Search Results - EGA European Genome-Phenome Archive

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Dac EGAC00001002434

Whole Genome Scan for Pancreatic Cancer Risk in the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium (PanScan)

Within the framework of the NCI-sponsored Cohort Consortium, investigators from 12 prospective epidemiologic cohorts formed the Pancreatic Cancer Cohort Consortium in 2006. This study, also known as "PanScan", is funded by the National Cancer Institute (NCI) and involves conducting a genome-wide association study (GWAS) of common genetic variants to identify markers of susceptibility to pancreatic cancer. In 2007, the study was expanded to include 8 case-control studies. The study team includes scientists from the cohorts comprising the Consortium, the NCI and the Pancreatic Cancer Case Control Consortium (PanC4). PanScan I and II were conducted in 12 cohort studies and 8 case-control studies, leading to the discovery of four novel regions in the genome associated with risk for pancreatic adenocarcinoma. The third phase of PanScan (PanScan III) was conducted using recently identified incident pancreatic cancer cases drawn from fourteen cohorts from the cohort consortium, including nine prospective cohorts who participated in PanScan I, and five newly joined cohorts. The nine cohort studies that participated in PanScan I and had new genotyping of cases in PanScan III include ATBC, CPS-II, EPIC, HPFS, NHS, PHS, PLCO, SMWHS, and WHI; the five newly joined cohort studies include the Agricultural Health Study (AHS), the Multiethnic Cohort Study (MEC), the Melbourne Collaborative Cohort Study (MCCS), the Vitamins and Lifestyle Study (VITAL), and Selenium and Vitamin E Cancer Prevention Trial (SELECT). In addition to the cases from cohorts, we also included cases from the Gastrointestinal Cancer Clinic of Dana-Farber Cancer Institute Study (DFCI-GCC); from the University Hospital in Heidelberg, Germany, which is part of a larger European clinical case-control study (PANDoRA); and from clinic-based cases from eastern Spain (PANKRAS-II). The dbGaP datasets available include all subjects previously made available from PanScan I and II, plus 1,582 new incident pancreatic cancer cases of European descent from prospective cohorts, case-control studies or case series (genotyped as part of PanScan III). Also included are 61 pancreatic cancer cases and 67 control subjects from PanScan I as well as 173 pancreatic cancer cases from PanScan III of Asian ancestry from the Shanghai Men's and Women's Health Study (Supplemental Table 10, Wolpin et al. (Nat Genet, 2014)). The control population used in the analysis for the Wolpin et al. manuscript included cancer-free individuals from the prospective cohorts that contributed pancreatic cancer cases to PanScan III and controls from the Spanish Bladder Cancer SBC/EPICURO study that were previously genotyped using the OmniExpress, Omni 1M or Omni 2.5M SNP arrays. The data from these control subjects were posted to dbGaP under the GWAS in which they were initially genotyped and will not be made available in duplicate under this dbGaP study.The summary statistics for PanScan I-III were generated as detailed in Wolpin BM. et al., Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer, Nature Genetics 2014; 46(9):994-1000 (https://www.nature.com/articles/ng.3052), and Klein, A. et al., Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer, Nature Communications, 2018;9(1):556 (https://www.nature.com/articles/s41467-018-02942-5). The dataset includes results from an association study of 5,117 individuals diagnosed with pancreatic ductal adenocarcinoma (PDAC) and 8,845 control individuals, or a total of 13,962 subjects of European ancestry (as compared to the genotype and phenotype information under this project that includes 9,437 individuals (PanScan I and II PDAC case and control individuals and PanScan III PDAC cases only). This is due to the fact that PanScan III “borrowed” GWAS data from control individuals genotyped separately from the PanScan GWAS project and are therefore not included as raw genotypes in phs000206.v5.p3. Association analysis was performed separately for PanScan I-II and PanScan III, followed by a meta-analysis of the two datasets. Results were filtered based on a minor allele frequency (MAF) < 0.01, an imputation INFO score < 0.3 and a heterogeneity P-value < 1x10-10 leaving a total of 9,758,390 variants. Columns in the summary statistics dataset are as follows: ID: variant rsIDChr: chromosome numberPosition: position in the chromosome, genome build GRCh37/hg19MarkerName: variant identifierAllele1: reference alleleAllele2: alternative alleleFreq1: allele frequency for allele2FreqSE: standard error of the allele frequencyMinFreq: the minimal allele frequency across studiesMaxFreq: the max allele frequency across studiesEffect: effect size for allele2StdErr: standard errorP-value: meta-analysis p-valueDirection: summary of effect direction for each studyHetISq: I^2 statistic which measures heterogeneity on scale of 0-100%HetChiSq: chi-squared statistic in simple test of heterogeneityHetDf: degrees of freedom for heterogeneity statisticHetPVal: P-value for heterogeneity statistic

Study phs000206

Center for Common Disease Genomics [CCDG] - Inflammatory Bowel Disease (IBD) - Global Microbiome Conservancy Host Exomes

