaP studies: phs001138 (Kids First) and phs001194 (TOPMed).

  Study phs002330

• Diet, Genetic Factors, and the Gut Microbiome in Crohn's Disease

  We investigate the hypothesis that consistent changes in the human gut microbiome are associated with Crohn's disease, a form of inflammatory bowel disease, and that altered microbiota contributes to pathogenesis. Analysis of this problem is greatly complicated by the fact that multiple factors influence the composition of the gut microbiota, including diet, host genotype, and disease state. For example, data from us and others document a drastic impact of diet on the composition of the gut microbiome. No amount of sequencing will yield a useful picture of the role of the microbiota in disease if samples are confounded with uncontrolled variables. We aim to characterize the composition of the gut microbiome while controlling for diet, host genotype, and disease state. Diet is controlled by analyzing children treated for Crohn's disease by placing them on a standardized elemental diet, and by testing effects of different diets on the gut microbiome composition in adult volunteers. Genotype is analyzed by large scale SNP genotyping, which is already underway and separately funded--team member Hakon Hakonarson is currently genotyping 50 children a week at ~half a million loci each and investigating connections with inflammatory bowel disease. Clinical status is ascertained in the very large IBD practice in the UPenn/CHOP hospital system. Effects of diet, host genotype, and disease state on the gut microbiome are summarized in a multivariate model, allowing connections between microbiome and disease to be assessed free of confounding factors. This project is divided into four sub-studies. In the Fecal Storage Methods (FSM) study, methods of stool storage and DNA extraction are compared to examine their impact on DNA sequence analysis results. The Controlled Feeding Experiment (CaFE) addresses the effects of controlled diets on the gut microbiome. In the Cross-sectional Study of Diet and Stool Microbiome Composition (COMBO), the effects of diet analyzed using surveys and deep sequencing of stool specimens. The fourth study, Pediatric Longitudinal Study of Elemental Diet and Stool Microbiome Composition (PLEASE), examines the effects of an elemental diet treatment on pediatric patients diagnosed with inflammatory bowel disease (IBD), particularly Crohn's disease. Fecal Storage Methods (FSM): Cross-sectional study Controlled Feeding Experiment (CaFE): Controlled trial Cross-sectional Study of Diet and Stool Microbiome Composition (COMBO): Cross-sectional study Pediatric Longitudinal Study of Elemental Diet and Stool Microbiome Composition (PLEASE): Longitudinal cohort study

  Study phs000252

• Discovery and Characterization of Genetic Risk Loci in Sjogren's Syndrome

  The Sjögren's Genetics Network (SGENE) is an international collaboration focused on identifying and understanding the genetic variations that influence Sjögren’s pathology. Collectively, SGENE collaborators from 26 different sites (5 in the United States; 21 in foreign countries) have recruited a large cohort of geographically diverse participants of European ancestry. Recruitment, sample collection, and genotyping were performed at unique SGENE sites in compliance with local institutional review board approval. High-density SNP genotyping data were collated by the Oklahoma Medical Research Foundation (OMRF) and used to perform a GWAS of Sjögren's of European ancestry. Participants underwent extensive medical assessment for Sjögren's Syndrome using internationally accepted American-European Consensus Group (AECG) classification criteria or the American College of Rheumatology/European League Against Rheumatism classification criteria. Data quality control, GWAS imputation using the Haplotype Reference Consortium, panel version 1.1, and dbGaP preparation/posting were performed at the OMRF. To facilitate research focused on understanding the genetics of Sjögren's syndrome, the Genomic Summary Results from this GWAS are being made available herein using a total of n=3232 Sjögren's cases and n=17,481 controls. A total of n=8962 controls were obtained from our SGENE collaborators or from our previous study (Lessard, et al. Nature Genetics 2013. PMID: 24097067). To achieve adequate case-to-control ratios for the GWAS analyses, population-based control GWAS data were also obtained from dbGaP (phs000428.v2.p2; phs000672.v1.p1; phs000196.v3.p1; phs000187.v1.p1). In accordance with IRB approval, subject consents, and data sharing restrictions, we are also making available the individual-level genotyping data for a subset of Sjögren's cases (n=1,199) that were genotyped at the OMRF.

  Study phs002723

• Kidney Two-Hit Mapping

  Germ-line genetic variants identified thus far generally account for only part of the genetic risk predicted for most cancers. A component of the remaining risk may be explained by functionally consequent genetic variants that are individually very rare (or private to that individual's family). While their identification may be highly informative for cancer etiology and biological knowledge, strategies that allow for agnostic (genome-wide) identification of such genes are not straight forward. This is particularly true for rare cancers where sufficient numbers of patients may simply not be available for appropriate statistically powered studies. In this project we have explored a study design based around the concept of "two-hit mapping" using the co-occurrence of germ-line and somatic mutations in the same gene to assist in the identification of susceptibility genes. The dataset includes 54 kidney cancer patients selected for enrichment of genetic disease, that is patients with: early age of onset and/or family history and/or bilateral disease. Germ-line and somatic (kidney cancer) tumor sequencing was carried out. These data may improve our understanding of kidney cancer.

  Study phs001971

• Epigenetics of Cocaine and Nicotine Addiction

  This project characterizes DNA methylation and gene expression changes that occur in the human brain, specifically in neurons from the rostral striatum. Major advances from NIDA funded initiatives for noninvasive neuroimaging studies have made it possible to study neuroanatomical, neurochemical and functional changes in the human brain that contribute to the vulnerability to abuse drugs, together with the neurotoxic consequences of years of drug misuse. Animal models have been developed to explain the fundamental behavioral and biological mechanisms of addiction, including reward, tolerance and dependence. From these studies, we learned that cocaine abuse not only alters the epigenetic status of genes, but also induces particular epigenetic modifications depending on the frequency of the drug's administration. Certain genes are switched on by infrequent (short-term exposure) administration, while others are switched on only after chronic administration (addiction/dependence). Animal studies have also suggested that cocaine-seeking habits modeling chronic cocaine addiction in humans depend upon dopamine-dependent serial connectivity linking the ventral (nucleus accumbens) with the dorsal striatum (caudate nucleus). The primary goal of this study is to identify DNA methylation and gene expression changes that occur in the transition from recreational cocaine use to cocaine addiction. High throughput sequencing studies were designed to investigate unique postmortem human brain specimens from individuals that met criteria for cocaine dependence, as compared to unaffected age-matched controls. Brain biospecimens were available from the University of Miami Brain Endowment BankTM, from a collection of phenotypically well-characterized postmortem tissues sampled from chronic cocaine abusers that came to autopsy. This biobank of postmortem brain specimens and annotated genomic data serve as a research resource to support NIDA's scientific mission.

  Study phs001377

• Whole Exome Sequencing Identifies

  Combined Immunodeficiency with Multiple Intestinal Atresias (CID-MIA) is a rare genetic disorder with the cause previously unknown. Symptoms of CID-MIA include atresias in the small and/or large intestine, as well as immunodeficiency. In this study, we sequenced the whole exome of 5 unrelated CID-MIA patients as well as their healthy family members, and identified deleterious homozygous or compound heterozygous mutations in the gene TTC7A in all the 5 patients, as well as in 3 additional patients with Sanger sequencing. Our findings strongly indicate TTC7A dysfunction to be the cause for CID-MIA.

  Study phs000641

• Large Scale Meta-analysis Characterizes Genetic Architecture for Common Psoriasis-associated Variants

  The genotypes obtained from the Affymetrix Biobank Plus array constituted one of eight Caucasian datasets used in a large genome-wide meta-analysis of the association of psoriasis cases versus unaffected controls. With a combined effective sample size of > 39,000 individuals, this study identified 16 new psoriasis loci achieving genome-wide significance, increasing the total number of identified psoriasis loci for European-ancestry populations to 63.

  Study phs001306

• NextGen Consortium: Globin Gene Expression in Sickle Cell Genotype-Specific iPS Cells

  Implement an efficient, highly reproducible and 'scalable' system for the production of large numbers of sickle cell anemia-specific iPS cells (iPSC). Derive and characterize a novel, in vitro system for the production of an unlimited supply of erythroid lineage cells from the directed differentiation of 'clinical grade' transgene-free iPS cells; use this system to recapitulate erythroid-lineage ontogeny in vitro with the sequential development of primitive and definitive erythropoiesis, accompanied by the appropriate expression of stage-specific globin genes. Identify developmental gene expression profile differences between erythroid precursors that produce primarily HbF and those that produce primarily HbA or HbS. Determine the effects of the three known HbF major quantitative trait loci (QTL) on globin gene expression in disease-specific iPS cells during in vitro erythropoiesis. Search for novel HbF genetic modifiers associated with markedly elevated HbF levels found in sickle cell anemia patients naturally, or in response to hydroxyurea treatment, by examining gene expression profiles and mRNA sequence of their iPSC-derived erythroid cells. Develop and use a CRISPR-based gene editing platform to study the effect of novel HbF genetic modifiers, explore globin switching, and correct the HbS mutation in sickle iPSC lines.

  Study phs001212

• Detection and Targeting of Splicing Deregulation in Pediatric Acute Myeloid Leukemia Stem Cells

  This study evaluates the gene expression and splicing changes between pediatric patients with and without Acute Myeloid Leukemia (AML) and pediatric and adult patients with AML. We obtained bone marrow or peripheral blood from patients and isolated CD34+ stem and/or progenitor cells from pediatric patients with AML (10) or without AML (6) and adult patients with AML (5). In parallel, a targeted analysis for known, deleterious, genetic mutations in the KRAS, NRAS, and KMT2C genes identified 2, 5, and 6 AML patients with alterations, respectively. Additionally, Tapestri analysis further identified a mutation in the intronic region of the SF3B1 gene in multiple pediatric AML patients. RNA-Seq was performed on the purified cell populations at The Scripps Research Institute Next Generation Core on an Illumina NextSeq 500 sequencer with 150bp paired-end reads.These datasets revealed that, similar to adult AML, pediatric AML samples were enriched for Leukemia Stem Cells (LSC) markers. A deeper analysis showed widespread dysregulation of splicing in pediatric AML samples compared to age-matched non-leukemic samples. In addition, the splicing regulator RBFOX2 was downregulated with an accompanying increase in specific CD47 splice isoforms in the pediatric AML samples. Thus, the increased presence of LSCs in pediatric AML is possibly driven by global splicing deregulation, and the treatment with splicing modulators like Rebecsinib has a potential therapeutic value for eradicating LSCs in these patients.

  Study phs003196

• Yale Center for Mendelian Genomics (YCMG)

  From 2012-2021, Yale University was home to one of four national centers created by the National Institutes of Health (NIH) to study the genetics of rare inherited diseases. Researchers at Yale University, University of Washington, the Broad Institute and a center operated jointly by Baylor University and Johns Hopkins University analyzed the genomes of thousands of patients who suffer from more than 6,000 rare Mendelian disorders affecting more than 25 million individuals in United States. The Centers for Mendelian Genomics (CMG) applied next-generation sequencing and computational approaches to discover the genes and variants that underlie Mendelian disorders. The discovery of new genes that cause Mendelian conditions expanded our understanding about their biology to facilitate their diagnosis, and potentially indicate new treatments. The CMG provided free exome sequencing and analysis to collaborating investigators for qualified phenotypes.

  Study phs000744

• Somatic Mutations and Cell Lineage in the Human Brain

  Genetic mutations causing human disease are conventionally thought to be inherited from one's parents and present in all somatic (body) cells. Increasingly however, somatic mutations are implicated in neurological diseases. Somatic mutations that arise during the cell divisions of prenatal brain development are inherited in clonal fashion and can cause neurodevelopmental diseases, even when present at low levels of mosaicism. In this study we use whole genome, RNA, and ATAC sequencing of single cells and bulk tissue to identify somatic mutations in control, and some disease, brains to: 1) identify and catalogue the mutations which shape the somatic neuronal genome; 2) perform a cell lineage analysis of the human brain using clonal somatic mutations in cortical neurons; 3) determine patterns of somatic mutations at different ages and in aging related disease phenotypes; and 4) relate cell lineage patterns to cell phenotype in the human brain through cell type-specific analyses.

  Study phs001485

• Maintenance of Brain Tumor Profile on Organotypic Brain Slice Culture (OBSC)

  We used uncultured tumor resection tissue from an NF2 mutation-driven grade II meningioma (MG-II) to investigate whether tumors engrafted onto organotypic brain slice cultures (OBSCs) maintained the genetic profile of the parent tumor. We prepared three groups of samples for whole exome sequencing (WES) from the same pool of dissociated MG-II tissue. Group HT is the original uncultured human tumor tissue (n = 3). Group CL is the parent tumor tissue expanded in standard in vitro cell culture until the minimum number of cells required for WES had grown. Because of initial cell loss and subsequent clonal expansion, this required six passages over the span of approximately one month (n = 3). Group BSHT is the uncultured tumor resection tissue engrafted onto OBSCs and subsequently dissected from the OBSCs at the conclusion of our standardized assay length (4 days; n = 4). WES analysis showed that tumor tissue engrafted onto OBSCs maintained a significant genetic resemblance to the parent tumor, while tumor tissue expanded in vitro displayed a distinctly different profile. Furthermore, the mutational profiles of all four BSHT biological replicates were markedly similar, indicating that each OBSC-engrafted tumor indeed contained a representative sample of the original patient tumor. A closer look at the hallmark NF2 mutations existing within all samples revealed that while all samples from the original tumor (HT1-3) and the OBSC-engrafted tumor (BSHT1-4) maintain the frame shift deletion at V24, this mutation was lost in all samples expanded in vitro (CL1-3) and replaced by mutations in other areas. Together, this data suggests that the rapid assay design and tumor-accommodating niche of our OBSC platform enables effective maintenance of the original patient tumor profile. The BBsplit algorithm from the BBtools suite was run on all samples to eliminate rat DNA contamination in the BSHT samples as well as to account for any biases that may result as a part of that process. Only the reads that were binned to the human reference were used for subsequent analysis. Reads were then mapped to the GRCh38 version of the human genome with BWA v0.7.17 and realigned together with ABRA2 v.23. Quality control was implemented using the GATK/Picard v4.1.7.0 toolkit. Somatic variants were called for each sample using the MuTect2 algorithm v4.1.7.0. Variants were merged into a single cohort variant call file and then converted to MAF via vcf2maf v1.6.21 tool. Variants were annotated using VEP v87. To identify mutations with potentially high biological impact, multiple filtering steps were applied to somatic mutation calling. First, we selected only the somatic variants that passed all filters from the MuTect2 FilterMutectCalls algorithm and second, only high/moderate impact (change coding) variants as defined by the VEP annotation were further analyzed. Over 1900 single nucleotide variants (SNVs) were detected across all samples. Figures that summarized the results were generated using maftools.

  Study phs003268

• Early progression to active tuberculosis is a highly heritable trait driven by 3q23 in Peruvians

  In a genome-wide genetic study of early progression to active tuberculosis (TB), we genotyped 4,002 active TB cases and their household contacts in Lima, Peru. We first established TB progression has a strong genetic basis, and is comparable to traits with well-established genetic bases (h2g=0.212). We identified a novel association between early TB progression and variants located in a putative enhancer region on chromosome 3q23 (rs73226617, OR = 1.18; P = 3.93 x 10-8). With in silico and in vitro analyses we identified genetic variant rs73226617 or rs148722713 as the likely functional variant and ATP1B3 as a potential causal target gene with monocyte specific function.

  Study phs002025

• Kids First Pediatric Research Study in Familial Predisposition to Hematopoietic Malignancies (SJFAMILY-HM)

  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 pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). 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. Acute lymphoblastic leukemia (ALL) is the commonest childhood tumor and a leading cause of cancer death in children, adolescents and young adults. Hodgkin and non-Hodgkin lymphoma are also important hematologic malignancies (HM) that occur in children. Each are genetic diseases with growing evidence for a germline predisposition of both familial and sporadic cases, however the inherited genetic basis of ALL/lymphoma are poorly understood. Such knowledge is essential to gain mechanistic insight into the basis of tumor formation, and to guide genetic counseling and genetic management. Here we have assembled a large collection of familial HM kindreds, and extended recurrence cohorts of ALL and HL which will be used to identify the genetic basis of familial HM, examine the frequency of germline variants in sporadic ALL and HL, and to integrate inherited and somatic genomic data. These studies have high potential to provide fundamental new insights into the inherited genetic basis of HM, to provide important information to guide clinical management, and to provide an invaluable public resource of genomic data.

  Study phs001738

• Rare Mendelian Disease in Old Order Amish and Mennonite Patients

  The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean = 4.4 Mb) that contain many genes (mean = 79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data.

  Study phs000623

• PGRN-RIKEN: Genetic Determinants of Clinical Cardiovascular Events in Patients Receiving Statins

  Coronary heart disease (CHD) is an important public health problem in developed countries. Statins are effective in the prevention and treatment of CHD; nevertheless, many patients receiving statins still suffer cardiovascular events (CV) such as heart attack. Identifying genetic variants responsible for differential clinical responses to statins will not only allow individual patients at high residual risk to be targeted for additional therapies, but also will define new biologic pathways contributing to statin response, and thus new targets for future therapies. Accordingly, the goal of this study is to identify genetic variants associated with clinical CV in patients receiving statins. Subjects identified for study are of European descent and include 1718 subjects with CV while on statins (cases) and 4172 subjects without CV while on statins (controls). Key research resources utilized in this effort include VanderbiltD's BioVU DNA databank and associated Synthetic Derivative database of clinical information, and software tools developed to identify drugs and clinical events using Electronic Health Record-derived structured and unstructured ("free text") data. Most cases and controls identified include three data types: ICD-9 codes, medication regimens, and medical test results. Genotyping, using IlluminaD's Infinium HumanOmniExpressExome BeadChip (OmniExpressExome), was performed by the RIKEN Integrative Medical Sciences Center (IMS) and supported by the Pharmacogenomics Research Network (PGRN)-RIKEN IMS Global Alliance.