The human body is a complex ecosystem, hosting tens of billions of bacteria, primarily in the gut. This community, known as the 'gut microbiome', is vital to human health, affecting functions ranging from metabolism, immunity, and development, to behavior. Conversely, reduced microbiome diversity and other imbalances of the gut community (dysbiosis) are associated with many diseases of the industrialized world, such as metabolic syndrome, asthma, and inflammatory bowel diseases among others. Microbiome-based interventions thus hold the potential to revolutionize our understanding of, and therapeutic approaches to, many aspects of human health and disease. Despite many advances, current understanding of the human microbiome is largely limited to majority ethnic groups in industrialized nations, and does not reflect the full diversity of human commensal microbiota. In addition to the scientific ramifications of minority underrepresentation, there are significant translational and ethical implications as well: First, failing to capture the full diversity of healthy human microbiota may limit our ability to understand and generate effective therapeutics for many microbiome-associated diseases. Second, underrepresented groups are less likely to benefit from microbiome-based medical advances tailored to well-studied populations, propagating healthcare inequities. The window of opportunity to characterize human microbiome diversity is closing rapidly. Human gut microbial diversity is diminishing around the globe, due to the spread of Westernized diets and lifestyles, which are associated with reduced microbiome biodiversity. The Global Microbiome Conservancy (GMbC) is a non-profit collaboration between scientists and communities around the world that aims to 1) preserve the full biodiversity of the human gut microbiome, 2) characterize its evolution across populations and host lifestyles and 3) investigate its interactions with the human host. We are collecting gut microbiome and human DNA samples from diverse populations around the world, from isolated groups to urbanized populations, to culture and study this essential biodiversity and to preserve it in a living "seed bank" as a long-term safeguard against future extinctions. The National Human Genome Research Institute (NHGRI) has funded a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Called the Centers for Common Disease Genomics (CCDG), this initiative will explore a range of diseases with the ultimate goal of: Undertaking variant discovery for enough different examples of disease architectures and study designs to better understand the general principles of the genomic architecture underlying common, complex inherited diseases. Understanding how best to design rare variant studies for common disease. Developing resources, informatics tools, and innovative approaches and technologies for multiple disease research communities and the wider biomedical research community. The initial focus of the CCDGs will be in cardiovascular disease (early-onset coronary artery disease, atrial fibrillation, hemorrhagic stroke), neuropsychiatric disease (epilepsy, autism), and autoimmune/inflammatory disease (type 1 diabetes, inflammatory bowel disease). The Broad Institute is one of four selected CCDG project centers. Both exome and genotyping information of GMbC participants will help understanding how recruited human populations are structured and genetically related. This human genetic structure will be analyzed in light of gut microbiome compositional and genomic differences to illuminate associations between specific microbiome traits and human groups and the evolutionary processes involved in the co-evolution of human hosts and their gut microbiome. It will also provide variant information for critical genes shaping the composition of microbiomes, such as genes involved in innate and adaptive immunity (e.g. antimicrobial peptides) or in the regulation of the immune response (e.g. Nod2). Association studies between specific variants in these genes and microbiome features will be performed, which will then be validated with in vitro and in vivo experiments. Human data from GMbC cohorts will also increase the genetic diversity of human populations, providing additional variant information for many susceptible loci that were found to be associated with Crohn's disease and ulcerative colitis. The whole genome sequencing data generated is comprised of samples from diverse and indigenous populations. Raw sequencing data, metadata, vcf and phenotype data at the individual level for a subset of the cohort's samples are available at https://anvilproject.org/data. For questions about availability, contact help@lists.anvilproject.org. Microbiome data for the samples sequenced in this study can be found in phs002235 Global Microbiome Conservancy Sequence Data.

Study phs002205

Trial of Late Surfactant for Prevention of Bronchopulmonary Dysplasia: A Study in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide (TOLSURF-BioLINCC)

Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.Objectives: To assess whether late surfactant treatment in extremely low gestational age newborn (ELGAN, ≤28 week gestation) infants requiring ventilation at 7-14 days safely improves survival without bronchopulmonary dysplasia.Background: Bronchopulmonary dysplasia (BPD) is the most common form of chronic lung disease in children with an estimated 15,000 new cases annually in the United States. BPD affects infants born prematurely, is a major contributor to the cost of prematurity each year, and is associated with long-term pulmonary disability, neurodevelopmental abnormalities and death.Increases in the survival of ELGAN infants have resulted in another form of BPD, which is characterized by impaired alveolar and microvascular development with excess tone and reactivity of airway smooth muscle. Despite treatments to enhance lung maturation, premature infants often need prolonged intubation and mechanical ventilation and/or oxygen support. When mechanical ventilation is required longer than 7 days, BPD results in 70% of surviving ELGAN infants. Most of these infants experience clinical episodes of increased requirement for ventilatory support that are associated with dysfunctional surfactant, which is primarily due to low surfactant protein B (SP-B). In pilot studies of late surfactant treatment in premature infants, there was short-term improvement in SP-B content. These prior studies provided the rationale for a larger clinical trial for later doses of surfactant treatment to prevent episodes of respiratory decompensation and BPD. Participants: 511 infants were eligible for randomization of the 2693 infants screened. Of the 511 infants eligible for randomization, there were 252 infants allocated to the treatment arm and 259 infants allocated to the placebo arm.Design: The study was designed to assess the effect of late doses of surfactant on survival without BPD at 36 weeks post menstrual age (PMA) in ELGAN infants who required intubation and mechanical ventilation between 7 and 14 days of age and were receiving Inhaled nitric oxide (iNO). Infants were stratified within clinical centers and gestational age groups and randomized to treatment with calfactant, a natural surfactant extracted from bovine lung lavage fluid, or a sham procedure.All infants received iNO according to the protocol used in the Nitric Oxide Chronic Lung Disease (NOCLD) trial. A masked syringe containing either a standard dose of calfactant for the treatment group, or air for the placebo group, was administered to the infant behind a screen by staff not involved in providing the infant's clinical care. Monitor and ventilator alarms were turned off during dosing to avoid unblinding of clinical staff. To accommodate research staff availability and infant instability, the dosing interval was not strictly set but could be repeated every 24 – 72 hours up to 5 doses if the infant still required intubation. Dosing could be discontinued by physician request or parental withdrawal from the study. Due to parental preference, the first infant in a multiple birth was randomized according to the randomization schedule and subsequent infants were assigned to the same treatment group. Follow-up to assess pulmonary and neurologic development continued until 2 years of age, with treatment group blinding maintained. The primary outcome was survival without BPD at 36 weeks PMA. Secondary outcomes included BPD at 40 weeks PMA, pulmonary outcome at 12–24 months of age, and neurodevelopmental outcome at 2 years of age. Conclusions: There were no significant differences observed between the treatment group and the control group for survival without BPD at 36 weeks or 40 weeks.