  Study phs000963

• CCG Multicentric Italian Lung Detection (MILD)

  For the CCG-MILD project, NCI will utilize whole genome sequencing and/or whole exome sequencing in conjunction with transcriptome sequencing to try to identify recurrent genetic alterations (mutations, deletions, amplifications, rearrangements) and/or gene expression signatures that would be important to the hypothesis(es) submitted by the investigators. The samples will be processed and submitted for genomic characterization using the established NCI Genome Characterization Pipeline. Subsequent genomic and clinical data will be hosted at the NCI Genomic Data Commons (GDC).

  Study phs002253

• A Genome-Wide Association Study of Lung Cancer Risk

  Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types genotyping 515,922 single nucleotide polymorphisms (SNPs) in 5,739 incident lung cancer cases and 5,848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from 10 additional studies for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication resulting in 3,333 adenocarcinomas (AD), 2,589 squamous cell carcinomas (SQ), and 1,418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT) on chromosome 5p15.33, was associated with risk of adenocarcinoma (OR=1.23, 95%CI=1.13-1.33, P=3.02x10-7), but not other histologic types (OR=1.01, P=0.84, and OR=1.00, P=0.93, for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR=1.24, 95%CI=1.17-1.31, P=3.74x10-14 for AD and OR=0.99, P=0.69 and OR=0.97, P=0.48, for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma. Note: The lung study dataset to be released to dbGaP and caBIG excludes 47 individuals from the PLCO cohort who consented to participate only in cancer research projects and 22 individuals because of updated QC. Thus, the released dataset is derived from 11517 subjects, 5699 cases and 5818 controls. After the updated QC, the dataset to be released to dbGaP and caBIG includes 506062 SNPs.

  Study phs000336

• Single Cell Colony Whole Genome Sequencing Data From Individuals With Telomere Syndromes

  This is an observational study which examined the phylogenetic evolution of somatic clonal mutations in POT1 mutation carriers. Two individuals with telomere syndromes who carry a heterozygous germline POT1 p.R273Q variant and one related control who did not carry this variant were studied. Single cell hematopoietic colonies were derived from peripheral blood mononuclear isolates. These colonies were analyzed by whole genome sequencing (WGS) and phylogenetic trees were reconstructed accordingly. Phylogenetic reconstruction of somatic mutations show clonality is increased among POT1 p.R273Q mutation carriers and co-occurs with known clonal hematopoiesis driver mutations, including DNMT3A and/or JAK2.

  Study phs003207

• Human Liver Cohort (HLC)

  The Human Liver Cohort (HLC) study aimed to characterize the genetic architecture of gene expression in human liver using genotyping, gene expression profiling, and enzyme activity measurements of Cytochrom P450. The HLC was assembled from a total of 780 liver samples screened. DNA samples were genotyped on the Affymetrix 500K SNP and Illumina 650Y SNP genotyping arrays. Only data from those samples which were collected postmortem are accessible through this submission. These 228 samples represent a subset of the 427 samples included in the Human Liver Cohort Publication (Schadt, Molony et al. 2008, PMID: 18462017). RNA samples were profiled on a custom Agilent 44,000 feature microarray composed of 39,280 oligonucleotide probes targeting transcripts representing 34,266 known and predicted genes, including high-confidence, noncoding RNA sequences. Gene Expression data for the samples from which it could be obtained is available in GEO under accession number GSE9588. Results and networks will be made available for download from Sage Bionetworks.

  Study phs000253

• Genetic Analysis of Substance Use Disorder Using the Indiana Biobank Data

  The goal of this study is to identify genes related to substance use disorders. The study participants were selected from the Indiana Biobank. The Indiana Biobank provides centralized processing and storage of specimens that are linked to participants' electronic medical information. Cases were defined as having any type of substance use disorders by using ICD9/10 codes, including alcohol, cannabis, cocaine, opioid, nicotine, and other substances. Controls were defined as not having any type of substance use disorders. The Indiana Biobank is part of the Indiana Clinical and Translational Sciences Institute (CTSI), a state-wide research partnership among Indiana University, Purdue University, and the University of Notre Dame.

  Study phs003025

• DCCT/EDIC Epigenetics (DNA Methylation) Study

  Metabolic memory (persistent benefits of early glycemic control on preventing/delaying diabetic complications development) was observed in the Diabetes Control and Complications Trial (DCCT) and follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study, dbGaP phs000086.v3.p1, but mechanisms are unclear. We investigated the involvement of epigenetic DNA methylation (DNAme) by examining its associations with preceding glycemic history, and subsequent complications development over 18 years in blood DNAs of 499 randomly-selected DCCT/EDIC participants with type 1 diabetes. We found associations between DNAme near DCCT-closeout and mean-DCCT-HbA1c at 186 CpGs (FDR<15%, including 43 at FDR<5%), many located in complications-related genes. These CpGs are enriched in C/EBP motifs, enhancer/transcription regions in blood cells/progenitors, and open chromatin-states in myeloid cells. Remarkably, several CpGs in combination explain 68-97% of the mean-DCCT-HbA1c risk of complications development during EDIC. DNAme at key CpGs appears to mediate the association between hyperglycemia and complications in metabolic memory, through modifying myeloid cell enhancer activity.

  Study phs002024

• Population Genetics Analysis Program: Immunity to Vaccines/Infections - Smallpox Vaccination (NIAID/NIH)

  The study examines the role of candidate human immune response gene polymorphisms (and their receptors, expression and function) and variations in immune response, among 1,000 active duty members of the military who were recently vaccinated with ACAM2000 or Dryvax Smallpox vaccine. In addition to the phenotype and genotype data available through dbGaP, extensive clinical data are available through NIAID's ImmPort data portal; information to map the the data available in dbGaP to the data available in ImmPort is provided in the dataset pht005302.v1.p1 of the current study, dbGaP phs001057.v1.p1.

  Study phs001057

• Characterization of Structural Variants in Acute Myeloid Leukemia Patients

  Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and is expected to increase in frequency as the population ages. Most subtypes of AML are difficult to treat, in part due to a lack of understanding of possible molecular targets. Furthermore, the peak incidence of AML is in the sixth decade, and patients over the age of 65 do not tolerate chemotherapeutic regimens well. Moreover, AML has been highly studied as a model for other cancers. An RNA Biology Program is established aiming to develop comprehensive datasets through the profiling of all different classes of RNA expression, RNA editing, alternative splicing, and non-coding RNAs in CD34+ normal hematopoietic stem cells (HSC), their differentiated progeny, and AML clinical samples that could be utilized to understand leukemia. These datasets will allow us to computationally identify and characterize various RNA species and processes to enable the development of effective therapeutics to AML, leukemia and other types of cancers. Epigenetic factors such as methylation and histone modifications will also be characterized from these clinical samples allowing for integrated dataset analysis to look at the cross-talk between RNA and DNA/epigenomics in leukemia. The following is a subsidiary study of the above study description where whole genome sequencing was performed on two collected AML patients' samples using Illumina and Oxford Nanopore sequencing technologies. The aim is to characterize the roles of structural variants (SV) in RNA biology which are potentially important for AML development using our own established long-read SV characterization tool, NanoVar. The advent of Oxford Nanopore sequencing technologies has opened a new avenue for better SV characterization by having longer sequencing reads. NanoVar is an accurate and rapid SV characterization tool that utilizes low-depth Nanopore sequencing data. NanoVar makes use of split-reads and hard-clipped reads for SV discovery and employs a simulation-trained neural network classifier for true positive enrichment. NanoVar exhibited higher accuracy and faster computational speed amongst other long-read SV detection tools in simulated data. In AML patient data, NanoVar displayed excellent accuracy in SV characterization (16/16 SVs validated in two patients) by using only 4x depth sequencing data. In summary, NanoVar improves the accuracy and speed of SV characterization at a lower sequencing cost, an approach compatible with clinical studies.

  Study phs001847

• Autism Sequencing Consortium (ASC)

  The ARRA Autism Sequencing Collaboration was created in 2010 bringing together expert large-scale sequencing center (at the Baylor College of Medicine, PI Richard Gibbs and the Board Institute of MIT and Harvard, PI Mark J. Daly) and a collaborative network of research labs focused on the genetics of autism (brought together by the Autism Genome Project and the Autism Consortium). These groups worked together to utilize dramatic new advances in DNA sequencing technology to reveal the genetic architecture of autism through comprehensive examination of the exotic sequence of all genes. The Autism Sequencing Consortium (ASC) was founded by Joseph D. Buxbaum and colleagues as an international group of scientists who share autism spectrum disorder (ASD) samples and genetic data. The PIs are Drs. Joseph D. Buxbaum (Icahn School of Medicine at Mount Sinai), Mark J. Daly (Broad Institute of MIT and Harvard), Bernie Devlin (University of Pittsburgh School of Medicine), Kathryn Roeder (Carnegie Mellon University, Matthew State and Stephan Sanders (University of California, San Francisco). The rationale for the ASC is described in Buxbaum et al. 2012, and this paper should be cited when referencing the data set. All shared data and analysis is hosted at a single site, which enables joint analysis of large-scale data from many groups. The ASC was first supported by a cooperative agreement grant to four lead sites funded by the National Institute of Mental Health (U01MH100233, U01MH100209, U01MH100229, U01MH100239), with additional support from the National Human Genome Research Institute. The NIMH recently renewed their support with a second grant (U01MH111661, U01MH111660, U01MH111658 and U01MH111662) to expand the project from 29,000 genomes to more than 50,000 exomes over the next 5 years. NHGRI provides ongoing sequencing support for the ASD through the Broad Center for Common Disease Genomics (UM1HG008895, Mark Daly, PI).