Study phs003899

Varieties of Impulsivity in Opiate and Stimulant Users

The study was conducted in Bulgaria as a collaboration between Virginia Commonwealth University (Richmond, VA, USA), the Bulgarian Addictions Institute (Sofia, Bulgaria), the Molecular Medicine Center/Medical University (Sofia, Bulgaria), and Indiana University (Bloomington, IN, USA). The overall aim of this study is to investigate the role of impulsivity as an endophenotype for drug addiction. Although impulsivity is considered one of the strongest candidate endophenotypes for addiction, progress in the field is hampered by the heterogeneity of impulsivity, characterized by multiple personality, psychiatric, and neurocognitive dimensions, rarely examined concurrently in the same population; and the heterogeneity of addiction phenotypes, due in part to the high rates of polysubstance dependence among substance users. To address these challenges, we have developed a program of addiction research in Bulgaria, a key transit country for heroin trafficking due to its strategic geographical location on the "Balkan Drug Route" and a major European center for production of synthetic amphetamine-type stimulants. This has allowed us to access rare populations of predominantly mono-substance dependent heroin and amphetamine users, many in protracted abstinence. Our preliminary results reveal a complex relationship between trait and neurocognitive (state) dimensions of impulsivity, often manifested in opposite directions in heroin and amphetamine dependent individuals. Pilot computational modeling analyses of decision-making, a central neurocognitive aspect of impulsivity, have proved particularly informative by indicating that different mechanisms may underlie the impaired decision-making of opiate and stimulant users. A different modeling approach, i.e. phenotypic modeling, holds significant promise to address the pervasive "missing heritability" problem in genetic studies. While genetic heterogeneity is often invoked as an explanation, the manner in which complex phenotypic traits are measured and modeled is equally important contributor to the missing heritability problem but has received much less attention in the literature. Despite the multidimensionality of traits measured by psychometric, diagnostic, and neurocognitive instruments, most GWAS studies typically use aggregate sum scores that do not reflect the underlying phenotypic multidimensionality. Therefore, at least part of the missing heritability problem may originate in misspecification of the phenotypic models. Consequently, sample sizes requirements may increase from ~800 subjects in correctly specified models to 6,000-16,000 subjects in incorrectly specified models. The current study aims to increase our understanding of the complex relationship between multiple putative impulsivity endophenotypes to help redefine endophenotypes as multi-level combination of measures that could inform multivariate multilevel models of complex phenotypes. The specific aims of the study are to: (1) Assess the utility of various personality, psychiatric, and neurocognitive indices of impulsivity (either individually or in combination) as candidate endophenotype(s) for drug addiction in general and for opiate and stimulant addictions in particular; (2) Evaluate the viability of computational model parameters modeling various neurocognitive dimensions of impulsivity as novel endophenotype(s) for addiction; and (3) Test the external validity of the optimal endophenotype(s) by evaluating their associations with HIV and other risk behaviors in opiate and stimulant users in protracted abstinence, a question of critical importance for prevention and intervention efforts in this much less-well understood stage of the addiction cycle.