  Study phs000298

• NHLBI GO-ESP: Family Studies (Hematological Cancers)

  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. Two major goals in the study of human malignancies are (i) to understand the genetic basis that underlies the predisposition of certain individuals to develop cancer and (ii) to identify the full spectrum of acquired mutations that occur in human cancers. There has been some progress in both of these areas with respect to hematologic malignancies but much remains to be discovered. As a result of recent advantages in sequencing technologies it is now feasible to sequence multiple individual whole exomes at reasonable cost. Such technologies provide a unique opportunity to transform our understanding of the biological basis of human cancer and to identify inherited genetic variants that predispose individuals to the development of hematologic malignancies. Myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS) and acute leukemia are clonal disorders of hematopoieis. Our study involves performing whole exome sequencing of individuals with these disorders for the purpose of identifying (i) novel inherited genetic variants associated with the risk of developing of MPN/MDS/acute leukemia and (ii) novel acquired mutations associated with the development of MPN/MDS/acute leukemia.

  Study phs000632

• INdiana GENomics: Implementing an Opportunity for the Under Served (INGENIOUS)

  The INGenious trial planed to enroll a total of 6,000 patients, with 2,000 patients assigned to a pharmacogenetic testing arm and 4,000 to a control arm who will be followed, but not tested. It is randomized between an intervention arm and one that receives no intervention in order that the genotyped group can be compared with one in which undisturbed, routine clinical care is carried out in patients taking the same drugs. Both arms will be followed for a year after being prescribed a targeted medication. Patients randomized into the intervention arm that are prescribed one or more of the 27 targeted index medication will receive pharmacogenomic testing using a custom micro-array measuring 43 Single nucleotide polymorphisms in 14 genes. The study is being conducted by the Indiana University School of Medicine and the Indiana University Institute of Personalized Medicine in collaboration with the Eskenazi and Indiana University Health Systems and will evaluate the economic and clinical outcomes associated with embedding a pharmacogenomics program in a system that serves as the primary health care safety-net in Indianapolis, Indiana. By successfully implementing a pharmacogenomics program and integrating it with the Electronic Health Record and Clinical Decision Support system, physicians will be able to optimize patient care by delivering tailored therapeutic decisions based on the patient's individual genetics.

  Study phs001701

• Autism Genome Project (AGP) Consortium - Whole Genome Association Study of over 1,500 Parent-Offspring Trios - Stage I and II

  Autism spectrum disorders (ASDs) are highly heritable (~90%), yet the underlying genetic determinants are largely unknown. To understand the genetic and phenotypic heterogeneity in ASDs, we analyzed 2,611 strictly defined ASD families with over 1,000,000 single nucleotide polymorphisms (SNPs), and applied multiple analytical strategies to examine these families for SNPs and Copy Number Variation (CNVs) affecting risk for ASDs. Secondary analyses examined associations in more homogenous subgroups. Furthermore, the use of large control datasets permitted contrasting case and control samples and addressed the potential increased burden of rare CNVs in ASD. Our data have allowed us to discern key features of the ASD genomic architecture, find new susceptibility loci, and chart a course for future studies in ASDs.

  Study phs000267

• Molecular Genetics of Heterotaxy and Related Congenital Heart Defects

  Heterotaxy syndrome is a congenital anomaly syndrome accompanied by thoracic and abdominal situs abnormalities. The study cohort comprises of individuals with heterotaxy or related congenital heart disease (CHD) who have undergone exome sequencing. The purpose of the study is to elucidate the molecular genetics of the disorder as well as contribute to knowledge about the biology of normal and abnormal development of left-right anatomic asymmetry. These results will further help delineate genotype-phenotype associations and provide important information on the causes, management, and prognosis of heterotaxy syndrome.

  Study phs001814

• The Finland-United States Investigation of NIDDM Genetics (FUSION) Study

  The Finland-United States Investigation of NIDDM Genetics (FUSION) study is a long-term effort to identify genetic variants that predispose to type 2 diabetes (T2D) or that impact the variability of T2D-related quantitative traits. The initial effort involved linkage analysis of affected-sibling-pair (ASP) families based on over 5,000 individuals living in Finland, and association fine mapping based on these family members and additional T2D cases and controls. Recently we completed a genome-wide association scan on 1161 T2D cases and 1174 normal glucose tolerant (NGT) controls. Individual-level data is available here for the 919 T2D cases and 787 NGT controls who reconsented to the use of their data or are deceased. Version 3 adds individual-level data for additional phenotypic variables.

  Study phs000100

• Cell and Circuit-Specific Exploration of HIV Neurogenomics in Context of Opiate and Cocaine Misuse

  Utilizing frozen postmortem brain tissue from the Manhattan HIV Brain Bank, we performed cell-type-specific, genome-wide sequencing of three different types: 1) single-nucleus RNA-sequencing (snRNA-seq), 2) in situ Hi-C, and 3) HIV integration site sequencing (IS-seq). We assayed tissue from three different donor types: 1) HIV-uninfected control (HIV-), HIV-infected (HIV+), and HIV-infected with HIV encephalitis (HIVE), who served as a positive control for active CNS viral infection. The diagnosis of HIVE was made by a board-certified neuropathologist on routine histopathology, based on the presence of a microglial nodule encephalitis with characteristic multinucleated syncytial cells and staining for HIV p24 antigen. Other HIV-infected individuals (the HIV+ group) did not have this histologic evidence of active HIV brain replication, and were variable with regard to cART status and virologic control prior to death. Donor characteristics, including ante-mortem plasma HIV loads, CD4 counts, and cART status, were documented. Quality controls were used for each assay: For snRNA-seq we applied filters to remove low quality nuclei from analysis and performed experiments in which mouse tissue was mixed with human tissue to determine a reliable HIV read count threshold. For Hi-C, we used paired HIV- and HIVE samples and processed all samples in parallel, at the same time. Correlation analysis was used to ensure biological replicates were aligned. For IS-seq, each time the assay was run, a positive and negative control were included. This allowed us to ensure a lack of contamination in IS-seq libraries and that, when a particular sample failed to yield library, this was due to low levels of HIV rather than a failure of the assay. Altogether, we built an integrative dataset from 79 sequencing files, including snRNA-seq, and cell type specific Hi-C, IS-seq, and ChIP-seq datasets. Human autopsy brain samples were collected by the Manhattan HIV Brain Bank (MHBB, U24MH100931), using protocols under the supervision of the Icahn School of Medicine at Mount Sinai (ISMMS) Institutional Review Board. Written informed consent was obtained either from decedents or their primary next of kin. Major Findings: Reorganization of open/repressive (A/B) compartment structures in HIVE microglia encompassing 6.4% of the genome was linked to transcriptional activation of interferon (IFN) signaling and cell migratory pathways and was partially recapitulated by IFN-gamma stimulation of cultured microglia. In contrast, decreased expression and repressive compartmentalization of genes regulating neuronal health and signaling was seen in both HIVE and HIV+ microglia. IS-seq recovered 1,221 integration sites in the brain that displayed distinct genomic patterns as compared to peripheral lymphocyte integration and were enriched for chromosomal domains newly mobilized into a permissive chromatin environment in HIVE microglia. Viral transcription occurred in a subset of highly activated microglia comprising 0.003% of all nuclei in HIVE brain. Our findings point to a disruption of microglia-neuronal interactions in the HIV infected brain and an interrelation of retroviral integration and expression with interferon-associated remodeling of the microglial 3D genome during progression to HIVE. Search terms: HIV, postmortem brain, microglia, substance abuse, viral integration, chromosomal conformation capture, Hi-C, chromatin, single nuclei RNA-seq, Irf8, NeuN, HIV encephalitis, neuron-microglia interaction, cytokine

  Study phs003080

• Ghana Prostate Study

  Participants were recruited through the Ghana Prostate Study-a population-based component, and a clinical component. The population-based component was a probability sample designed using the 2000 Ghana Population and Housing Census data in an attempt to recruit approximately 1,000 men aged 50-74 years in the Greater Accra region (~3 million people), which successfully recruited 1,037 healthy men between 2004 and 2006 with a response percentage of 98.8 %. Consented individuals underwent an in-person interview, and within 7 days had a digital rectal examination (DRE) and provided an overnight fasting blood sample for prostate-specific antigen (PSA) testing, biomarker assays, and genetic analysis. Subjects who had a positive screen by PSA (>2.5 ng/ml) or DRE underwent a transrectal ultrasound-guided biopsy. A total of 73 histologically confirmed prostate cancer cases were identified through the population-based screening component of the Ghana Prostate Study and were included in the case population in the published GWAS (Cook et al., Human genetics, 2013). From the remaining 964 screen-negative individuals, 836 had at least 20 μg DNA extracted and available for analysis, and 500 of these were matched to cases for analysis by age (in 5-year categories). In the Ghana Prostate Study, we recruited 676 prostate cancer cases at Korle Bu Teaching Hospital in Accra, Ghana, between 2008 and 2012. All consented cases were interviewed and provided an overnight fasting blood sample. At the time of selection for this analysis we had recruited 582 prostate cancer cases, from which we selected 427 for analysis. Combined with the 73 cases diagnosed through the population-based component of the study, this yielded 500 available prostate cancer cases for analysis.