Study phs001647

Federated EGA

Federated EGA Federated EGA Index Overview Map of FEGA status across the world Current status of the FEGA Network Documentation Overview Federated EGA is a global network of repositories enabling secure discovery and access to sensitive human data. Our vision is to accelerate scientific discovery and healthcare breakthroughs by creating the go-to worldwide sensitive human data resource. Our values are: Privacy & Trust: Ensuring privacy of data subjects, security of services and acting with integrity to build community trust.FAIRness: Driving reuse of data through standardisation of metadata and clear access policies.Diversity: Expanding our network and representing global diversity in the data we host to bring benefits worldwide. Federated EGA - European by name, global by nature Federated EGA collaborates with European and global initiatives (GA4GH, ELIXIR, 1+ Million Genomes Framework, GDI), demonstrating that a network for transnational discovery of and access to human data is possible. By providing a solution to emerging challenges around secure and efficient management of human omics and associated data, the FEGA Network fosters data reuse, enables reproducibility, and accelerates biomedical research. For general enquiries or to request more information about Federated EGA, please send an email to fega-info [at] lists [dot] ega-archive [dot] org. Read more about the Federated EGA in our commentary in Nature Genetics! Learn more about joining the Federated EGA Network in our onboarding documentation. Map of FEGA status across the world Current status of the FEGA Network Node Description Joined CEGA Central EGA is managed by the Centre for Genomic Regulation (CRG) and EMBL-EBI. The EGA has been a trusted repository for sensitive data since 2008. CEGA coordinates the FEGA network, hosts central services and the EGA catalogue. 2022 Finland FEGA Finland is hosted by CSC - IT Center for Science Ltd., which is the national ELIXIR Node in Finland. CSC is a state-owned company specialising in providing high-quality IT infrastructure and services for Finnish higher education and research. 2022 Germany The German Human Genome-Phenome archive (GHGA) is part of the German National Research Data Infrastructure (NFDI). It is coordinated by the German Cancer Research Center (DKFZ) and includes over 20 academic partners. 2022 Norway FEGA Norway is a service by ELIXIR Norway, the Norwegian node of the European organisation ELIXIR. University of Oslo as a partner institution in ELIXIR Norway is hosting the service relying on the TSD infrastructure for sensitive data. ELIXIR Norway is a consortium of 5 Norwegian universities and is coordinated by University of Bergen. 2022 Spain FEGA Spain is co-hosted by the Barcelona Supercomputer Center (BSC) and the Centre for Genomic Regulation (CRG), both part of ELIXIR Spain and the Spanish National Infrastructure for Personalised Medicine associated with Science and Technology (IMPaCT). 2022 Sweden FEGA Sweden is hosted by the National Bioinformatics Infrastructure Sweden (NBIS), which legally is part of Uppsala University. NBIS forms the bioinformatics platform at SciLifeLab and constitutes the Swedish node of the European organisation ELIXIR. 2022 Poland FEGA Poland is hosted by Biobank Lodz, which is part of University of Lodz. Biobank Lodz is an element of the infrastructure of the Regional Digital Medicine Centers established by the Medical Research Agency. 2022 Portugal FEGA Portugal is managed by BioData.pt, the distributed infrastructure for Life and Health data for Portugal. This entity is a non-profit association of 15 life sciences R&I organisations spread across the country, and the home of ELIXIR Node in Portugal. 2023 Canada Canadian Genome-phenome Archive is part of the Pan Canadian Genome Library, with the mandate to allow the secure and responsible sharing and analysis of Canadian genomic information. 2024 Switzerland Swiss FEGA is hosted by SIB Swiss Institute of Bioinformatics, which is the national ELIXIR Node in Switzerland, on behalf of the Swiss FEGA Partnership which includes 4 other key partners (ETH Zurich, Health 2030 Genome Center, Swiss Data Science Center and Switch). 2025 Documentation Title Version Description Mission, vision, values Federated EGA Mission, vision, values 1.0 The official Mission-Vision-Values statement for FEGA, produced and formally approved by the FEGA Strategic Committee in September 2025. Structure and Organisation Federated EGA Structure and Organisation 2.0 The structure of the FEGA network and service expectations, responsibilities and commitments. FEGA is organised into three tiers: Central EGA, FEGA Nodes and FEGA Affiliates. Strategic Committee Federated EGA Strategic Committee 1.1 Terms of reference for the FEGA Strategic Committee describe the purpose and objectives of the committee, which is to provide direction and strategic planning for the FEGA network. The committee receives input from, and provides feedback for the EGA Strategic Committee. Operations Committee Federated EGA Operations Committee 1.1 Terms of reference for the FEGA Operations Committee describe the purpose and objectives of the committee, which is to review operational performance and coordinate technical roadmaps of FEGA Nodes and Central EGA. The committee receives advice from, and provides operational reporting to the FEGA Strategic Committee. Guidelines Federated EGA Node Operations Guidelines 2.1 An overview of the operational areas which require resources in order to create a FEGA Node. The document is based on more than 15 years' experience of EMBL-EBI and CRG operating the EGA and initial expericences of the inaugural FEGA Nodes. The operational areas of responsability are in line with the FEGA Maturity Model, which guides establishment and operation of FEGA Nodes. Collaboration Federated EGA Node Collaboration Agreement 1.3 Nodes are welcome to make a copy of this current version of the CA to start its review with their legal teams and understand the responsibilities of joining FEGA. Nevertheless, this version (the one with a watermark) shall not be signed: the official version needs to be obtained from FEGA prior to signing through its official channels. Federated EGA Affiliate Collaboration Agreement 1.0 Affiliates are welcome to make a copy of this current version of the CA to start its review with their legal teams and understand the responsibilities of joining FEGA. Nevertheless, this version (the one with a watermark) shall not be signed: the official version needs to be obtained from FEGA prior to signing through its official channels.

Documentation about/projects-and-funders/federated-ega

Brain Arteriovenous Malformation Genetics Study

The Predictors of Spontaneous Cerebral AVM Hemorrhage study was designed to identify genetic markers that predict adverse outcomes in brain arteriovenous malformation (BAVM) patients, examine race-ethnicity influences on BAVM hemorrhage risk, and use genome-wide association analysis to identify novel genetic predictors of AVM and hemorrhage using the Affymetrix GeneChip. We performed the first genome-wide association study (GWAS) (PMID: 26818729) of sporadic BAVM to investigate association of common single nucleotide polymorphisms (SNPs) with risk of sporadic BAVM in the international, multicenter Genetics of Arteriovenous Malformation (GEN-AVM) consortium. The study included a Caucasian discovery cohort of 515 BAVM cases and 1,191 controls genotyped using Affymetrix genome-wide SNP arrays. The Phase 1 discovery cohort comprised of 338 BAVM cases (154 male) and 504 controls genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0. The molecular data (individual genetic data) for the Phase 1 discovery cohort 338 BAVM cases (self-reported Caucasian) recruited at University of California, San Francisco, or Kaiser Permanente of Northern California (KPNC) are included in the dbGaP Study Report: Brain Arteriovenous Malformation Genetics Study, with the additional BAVM case phenotypic and sample attribute characteristics: sex, race, age at BAVM diagnosis, hemorrhagic presentation, BAVM size. Written informed consent was obtained from all participants and the study was approved by the respective Institutional Review Boards. The molecular dataset for this study in dbGaP is based on the genotypes obtained for the initial set of 906,600 SNPs for cases and controls called together using Birdseed v2 algorithm in Affymetrix Genotyping Console Software. The final QC'd dataset includes 717,335 markers as SNPs with MAF<0.01 or deviating from Hardy-Weinberg equilibrium (P<0.00001) in controls were excluded. After QC, the average genotyping call rate was 99%. The discovery phase GWAS identified 57 top BAVM-associated SNPs which were tested in a replication cohort including 608 BAVM cases and 744 controls. The molecular dataset for these 338 BAVM cases was also included in a report investigating common and rare genome-wide copy number variation for association with BAVM (PMID: 24098321), which included a total sample size of 371 sporadic Caucasian BAVM cases and 563 Caucasian controls. This study identified a CNV region on 1p36.13 (NBPF1 locus) that was significantly enriched with duplications in BAVM cases compared to controls, although this association did not replicate in an independent cohort of 184 sporadic BAVM cases and 182 controls. This resource will help researchers to better understand the genetic risk factors for BAVM and/or hemorrhage. These data may be applied to examine the genetic contributions to arteriovenous malformation, stroke, and related vascular disorders and may help generate hypotheses regarding the genetics of cerebrovascular disease.