  Study phs000838

• Drug Resistant Hypertension in African Americans' Exome

  Resistant hypertension is defined as blood pressure that remains above goal in spite of the concurrent use of 3 antihypertensive agents of different classes or the concurrent use of 4 or more antihypertensive agents regardless of control. Its diagnosis is important for the identification of patients who are at high risk of having reversible causes of hypertension and/or patients who, because of persistently high blood pressure levels, may benefit from special diagnostic and therapeutic considerations. Resistant hypertension represents an extreme phenotype, thus, it has been predicted that genetic factors could play a larger role than for the general hypertensive population. Genetic assessments of patients with resistant hypertension have been limited. The current study assayed the exome of 91 African American patients with treatment resistant hypertension.

  Study phs000442

• Characterization of Immune-Related Gene Expression in Lung Cancer

  We performed a comprehensive analysis of inter- and intratumor heterogeneity of immune gene expression in 160 lung cancer patients from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. The transcriptome was profiled with RNA sequencing in 269 tumor samples and 110 normal tissue samples from 160 subjects.

  Study phs002346

• National Institute on Aging (NIA) SardiNIA Study

  Sardinia is the second largest island in the Mediterranean and constitutes a genetically isolated founder population. This population has aided in the identification of genes involved in several Mendelian disorders and is attractive for genetic studies due to its organization in long-established settlements that developed from an initial group of founder settlers (~1,000) thousands of years ago. The current study has recruited 6,148 Sardinians aged 14 and older, from a cluster of four towns in the Lanusei Valley in the Ogliastra region of the province of Nuoro. This sample corresponds to approximately 62% of the population eligible in the area for recruitment. Information collected during enrollment allowed the individuals to be organized into 711 complex pedigrees, each up to five generations deep, with an average kinship coefficient of 0.1628. All volunteers have been characterized for 98 quantitative traits. Traits include anthropomorphic measures, plasma and serum markers (including cholesterol and other markers of cardiovascular disease), and personality traits (using the five-factor model). The main goal of the study is to examine phenotypic similarities between relatives that yield information on the overall contributions of genes to trait variability. Data given here provide p-values for 98 traits studied in 1,412 individuals, based on genotyping with the Affymetrix 500K chip and imputed markers using the HapMap population as a reference (N=2,259,179). Sharing this genome assessment data at high level of resolution for a variety of quantitative traits will be useful for other groups to validate newly observed associations and to investigate possible pleiotropic effects. For ulterior information, and in particular for any individual genotype information, a formal request should be addressed to the Steering Committee, c/o David Schlessinger, Chief, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, NIH Biomedical Research Center, 251 Bayview Blvd., Suite 100 Baltimore, MD 21224 USA and should include IRB approval of a detailed proposal, along with a signed statement guaranteeing that no attempt will be made to identify any individual participant.

  Study phs000338

• AC-ICAM: An Atlas and Compass of Immune-CAncer-Microbiome Interactions in Colon Cancer

  Fresh frozen tumor samples and matched normal colon specimens from chemotherapy naïve, consecutive patients with a histological diagnosis of colon adenocarcinoma at Leiden University Medical Center (LUMC) were subjected to multi-omics profiling at Sidra Integrated Genomics Services, part of Sidra Medicine, Doha, Qatar. This resulted in a high-quality dataset of samples collected between 2001 and 2015. Multi-step QC was performed, including assessment of the quality of the nucleic acid extraction, sequencing, and genetic concordance between DNA/RNA sequences from the same patient. After QC, this resulted in RNA sequencing on 348 tumor samples, whole exome sequencing (WES) on 281 tumor-normal sample pairs (n=562 samples), TCR sequencing of the TCR β locus (TRB) for 114 tumor and 10 matched normal samples, and 16S rDNA sequencing on 246 tumor-normal sample pairs (n=492 samples) and 42 tumor only samples, and 167 WGS non human-aligned reads of the tumor samples. Extensive clinicopathological and survival data of the cohort are available. The median follow-up time for this cohort is 4.6 years, and the distribution of gender and pathological stage are within expected ranges for this patient population with a mean age of 68. We refer to this resource as the Sidra-LUMC (SILU) colon adenocarcinoma (COAD) Atlas and Compass of Immune-Colon cancer-Microbiome interactions (AC-ICAM)."Reprinted from Nature Medicine,Roelands, J., Kuppen, P.J.K., Ahmed, E.I. et al. An integrated tumor, immune and microbiome atlas of colon cancer. Nat Med (2023). https://doi.org/10.1038/s41591-023-02324-5, with permission from Nature."

  Study phs002978

• Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma

  Immune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab and tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Anti-CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4 blockade activates T cells and enables them to destroy tumor cells. We obtained tumor tissue from patients with melanoma who were treated with ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and matched blood samples. Somatic mutations and candidate neoantigens generated from these mutations were characterized. Neoantigen peptides were tested for the ability to activate lymphocytes from ipilimumab-treated patients. Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing. A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P = 0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neo-antigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature in a second set of 39 patients with melanoma who were treated with anti-CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab.

  Study phs001041

• Development and Use of Network Infrastructure for High-Throughput GWA Studies

  The "Development and Use of Network Infrastructure for High-Throughput GWA Studies" project is collaboration between Group Health Cooperative (GH), the University of Washington (UW), and the Fred Hutchinson Cancer Research Center (FHCRC). It is one of 5 sites participating in The Electronic Medical Records and Genomics (eMERGE) Network funded by the National Human Genome Research Institute (NHGRI) with additional funding from the National Institute of General Medical Sciences (NIGMS). The overall eMERGE project is designed to assess whether linking biorepositories of patients in healthcare delivery systems with electronic medical records (EMRs) is an efficient strategy for high-throughput genome wide association (GWA) studies and whether information can be pooled across sites. The primary phenotype in the Group Health/UW Aging and Dementia eMERGE study project is dementia. Phenotyped participants originated from four population-based sources. Seattle-area members of GH (a large integrated health care system in Washington State) consented and enrolled in 1) the University of Washington Alzheimer's Disease Patient Registry (ADPR) and 2) the Adult Changes in Thought (ACT) study, 3) Marshfield Clinic Personalized Medicine Research Project (PMRP), a population-based DNA, plasma and serum biobank of 20,000 adults, 4) Vanderbilt's BioVU, a de-identified DNA biobank. The ADPR (PI: Eric B. Larson; NIH/NIA U01 AG 006781) is a population-based registry of incident dementia cases designed to identify all new dementia cases within GH from 1987 to 1996. Potential dementia cases were identified through referrals from primary care physicians, mental health services, and neurologists, as well as review of CT scans, neurology, emergency room, geriatrician, and mental health clinic logs, and hospital discharge diagnoses. Medical history, physical, laboratory testing, and neuropsychological testing were performed on all consenting potential cases. These data were reviewed by a consensus conference including a neuropsychologist, study physicians, and an epidemiologist. After discussion of the case, dementia status is assigned using DSM-III-R criteria. Alzheimer's disease status was assigned using the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. The study base of the ADPR population was stable with an attrition rate of less than 1%/year. The ACT study (PI: Eric B. Larson; NIH/NIA U01 AG 006781) is an ongoing community-based cohort study designed to determine the incidence of Alzheimer's Disease (AD), other types of dementia, and cognitive impairment and to determine risk factors for these conditions. The original cohort of 2,581 was enrolled in 1994-1996. An expansion cohort of 811 was enrolled in 2000-2002. Continuous enrollment to keep 2,000 persons enrolled and at-risk for dementia outcomes was begun in 2005. To date the study has accrued more than 4,000 participants. Dementia-free participants are enrolled in this cohort and evaluated every two years by study personnel with many evaluations including an assessment of cognitive functioning using the Cognitive Abilities Screening Instrument (CASI), which is an extended version of the Mini-Mental State Examination that has been widely used in epidemiological studies of the elderly. Persons with CASI scores lower than 86 or in whom interviewers suspect unusual cognitive decline are followed up with dementia diagnostic evaluations which include physical and neurological examinations and neuropsychological tests. Medical records are reviewed, and laboratory tests and neuroimaging are obtained if not available. The dementia diagnoses and dementia subtypes are determined during a consensus conference attended by the examining clinicians and other study physicians, a neuropsychologist, and research nurse. After discussion of the case, dementia status is assigned using DSM-IV criteria. Alzheimer's disease status was assigned using NINCDS-ADRDA criteria. Individuals diagnosed with dementia are seen again one year following diagnosis using the same procedures. Individuals not diagnosed with dementia are returned to the pool of at-risk individuals and are seen at their next routinely scheduled biennial visit. The ACT sub-sample is stable; for the original cohort, median enrollment in GH was 19 years prior to joining the ACT study, and 85% of the cohort has ≥ 10 years of GH enrollment. DNA for the ADPR participants were obtained through a companion study, Genetic Differences in Cases and Controls (PI: Walter Kukull; NIH/NIA R01 AG007584). DNA obtained through both studies were extracted from blood using Gentra Systems Puregene methods. DNA concentration is determined by UV optical density. All samples are checked for quality by OD 260/280 ratio. For long-term storage, samples are aliquoted and stored at -70°C. The Marshfield study, Personalized Medicine Research Project (PMRP), a population-based DNA, plasma and serum biobank of 20,000 adults. PMRP was started in 2002 as a 3 Phase project. Completed in April 2004, the objectives of Phase I were to build and develop a large population-based biobank with DNA, plasma and serum samples to facilitate genomics research. Phase 1 was also to educate, inform and consult with the Marshfield Epidemiologic Study Area population and communities concerning potential studies, create the DNA foundation of the personalized medicine database and build the bioinformatics tools to store securely and analyze genotypic and phenotypic data. Phase I tasks included operation of the ethics and security advisory board, scientific advisory board and community advisory group. More than 18,000 residents aged 18 and above from 19 different zip codes surrounding Marshfield, WI were invited to participate in Phase I. After providing written informed consent, participants completed brief questionnaires that included questions about demographics, some environmental exposures, family history of disease, and adverse drug reactions, as well as family members living in the area. Participants provided 50ml of blood from which DNA was extracted and plasma and serum samples were stored. The informed consent process allowed access to electronic medical records and included language about non-disclosure of personal research results. A tick-off box was included so that participants could either allow or decline subsequent recontact for future research studied. The objectives of Phase II are to create the phenotypic database, establish the scientific and administrative infrastructure to support genetic mapping of the DNA and the initial discovery projects and genotype a sufficient portion of the genetic material to support these discovery projects. The objectives of Phase III are to expand the discovery projects, complete the genotyping of the genetic database and expand physician/health care provider education and community consultation. The Vanderbilt BioVU model uses discarded blood leftover from clinical care and de-identified clinical information, both of which are tracked with a Research Unique Identifier that is permanently disconnected from the medical record number used to generate it. The Vanderbilt IRB determined that the project does not qualify as "human subject" research under §46.102(f)(1)(2). The program has been reviewed by OHRP twice (the latest immediately prior to launch), and the determination of the Vanderbilt IRB that the project is consistent with the 8/10/2004 guidance has been validated. The model includes a simple opt out mechanism developed for patients who do not wish to have their samples included. Planning (including community involvement, ethics and IRB discussions, focus groups, development of operating procedures and pilot studies to assess them) began in May 2004, and the resource commenced sample collection in February 2007 and as of May 2009 contains approximately 56,000 samples. The current resource will be available to all Vanderbilt investigators who sign a Data Use Agreement. The resource represents Vanderbilt's broad patient population and thus provides a potential resource for research in a range of common and rare diseases as well as drug response or medication safety. BioVU patient protection model: There has been extensive involvement by the ethics community and the IRB to put in place procedures to provide privacy protection. The overall protection plan is multifaceted and includes a combination of technology and policy: (1) creation of the SD described above; (2) return of only the specific clinical data items requested by investigators (rather than the complete de-identified chart); (3) submission of any specific proposed project to the IRB and to a separate protocol review committee, both of which must approve; (4) implementing a Data Use Agreement that permits only approved queries and data analyses, specifically prohibits attempts at re-identification (at the risk of institutional sanctions), and mandates redeposit of all genetic information generated in a research study back into a genomic database; and (5) tracking and auditing all use.

  Study phs000234

• Cystic Fibrosis Nasal Epithelium Gene Expression by RNAseq

  Cystic fibrosis (CF) is a monogenic disorder leading to multi-organ system dysfunction, with the primary cause of morbidity and mortality being lung disease. Mutations in CFTR result in defective ion channel transport leading to hyperviscous mucus, airway infection, inflammation and lung function decline. While the Phe508del mutation is the most common CFTR mutation in North American people with CF, it is well known that there is a broad range of lung disease severity even amongst Phe508del homozygotes, including twins/siblings. Heritability analyses showing the relative contribution of non-CFTR modifier genes in such differences in phenotype, have led to our genomic and transcriptomic studies of gene modifiers in CF. Complementary to two international CF GWAS studies, this study was performed to a) determine differential expression of genes relative to a quantitative lung disease severity phenotype score (KNoRMA; as used in CF GWAS studies) and b) to assess expression quantitative trait loci. To better understand genetic modification of CF lung disease severity, we analyzed gene expression (transcriptomic) profiles by mRNA sequencing from nasal mucosal biopsy specimens of 134 people with CF. Each study participants was characterized for CF lung disease severity phenotype by averaging three years of lung function data (forced expiratory volume in 1 second; FEV1), normalized to a CF-specific reference population matching for age, sex, and height. Participants completed nasal lavage and nasal curettage mucosal sampling, with directed sampling to the inferior nasal turbinate, a well validated surrogate for cellular characteristics and CFTR function of the lower CF airways. Participants were further invited to complete a second set of these sampling procedures for validation analysis. Specimen and concurrent clinical data collection occurred across four North American study sites and nasal mucosal specimens were subjected to RNASeq analysis. These data were to be made available in the dbGaP. Our association analyses of gene expression relative to quantitative CF lung disease phenotype, taken together with previously identified GWAS signals, identified biological pathways correlated with CF lung disease pathogenesis. Our further association analyses of gene expression relative to single nucleotide polymorphism variation at significant CF GWAS loci further identified potential mechanisms of genetic variants associated with CF lung disease. This resource is intended to aid researchers in characterizing airway mucosal gene expression from the CF airways for the purpose of gene expression profiling in CF and in muco-obstructive airways disease.

  Study phs002254

• Large Scale Genotyping of Psychiatric Disorders

  Psychiatric disorders cause enormous human suffering and cost to society. The goal of this project is to elucidate the genetics of psychiatric disorders through a large consortium effort and genome-wide genotyping. The Psychiatric Genomics Consortium (PGC) (https://www.med.unc.edu/pgc) is an international consortium to pursue genome-wide analyses of common psychiatric disease. The PGC was founded in 2007 to unite investigators from around the world to conduct mega-analyses of individual genome-wide genotype data for schizophrenia (SCZ), bipolar disorder (BIP), autism (AUT), attention-deficit hyperactivity disorder (ADHD), and major depressive disorder (MDD). Subsequently, the PGC has expanded to include Tourette syndrome (TS), obsessive-compulsive disorder (OCD), eating disorders (ED), post-traumatic stress disorder (PTSD), and substance abuse (SUD). The PGC partnered with Illumina to develop the PsychChip, a custom GWAS array aimed at capturing common variation genome-wide for imputation, rare coding variation drawn from the exome chip and dense genotypes for loci with suggestive evidence for association across the initial PGC analyses of SCZ, MDD, BPD, ASD and ADHD. Samples (cases, controls, and families) were collected from Institutional Review Board-approved protocols that aim to study the genetics of psychiatric disorders. Genome-wide genotyping was performed at the Broad Institute (Cambridge, MA, USA) and the Mount Sinai School of Medicine Friedman Brain Institute (New York, NY, USA) using the PsychChip or Exome Chip.