Study phs002069

Kids First: Genomic Etiologies of CHARGE Syndrome, Related Conditions and Structural Anomalies

Developmental disorders with structural birth defects account for the majority of morbidity and mortality in children's hospitals, and the genetic bases of many clinical phenotypes remain unknown. Genetic testing for individuals with structural malformations has uncovered the basis of many such birth defects; however, many more cases remain unsolved, posing challenges for diagnosis, treatment, and prevention. Multiple anomaly conditions are particularly challenging to diagnose, since they often present with unique combinations of clinical features that vary widely between affected individuals, even in the same family. CHARGE Syndrome (Coloboma of the eye, Heart Defects, Atresia of the choanae, Retardation of growth and development, Genital abnormalities including pubertal delay and infertility, Ear abnormalities with deafness and vestibular disorders) is a multiple anomaly condition that affects a wide variety of organ systems. CHARGE Syndrome is caused in most cases by monoallelic pathogenic variants in CHD7, the gene encoding ATP-dependent helicase chromodomain DNA binding protein 7. Both de novo and inherited variants in CHD7 have been reported in CHARGE, and a growing number of families present with individuals who test positive for a pathogenic CHD7 variant yet exhibit only mild features. Similarly, individuals with CHARGE Syndrome often exhibit broad variability and reduced penetrance of clinical features, consistent with pleiotropic roles for CHD7 during development and/or additional genetic contributors or modifying alleles. Recent work has also implicated RERE, KMT2D, EP300, and PUF60 in having a role in CHARGE Syndrome.We hypothesize that (1) some cases of CHARGE are due to other genetic etiologies including oligogenicity, and (2) genetic modifiers contribute to the broad clinical variability and reduced penetrance of CHARGE features. To address these hypotheses, we have generated a cohort of 223 deeply clinically phenotyped individuals with CHARGE Syndrome and related disorders and structural anomalies who tested negative by chromosomal microarray, single gene sequencing, next generation panel sequencing, or exome sequencing. These individuals exhibit clinical CHARGE-like features including structural birth defects affecting craniofacial, ocular, neurosensory, brain, heart, mediastinal, renal, genitourinary, and skeletal organs. Our cohort includes these 223 individuals as well as affected and unaffected family members who consented to clinical and research genetic testing and donated blood samples for DNA and RNA isolation and sequencing. Building on this valuable cohort, we propose to use exome and genome sequencing to identify novel genetic etiologies of CHARGE and related developmental disorders for which alternative genetic tests have been inconclusive. Identification of novel pathogenic genetic variants and contributing modifier alleles within the coding and non-coding portion of the genome of these individuals will improve genetic diagnosis and provide important insights toward understanding the developmental mechanisms of structural birth defects.

Study phs002592

National Institute of Dental and Craniofacial Research (NIDCR) Sjögren's International Collaborative Clinical Alliance (SICCA): Center for Inherited Disease Research (CIDR) Genome-Wide Genotyping

The Sjögren's International Collaborative Clinical Alliance (SICCA) is a multisite observational cohort study that recruited a large cohort of geographically diverse participants. Enrollment of participants began in late 2004 at five (one domestic and four international) sites, in which all groups used the same protocol-directed methods to provide uniform evaluations; collect oral, ocular, and rheumatologic data; and collect specimens. The sites were located at the University of Buenos Aires, Argentina; Peking Union Medical College, Beijing, China; Rigshopitalet (formerly at Glostrup Hospital), Copenhagen, Denmark; Kanazawa Medical University, Ishikawa, Japan; King's College, London, UK (joined in 2007); and the University of California, San Francisco (UCSF). In 2009, Aravind Eye Hospital, Madurai, India; Johns Hopkins University, Baltimore, MD; and University of Pennsylvania, Philadelphia, PA were added as additional SICCA sites. UCSF is the coordinating center for SICCA. All specimens and data collected for SICCA are housed at UCSF. To facilitate the research focused on understanding the genetics of Sjögren'sSjögren's syndrome, high-density SNP genotype data and SICCA clinical information are being made available to the research community. This includes participants recruited from all SICCA research groups (RG). These participants (3,382), blood relatives (439), and unrelated healthy controls (25) had their whole blood or saliva sample (Oragene) extracted for DNA for the GWAS at the UCSF DNA Bank. Eighty eight percent of the participants are women, most are of European or Asian ancestry and the median age is 55. To assess potential batch effects when doing case-control comparisons using planned external controls, 30 DNA samples from each of three studies were genotyped with SICCA DNA samples: The Genetic Architecture of Smoking and Smoking Cessation - Collaborative Genetic Study of Nicotine Dependence (COGEND) - PI: Laura Bierut. NEI-Age-related disease study (AREDS) - Genetic Variation in Refractive Error Substudy - PI: Dwight Stambolian. Controls from the National Institute of Mental Health's (NIMH's) Human Genetics Initiative. Genome-Wide Association Study of Schizophrenia - PI: Pablo V. Gejman. Molecular Genetics of Schizophrenia - nonGAIN Sample (MGS_nonGAIN) - PI: Pablo V. Gejman. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data quality control, dbGaP preparation and posting, and imputation to 1000 Genomes to increase SNP density was performed by the Center for Biomedical Statistics at the University of Washington. Data analysis was performed at UCSF using software PLINK, EIGENSOFT, and SNPTEST.