  Study phs001413

• Genome-Wide Association Study of Patients with Coccidioidomycosis

  BackgroundValley Fever is typically an infection of the lungs caused by the fungi Coccidioides immitis and Coccidioides posadasii. The incidence of Coccidioidomycosis (CM), or infection with Coccidioides, has dramatically increased over the last 20 years. This is particularly true in the Southwest of the United States, where people often breathe fungal spores that arise from the soil. Reasons for increased infection rates are thought to include population growth and construction in these endemic regions, an increase in the number of people whose immune systems are compromised due to infection or treatment with drugs required for organ transplants, climate change, as well as improved testing practices and greater physician awareness. Mild CM most commonly presents itself with flu-like symptoms and rashes, which can last weeks to months. Individuals with compromised immune systems, specifically-- substantial suppression of the immune cells known as T cells, can develop severe pulmonary and disseminated disease. Infection that remains localized to the lungs is referred to as pulmonary disease, but when the infection spreads out of the lungs into other parts of the body it represents a more serious condition referred to as a disseminated disease, or disseminated CM. In nature, Coccidioides spp. exists as mold and lives in dust and soil. When the contaminated soil or dust is disturbed by human activity, animals, or weather, the Coccidiodies spores are released into the air. Airborne spores are taken up by breathing and settle in the lungs. Once in the moist and warm environment of the lung, spores transform into spherules, which divide and become filled with smaller spores, called endospores. When the spherules get large enough, they rupture and release these endospores, which can spread and disseminate to surrounding tissue. The cycle then repeats itself as these endospores develop into new spherules3. Different ethnic groups have been described to vary in their susceptibility to developing disseminated CM after initial infection with Coccidioides. For example, evidence suggests that African-American and Filipino patients suffer the disseminated disease at a greater rate than other ethnicities. The suggestion that race plays a role in the clinical expression of the disease is still a source of debate amongst the scientific community and any genetic mechanisms responsible for these differences have yet to be fully elucidated. If our genetic makeup influences our ability to limit the spread of infection, finding which DNA differences cause these variances could provide clues to how the body successfully fights infection, and provide opportunities to boost the body’s ability to do this. Further, if we are able to identify the specific genetic risk factors that correlate with the development of disseminated infection, physicians could perform genetic screenings to identify high-risk patients and provide them with preemptive antifungal therapy prior to developing disseminated disease.The genome, made up of DNA, contains all of the information needed for humans to develop and grow. Genome-wide association studies (GWAS) allow us to look for inherited differences that are more common between people who share a particular trait, for example, height or susceptibility to certain diseases, compared to those who do not share the trait. Although some traits and diseases are controlled by a single gene, the majority are influenced by contribution from several, or even many, different genes. To find evidence of genes that contribute to specific traits, GWAS typically compares genome information from large numbers of people who have a particular disease (referred to as “cases”) looking for DNA sequences that are common among these samples, and are different from DNA sequences seen in large numbers of people who lack the trait, but are as much like the cases as possible (referred to as “controls”). The DNA sequence data from each group, cases versus controls, are analyzed to see if there are specific genomic differences that tend to be associated with the disease. MethodsTwo separate GWAS approaches were taken to look for genetic differences that could be responsible for the observed differences between the different patient populations we are studying. The first method, known as genotyping, scans for differences at a set of positions across the genome, which includes both the genes that encode our proteins and the larger amount of DNA that does not. The second method, known as exome sequencing, allows us to compare the entire sequence of the portion of the genome that codes for proteins.  For this study, DNA from patients with either pulmonary or disseminated CM were genotyped and exome sequenced to look for DNA differences that are associated with one condition or the other. All patients were at least 18 years old, had no evidence of immunosuppression, and had proven or probable pulmonary coccidioidomycosis according to established diagnostic criteria. Of these patients, a subset demonstrated disseminated disease, i.e., they showed evidence of coccidioidal infection outside of the thorax by biopsy/aspiration, had radiographic imaging, and show positive coccidioidal serology. Our criteria for including patients with the pulmonary disease were that they must not require ongoing antifungal treatment or show evidence of active CM (in skin test positive patients), show no evidence of extrapulmonary dissemination, and have no evidence of ongoing pulmonary infection (pulmonary nodules are accepted) beyond six months from diagnosis.Patient DNA was purified from blood or from sputum samples by the labs of our collaborators, Drs. George Thompson (UC Davis School of Medicine) and John Galgiani (University of Arizona Health Sciences). Genome-wide association (GWAS) analysis was carried out to look for candidate loci associated with pulmonary versus disseminated disease, taking into account the population structure of the samples. Single nucleotide or insertion/deletion variants were identified from whole-exome sequences (WES) using the Picard/BWA/GATK pipeline. ResultsTable 1. Pulmonary versus Disseminated Cases of Coccidiomycosis for GWAS, Sorted by EthnicityEthnicityPulmonary CasesDisseminated CasesAsian85Black/African American1664Caucasian/White4015Filipino03Hispanic/Latino3414Indian21Mexican American1039Pacific Islander01Samoan03Vietnamese10Unknown16917More than one race02Total373134Table 1 shows the number of samples analyzed from patients with pulmonary versus disseminated disease, and patient ethnicity, where known. In all, we worked with 507 samples, including 134 samples from patients with disseminated disease and 373 samples from patients with pulmonary disease. Of these, 505 samples were genotyped using the Multi-Ethnic Global Array from Illumina Inc. In addition, we were able to generate whole-exome sequence from 498 patient samples. No significant associations were detected that differed between samples from patients with pulmonary versus disseminated disease; that is, no particular DNA sequences were found to be significantly enriched in patients with disseminated disease compared to patients with pulmonary disease. The ability to detect genetic association between specific sequences and genetically determined traits is influenced by several factors, including how many patient samples are available to compare, how many different genes contribute to the trait and how strong their contributions are. When the number of genes is small and the contribution of each gene is great, smaller numbers of patient samples are needed to detect an association. When more genes are involved, or the contribution from each gene is more modest, larger numbers of patient samples must be examined. While we were not able to detect any associated within this study, it does not mean that subsequent studies would not find this connection. Our study suggests significantly more samples should be analyzed in further studies.Whole-exome sequences were generated from 498 samples and were aligned to reference sequences to identify positions where the sequences differed from the reference. These data are being analyzed to determine if any variants are associated with pulmonary, versus disseminated, disease. 

  Study phs002170

• Pharmacogenomics of Rheumatoid Arthritis Therapy

  Rheumatoid arthritis (RA) is the most common autoimmune inflammatory arthritis worldwide and affects 1.3 million adults in the USA. It has previously been studied using phenotype algorithms to identify electronic health records (EHR) case cohorts. Early genetic studies of EHR-linked cohorts of RA patients have been replicated in known associations. Further development of collections of EHR-linked cohorts for RA and other phenotypes may enable not only enhanced understanding of disease risks but also the investigation of outcomes and treatment responses.

  Study phs000983

• Whole Genome Sequencing Analysis in a Family of Discordant Twins With Non-Syndromic Microtia and Hemifacial Microsomia: Identification of Novel Candidate Genes and Variants

  This research is a non-NIH effort to discover the pathogenesis of non-syndromic microtia and to detect potential candidate genes. Microtia (OMIM 600674, 612290, 251800) is a spectrum of congenital anomalies and facial abnormalities, 90% of the cases followed by hearing loss. Two types of the disease are described in terms of connection to the affected syndromes: anomalies (syndromic) and only clinical manifestation (non-syndromic) associated with other symptoms. Though the exact pathogenesis of microtia remains unknown, pathogenic genes of majority of the microtia syndromic types have been identified. However, the genetic mutation of the non-syndromic microtia has not been confirmed. In this study, whole genome sequencing (WGS) was utilized to screen mutations in monozygotic discordant twins of congenital microtia-atresia and their family members. One of the twins, along with her grandfather, was discordant for microtia-atresia. By bioinformatic analysis of the WGS data from monozygotic twins with microtia and their non-microtia relatives, we proposed that among 28 identified potential genes, 4 of them (CNOT1, ODAD4, TBX15, and GIPC3) could be more responsible for non-syndromic microtia development and phenotypic features. Interested investigators may request to access the DNA genomic sequencing data of the study participants via dbGaP authorized access. In addition to raw genomic sequencing data, datasets of germline mutations and candidate gene mutations may also be available for investigators to request.

  Study phs003216

• ARDSnet and the iSPAAR Consortium: Genomic Basis of Susceptibility and Outcomes in Patients with the Acute Respiratory Distress Syndrome (ARDS)

  Acute Respiratory Distress Syndrome (ARDS)/ Acute Lung Injury (ALI) is a syndrome defined by the presence of acute hypoxemic respiratory failure, bilateral pulmonary infiltrates on chest radiograph, a known clinical risk factor (e.g. sepsis, pneumonia, trauma, gastric fluid aspiration, pancreatitis, massive transfusion), and the absence of physiologic or clinical evidence of congestive heart failure. The Identification of SNPs Predisposing to Altered ALI Risk (iSPAAR) study is a multi-institutional cooperative study, funded through the NHLBI Recovery Act, that assembled samples and phenotype information from existing cohorts. The consortium included samples from patients with ARDS from the NIH NHLBI ARDS Clinical Trials Network (ARDSNet). Samples were obtained from 3 interventional treatment trials in patients with ARDS, including the Fluid and Catheter Treatment Trial (FACTT), the Albuterol to Treat Acute Lung Injury (ALTA) trial, and the Omega-3 Fatty Acid/Antioxidant Supplementation for ALI trial (Omega). In addition to ARDSnet samples, samples from the other cohorts included cases of established ARDS but also controls: critically ill patients who were at-risk for ARDS but who did not develop ARDS during their hospital course. These cohorts included the Molecular Epidemiology of Acute Respiratory Distress (MEA) Study enrolled at the Harvard University/Massachusetts General Hospital, the Systemic Inflammatory Immune Response Syndrome (SIRS) Patient Database and ICU Traumatic Injury cohorts from Harborview Medical Center, and cohorts collected from the ALI research programs at the University of Pennsylvania and the University of California, San Francisco. The Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs000631 ARDSnet iSPAAR Consortium. phs000334 ESP_LungGO_ALI phs000686 ALI_GeneticRisk

  Study phs000631

• eMERGE Network Imputed GWAS for 41 Phenotypes

  The electronic Medical Records and Genomics (eMERGE) Network is a consortium of ten participating sites (Cincinnati Children's Hospital Medical Center/Boston Children's Hospital, Children's Hospital of Philadelphia, Essentia Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University, Geisinger Clinic, Group Health Cooperative/University of Washington, Mayo Clinic, Icahn School of Medicine at Mount Sinai, Northwestern University, Vanderbilt University Medical Center) funded by the NHGRI to investigate the use of electronic medical record (EMR) systems for genomic research. The goal of eMERGE is to conduct genome-wide association studies in approximately 55,000 individuals using EMR-derived phenotypes and DNA from linked Biorepositories. Using electronic phenotyping methods, the consortium used DNA samples from all participating sites to explore the genetic determinants of over forty phenotypes, including Abdominal aortic aneurysm; Ace-Inhibitor/Cough; Attention Deficit Hyperactivity Disorder; Age-related macular disease; Appendicitis; Asthma; Atopic Dermatitis; Autism; Benign Prostatic Hyperplasia; Carotid artery disease as a Quantitative Measure; caMRSA; Cataract; Clostridium difficile colitis; Extreme Obesity; Chronic Kidney Disease; Chronic Kidney Disease and Type 2 Diabetes; Chronic Kidney Disease, Type 2 Diabetes and Hypertension; Colon Polyps; Cardiorespiratory Fitness; Dementia; Diverticulosis; Diabetic retinopathy; Gastroesophageal Reflux Disease; Glaucoma; Height; Heart failure; Hypothyroidism; Lipids; Ocular hypertension; Peripheral Arterial Disease; QRS duration; Red blood cell indices; Remission of Diabetes after ROUX-EN-Y gastric bypass surgery; Resistant hypertension; MACE while on Statins; Type 2 Diabetes; Venous Thromboembolism; White blood cell indices; and Zoster virus infection, as well as using the phenome-wide association study (PheWAS) paradigm to replicate and discover relationships between targeted genotypes with multiple phenotypes. Sites and participants include: Children's Hospital of Pennsylvania (CHOP): The Center for Applied Genomics (CAG) at the Children's Hospital of Philadelphia (CHOP) is a high-throughput, highly automated genotyping and sequencing facility equipped with state-of-the-art genotyping and sequencing platforms. Children who are treated at the Children's Hospital Healthcare Network and their parents may be eligible to take part in a major initiative to collect more than 100,000 blood samples, covering a wide range of pediatric diseases. A large majority of participants consenting to prospective genomic analyses also consent to analysis of their de-identified electronic medical records (EMRs). EMRs are longitudinal, with a mean duration of 6.5 years. Cincinnati Children's Hospital Medical Center/Boston's Children's Hospital (CCHMC/BCH): Cincinnati Children's Hospital Medical Center (CCHMC) and Boston Children's Hospital (BCH) are pediatric institutions dedicated to improving health and welfare of children and to the shared purpose of discovery and practical application of new genomic information to the ordinary care of children. The CCHMC/BCH site has been built on a five-year history of collaboration, particularly in patient electronic record (ERM)-related informatics, the basis of much of eMERGE II. CCHMC and BCH together bring an extraordinary faculty to eMERGE II who are committed to diseases that afflict children, specifically phenotypes that focus upon diseases of children in ways that will leverage the available eMERGE adult GWAS and EMRs to discover meaningful use results. CCHMC/BCH plans to demonstrate real-time execution of phenotypic selection across their two distinct pediatric institutions as a model for ensuring phenotypic standardization and for national scalability. They will also look carefully at parents' responses to results and use of their children's research results and better understand the factors that influence their decisions about learning incidental findings. In addition to patient and parent perceptions CCHMC/BCH will also explore clinician perceptions of pharmacogenetic research results after EMR integration. Geisinger Health System: A research cohort of adult Geisinger Clinic patients was enrolled from community-based primary care clinics of the Geisinger Health System. Patients were eligible for enrollment if they were a primary care patient of a Geisinger Clinic physician and were scheduled for a non-emergent clinic visit. All participants provided written informed consent and HIPAA authorization. Consenting patients agreed to provide blood samples for broad biomedical research use, and permission to access data in their Geisinger electronic medical record for research. The enrollment rate was 90% of patients approached. The demographics of the cohort approximate those of the Geisinger Clinic outpatient population. Research blood samples were collected during an outpatient clinical phlebotomy encounter. Research blood samples are coded and stored in a central biorepository. Samples are linkable to clinical data in a de-identified manner for research via an IRB-approved data broker process. For genomic analysis, DNA is extracted from EDTA-anticoagulated whole blood. Group Health(GH)/University of Washington (UW): GH participants for the PGx project were enrolled in the eMERGE Network through the Northwest Institute of Genetic Medicine (NWIGM) biorepository, and provided the appropriate consent to receive clinically relevant genetic results (N~6300.) Participants were eligible if aged 50 - 65 years old at the time of their enrollment into the NWIGM repository, living, enrolled in GH's integrated group practice, and had completed an online Health Risk Appraisal. The selection algorithm was based on several data sources from the EHR at Group Health: 1. Demographics - participants with self-reported race as Asian or African ancestry were prioritized and selected to enrich for non-European ancestry; 2. Diagnosis and procedure codes - participants were selected if found to have a history of hypertension, atrial fibrillation (AF), or congestive heart failure (CHF). Participants with a history of arrhythmia were added if the entire selection algorithm did not generate 900 individuals. We also enriched for participants with EHR evidence of actionable indications related to PGRNSeq genes. Participants were selected if found to have an ICD9 code for malignant hyperthermia, hypertension, atrial fibrillation, congestive heart failure or long QT syndrome (LQTS); 3. Laboratory values - if participants had any laboratory event of creatine kinase (CK) >1000, and were dispensed statins within 6 months of the event, then they were selected; and 4. Medications - participants were excluded if ever on carbamazepine or had a current regimen of warfarin. Essentia Institute of Rural Health, Marshfield Clinic, Pennsylvania State University (Marshfield): The Marshfield Clinic Personalized Medicine Research Project is a population-based biobank in central Wisconsin with more than 20,000 adult subjects who provided written, informed consent to access their medical records and provided a blood sample from which DNA was extracted and plasma and serum stored. In addition to an average of 30 years of medical history data, a questionnaire about environmental exposures, including a detailed food frequency questionnaire, is available to facilitate gene/environment studies. Mayo Clinic: The Mayo biobank is a disease-specific biobank for vascular diseases including peripheral arterial disease (PAD). PAD patients were identified from individuals referred to the non-invasive vascular laboratory for lower extremity arterial evaluation. Since 1997, laboratory findings have been recorded into an electronic database employing an in-house software package for data archiving and retrieval; this data becomes part of the Mayo EMR. Patients referred to the center with suspected PAD undergo a comprehensive non-invasive evaluation including the ankle-brachial index (ABI) - the ratio of blood pressure measured in the upper arms divided by blood pressure measured at the ankles. Controls subjects are identified from patients referred to the Cardiovascular Health Clinic for stress ECG. The prevalence of PAD in patients with normal exercise capacity who do not have inducible ischemia on the stress ECG , was <1%. Data regarding risk factors for atherosclerosis such as diabetes, dyslipidemia, hypertension, and smoking are ascertained from the EMR. Icahn School of Medicine at Mount Sinai School (Mt. Sinai): The Institute for Personalized Medicine (IPM) Biobank Project is a consented, EMR-linked medical care setting biorepository of the Mount Sinai Medical Center (MSMC) drawing from a population of over 70,000 inpatients and 800,000 outpatient visits annually. MSMC serves diverse local communities of upper Manhattan, including Central Harlem (86% African American), East Harlem (88% Hispanic Latino), and Upper East Side (88% Caucasian/white) with broad health disparities. IPM Biobank populations include 28% African American (AA), 38% Hispanic Latino (HL) predominantly of Caribbean origin, 23% Caucasian/White (CW). IPM Biobank disease burden is reflective of health disparities with broad public health impact: average body mass index of 28.9 and frequencies of hypertension (55%), hypercholesterolemia (32%), diabetes (30%), coronary artery disease (25%), chronic kidney disease (23%), among others. Biobank operations are fully integrated in clinical care processes, including direct recruitment from clinical sites, waiting areas and phlebotomy stations by dedicated Biobank recruiters independent of clinical care providers, prior to or following a clinician standard of care visit. Recruitment currently occurs at a broad spectrum of over 30 clinical care sites. Northwestern University: The NUgene Project is a repository with longitudinal medical information from participating patients at affiliated hospitals and outpatient clinics from the Northwestern University Medical Center. Participants' DNA samples are coupled with data from a self-reported questionnaire and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 2 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators. Vanderbilt University: BioVU, Vanderbilt's DNA databank, is an enabling resource for exploration of the relationships among genetic variation, disease susceptibility, and variable drug responses, and represents a key first step in moving the emerging sciences of genomics and pharmacogenomics from research tools to clinical practice. BioVU acquires DNA from discarded blood samples collected from routine patient care. The biobank is linked to de-identified clinical data extracted from Vanderbilt's EMR, which forms the basis for phenotype definitions used in genotype-phenotype correlations.

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