Study phs000672

Center for Oral Health Research in Appalachia (COHRA) Genomic Studies of Oral Health and Disease

The purpose of this project is to identify the genetic factors contributing to dental caries in children and adults. The datasets come from the Center for Oral Health Research in Appalachia (COHRA), which has the long-term goal of determining the sources of oral health disparities in a high risk, Northern Appalachian population so that effective preventive interventions can be designed and targeted. The Specific Aims of this project are to perform genome-wide association scans of dental caries of the (1) primary dentition in children, and (2) permanent dentition in adults, to identify novel risk variants and to replicate previously nominated risk variants. This project brings together samples from three cohorts: COHRA1 is a cross-sectional cohort comprising members of 862 northern Appalachian families; approximately 80% of the cohort has been previously genotyped by the Center for Inherited Disease Research with support from NIDCR using the Illumina Quad W array (see dbGaP Study Accession: phs000095.v3.p1). Dental SCORE is a cross-sectional cohort comprising approximately 550 unrelated individuals who underwent the same data collection protocol as COHRA1. COHRA2 is an ongoing longitudinal cohort that recruited approximately 1100 northern Appalachian women during pregnancy, and followed them and their children through their children's early childhood; the current project period will continue data collect though age 6 of the child. Phenotypes for this project were derived from intra-oral examinations performed by trained and calibrated research hygienists. In brief, each tooth was recorded as present or absent, and each surface of each present tooth was scored for evidence of decay. From these data, dental caries indices were generated. This project contains two phases of genotyping: (1) collection of exome SNP Chip data for the previously genotyped COHRA1 samples, and (2) collection of whole-genome SNP Chip data for the remaining COHRA1 samples and all Dental SCORE and COHRA2 samples. These data will support efforts to test hypotheses regarding the causal relationships of risk factors contributing to the unusually high rates of caries formation in the Appalachian population. Ultimately, these data may inform the development of an integrated model of caries risk, in which the effects of genetics, oral ecology, diet, and other environmental/psychosocial factors and behaviors are modeled in concert to explain the disparities, including the high rate of caries onset before age 6. The gene-mapping Aims of this project, which seek to identify the genetic factors that contribute to caries risk, are a requisite step in realizing this integrated model.

Study phs001591

Surveillance, Epidemiology and End Results (SEER) Formalin Fixed Paraffin Embedded (FFPE) Tissue Feasibility Study

Next Generation Sequencing (NGS) technologies are being used for detection of somatic mutations in tumors and studies of germline variation. However, most NGS studies used DNA isolated either from whole blood or fresh frozen tissue specimens. Meanwhile, the tissue specimens available from most National Cancer Institute (NCI) funded cohorts and the Surveillance, Epidemiology and End Results (SEER) registries (http://seer.cancer.gov/biospecimen) are primarily formalin fixed paraffin embedded (FFPE). There are limited data, on a small number of FFPE tissue samples, which suggest NGS is feasible. Much less is known about the feasibility of these technologies for large scale studies or using older FFPE specimens (e.g. 5-30 years old). The SEER cancer registries cover approximately 28% of the United States population, providing high quality demographic, clinical, pathologic, and survival data. The SEER Residual Tissue Repository (RTR) program was established in 2003. The RTR maintains biospecimens obtained from three of SEER' population-based cancer registries: Iowa, Hawaii, and Los Angeles. Investigators at government, academic, and nonprofit institutions may apply to the program to obtain annotated FFPE tumor tissue specimens to study biomarkers, etiology, and other aspects with a population-based sample of cancer cases. The main objective of this project was to conduct a pilot study to determine whether the DNA obtained from archival FFPE tissue from 3 SEER Registries is of sufficient quality and quantity to conduct NGS. For Exome sequencing, sixty high-grade serous ovarian adenocarcinomas from FFPE tissues which were between 7 and 31 years old were obtained from three SEER registries. DNA was extracted, quantified, quality assessed, and subjected to whole exome sequencing. DNA extraction (yields and quality) and whole exome sequencing (depths of coverage and exome coverage obtained) results from this study will be presented. For RNA-sequencing, sixty-seven high-grade serous ovarian adenocarcinomas from FFPE tissues which were between 7 and 31 years old were obtained from three SEER registries. Total RNA was extracted, quantified, quality assessed, and subjected to whole transcriptome sequencing. Ultimately data derived from this analysis could serve as the basis for determining the utility of archival FFPE biospecimens for characterization and discovery projects utilizing NGS technologies instead of relying on frozen biospecimens.

Study phs000950

Genomics of Opioid Pharmacogenomics and Acute/Chronic Postsurgical Pain after Major Surgery in Children

Pain management after surgery is not optimal, partly due to great interindividual variability in pain perception and coping. This can lead to persistent pain beyond the healing period and disability. Up to two-thirds of the inter-individual variability results from genetic variations in pain perception as well as response to the pain medicine. The investigators aim to identify genomic (genetic/epigenetic), psychological and drug profiles contributing to this variability. Opioids are the mainstay for treatment of postoperative pain in children. Experience dictates that opioids have narrow therapeutic indices and large inter-patient variability in response. This leads to serious side effects like respiratory depression in up to 50% of children undergoing invasive surgery, which can be fatal. It is evident that there are particular children who are more susceptible to suffering side effects and having inadequate pain relief from opioids.It is hypothesized that much of the genetic variability can be explained by gene function which is modulated by a) Single Nucleotide Polymorphisms (SNPs) in genes that encode proteins involved in pain perception, opioid transport/metabolism (pharmacokinetics), and opioid receptor signaling (pharmacodynamics); b) epigenetics which modify gene expression without structural changes to the DNA, and c) genes that influence psychological factors.The purpose of this research study is to identify factors and genes that may be associated with acute and chronic post-surgical pain, and to develop pharmacometric models for response to opioids, like morphine and hydromorphone. While children undergoing different surgeries will be recruited for acute outcomes, children undergoing spine fusion will be followed for 10-12 months for evaluation of psychological and genomic factors affecting chronic post-surgical pain, with a goal of identifying genetic and epigenetic risk models for prediction of acute and chronic post-surgical pain. Although opioids are used every day, some children have bad reactions from their use, like breathing problems, sedation, etc. The investigators want to study factors that may be associated with pain sensitivity, opioid requirements after surgery, their metabolism, efficacy and their side-effects. The investigators expect that the information obtained in this research study will help to develop effective, safer, and tailored treatment options in the future.

Study phs002105

GEI Studies - Psoriasis

The GEI Studies Project was started as an NIH consortium involving 5 disease groups with funding provided through the Genes, Environment, and Health Initiative (GEI). The objective of the project was to optimize strategies for identifying rare variants as a follow up to genome-wide association studies (GWAS) using next-generation sequencing technology. One of the five targeted diseases, Psoriasis, is a multifactorial skin disease characterized by epidermal hyperproliferation and chronic inflammation that affects approximately 2% of Americans. Because only about one-third of all patients with psoriasis have a relative who is also affected with the disorder, psoriasis is not widely recognized as a genetic disease. However, previous research on families and identical twins has shown psoriasis has a strong genetic component, although environmental factors (such as infections, stress, and injuries) are also important. Although no definite psoriasis gene has yet been identified, research during the last ten years has revealed over forty potential gene locations that may contribute to the disease. Large amounts of data generated using next-generation sequencing technology would provide a more detailed characterization of sequence variation which would in turn increase the likelihood of detecting causative loci. With the presumption that rare variants are frequently the cause of a large portion of phenotypic variation, it was necessary to use large sample sets. In the main body of this study, we sequenced 4,966 samples (812 dermatologist-diagnosed cases of purely cutaneous psoriasis (PsC), 1,497 cases of rheumatologist-diagnosed psoriatic arthritis, 665 cases of cutaneous psoriasis with uncertain psoriatic arthritis status (PsV) and 1,992 controls) across 5.7 Mb of sequence containing 100 psoriasis candidate loci and 769 genes. For each candidate locus, we considered sequences within 250 kb of the strongest association signal. Within this window, three strategies were employed. For ten of the strongest psoriasis signals, we used a whole-region approach which included non-coding intergenic and intronic sequence. For four established loci of lesser significance, we targeted all full transcription units within the +/- 250 kb interval. For the remaining signals, we targeted the exons of all transcription units within the +/- 250 kb interval. Due to complexities of high-efficiency targeting of HLA genes we selected 5 specific candidate genes for sequencing near the HLA-C gene.

Study phs000766

Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR and PEAR-2)

The primary aim of the Pharmacogenomic Evaluation of Antihypertensive Responses grant (funded by NIH Pharmacogenomic Research Network grant U01 GM074492) was to identify genetic determinants of blood pressure response and adverse events after antihypertensive treatments. Two different clinical trials with genomic information available were included: PEAR-1 and PEAR-2 studies. The PEAR-1 study (clinicaltrials.gov identifier NCT00246519) was a randomized controlled clinical trial evaluating genetic determinants of BP responses and adverse metabolic responses to atenolol and hydrochlorothiazide (HCTZ) monotherapy and in combination (PMID: 19249413). Briefly, PEAR-1 recruited 768 hypertension individuals with uncomplicated hypertension who were randomized to either monotherapy of atenolol 50 mg daily or HCTZ 12.5 mg daily for 3 weeks, followed by dose titration to 100 mg and 25 mg daily, then the combination therapy. BP and metabolic responses to monotherapy and combination therapy were assessed after an average of 9 weeks of antihypertensive treatment. BP was measured using three different methods: home, office and ambulatory. For the BP analysis, a composite weighted average of the office, home, ambulatory daytime and nighttime BP responses was calculated based on the row sums of the inverse of the inter-method covariance matrices. Genomic DNA from PEAR-1 participants was genotyped using the Illumina Human Omni1MQuad BeadChip (Illumina, San Diego, CA, USA). The PEAR-2 study was a multicenter sequential monotherapy clinical trial (clinicaltrials.gov identifier NCT01203852) evaluating genetic determinants of BP response to metoprolol monotherapy and chlorthalidone monotherapy. After a washout period (if necessary), eligible hypertensive patients with uncomplicated hypertension received metoprolol tartrate 50 mg twice daily for 3 weeks and the dose was increased to 100 mg twice daily for an additional six weeks if an inadequate response was observed (>120/70 mm Hg and heart rate >55 beats/min). After second washout period, patients received chlorthalidone monotherapy. Home and office BP measurements were collected in PEAR-2 study. We have previously demonstrated that home BP is the more informative single BP measurement compared to the office BP measurement. Therefore, home BP is the phenotype used for the genome-wide association analysis for PEAR-2. PEAR-2 samples were genotyped using the Illumina Human Omni2.5S Beadchip (Illumina, San Diego, CA, USA).

Study phs000649

DNA Methylation Analysis of Prostate Cancer Cell Lines and Tissues Using Next Generation Sequencing

Aberrant DNA methylation changes are known to occur during prostate cancer progression beginning with precursor lesions. Utilizing fifty nanograms of genomic DNA in Methylplex-Next Generation Sequencing (M-NGS) we mapped the global DNA methylation patterns in prostate tissues (n=17) and cells (n=2). Peaks were located from mapped reads obtained in each sequencing run using a Hidden Markov Model (HMM)-based algorithm previously used for Chip-Seq data analysis(http://www.sph.umich.edu/csg/qin/HPeak). The total methylation events in intergenic/intronic regions between benign adjacent and cancer tissues were comparable. Promoter CGI methylation gradually increased from -12.6% in benign samples to 19.3% and 21.8% in localized and metastatic cancer tissues and approximately 20% of all CpG islands (CGIs) (68,508) were methylated in tissues. We observed distinct patterns in promoter methylation around transcription start sites, where methylation occurred directly on the CGIs, flanking regions and on CGI sparse promoters. Among the 6,691 methylated promoters in prostate tissues, 2481 differentially methylated regions (DMRs) are cancer specific and several previously studied targets were among them. A novel cancer specific DMR in WFDC2 promoter showed 77% methylation in cancer (17/22), 100% methylation in transformed prostate cell lines (6/6), none in the benign tissues (0/10) and normal PrEC cells. Integration of LNCaP DNA methylation and H3K4me3 data suggested a role for DNA methylation in alternate transcription start site utilization. While methylated promoters containing CGIs had mutually exclusive H3K4me3 modification, the histone mark was absent in CGI sparse promoters. Finally, we observed difference in methylation of LINE-1 elements between transcription factor ERG positive and negative cancers. The comprehensive methylome map presented here will further our understanding of epigenetic regulation of the prostate cancer genome. Overall Design: We mapped the global DNA methylation patterns in prostate tissues (n=17) and cells (n=2) from fifty nanograms of genomic DNA using Methylplex-Next Generation Sequencing (M-NGS). For replicate analysis in cell lines, a total of 4 runs were completed for PrEC prostate normal cell line, and 5 runs were completed for LNCaP prostate cancer cell line. For tissue samples, 2 benign prostate samples were sequenced twice on Illumina next generation sequencing platform to access overall repeatability of M-NGS.

Study phs000597

Kids First: Congenital Heart Defects and Laterality Birth Defects

Laterality defects occur in approximately 1:10,000 newborns and are associated with a range of structural birth defects and abnormalities of organ positioning. Gut malrotation, biliary atresia, asplenia or polysplenia, complex cardiovascular malformations, and midline defects such as neural tube defects, vertebral anomalies and rib fusions are found in various combinations in patients with laterality defects. In addition, a subset of laterality defects caused by abnormalities of cilia position or function are associated with additional medical problems such as chronic sinusitis and bronchiectasis that require specific preventive care; however these patients frequently are undiagnosed until late in disease course. The goal of this project is to elucidate the genetic architecture of laterality disorders in order to inform medical management and risk stratification and to prevent complications. Laterality disorders are genetically heterogeneous and we and others have previously identified single nucleotide variants inherited in an X-linked or autosomal recessive manner as explanations for a minority of cases. In addition, we have demonstrated copy number variants (CNVs) as a mechanism of disease that requires additional investigation. We hypothesize that the majority of cases result from complex genetic inheritance. We propose to investigate this hypothesis using a multifaceted analysis approach in our extremely well phenotyped cohort of 538 probands with laterality disorders. Nested within this cohort are 105 trios who have not had previous sequencing, probands who have had exome sequencing and are excellent candidates for gene discovery via whole genome sequencing (WGS), and families with multiple affected family members for family-based analysis. All trios will be analyzed by transmission disequilibrium test (TDT) including rare variant TDT. De novo mutations will also be identified from trios for potential gene discovery. Using all probands, we will identify the prevalence of pathogenic CNVs. In addition, we will perform burden analyses to identify genes, gene interactions, and pathways important for susceptibility to laterality disorders. Finally, our rare families with multiple affected members will be studied using family based segregation analysis. This comprehensive genetic analysis in patients with laterality disorders is necessary to identify the appropriate clinical diagnostic testing for risk stratification, to elucidate underlying genetic architecture and facilitate novel gene discovery, and to provide essential knowledge about genes and pathways impacting the development of laterality disorders.

Study phs002589

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

Discovery of Colorectal Cancer Susceptibility Genes in High-Risk Families

Colorectal cancer remains one of the most common cancers in the US with 146,970 new diagnoses and 49,920 deaths estimated for 2009. Colon cancer is also one of the most familial of cancers. Individuals with a first-degree relative with colon cancer have a 2- to 3-fold increased risk, and those with more than one first-degree relative with colon cancer, or a single first-degree relative affected at age 50 years, have a 3- to 6-fold greater risk than those with no family history. The most prominent high-risk colorectal cancer susceptibility genes, APC, MLH1, MSH2, MSH6, and PTEN, were all discovered more than a decade ago. Currently, mutation screening of these genes, plus a short list of additional genes that are responsible for a very small fraction of colorectal cancer, plays an important role in the clinical management of individuals with a strong family history of the disease or syndromic evidence for the presence of a gene mutation. At the other end of the risk spectrum, genome-wide association studies have identified a number of common alleles with very modest effects on colorectal cancer risk; their clinical utility has yet to be established. However, taken together, the known spectrum of genetic effects only explain about one quarter of the overall familial excess of colorectal cancer. It should be emphasized that, at present, the vast majority of individuals seen at familial cancer clinics are counseled on the basis of their family history alone because they do not have mutations in the known susceptibility genes. Accordingly, the long-term objective of this project is to identify the majority of genes responsible for the unexplained component of inherited colorectal cancer risk. Nextgen DNA sequencing is well suited for application to research questions in genetic susceptibility for which linkage analysis is confounded by extensive genetic heterogeneity. Taking advantage of unparalleled familial cancer genetics resources available through the Utah Population Database, candidate genes have been identified by sequencing all of the gene exons in the human genome from a series of colorectal cancer cases with a very strong family history of colorectal cancer not explained by one of the currently known high-risk susceptibility genes.

Study phs001787

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