3413 results for "*geneti*"

in 130.47 milliseconds.

• PROstate Cancer Medically Optimized Genome Enhanced ThErapy (PROMOTE) of Castration Resistant Prostate Cancer (CRPC) Patients Treated with Abiraterone Acetate

  The Prostate Cancer Medically Optimized Genome-Enhanced Therapy (PROMOTE) study uses genetic clues in castration-resistant prostate cancer that may identify an individualized treatment approach for men with the disease. Understanding the molecular biology behind castration-resistant prostate cancer has led to more treatment options, but there are still no definite conclusions about which specific drug best treats patients - maximum suppression of cancer growth while minimizing side effects. The PROMOTE study explores the genetic characteristics of each tumor to predict these treatment paradigms for the future, resulting in more effective and less toxic options for patients. Our long-term goal is to improve treatments for men with advanced prostate cancer by using genomic sequencing to increase life span and quality of life. We also will uncover novel vulnerable targets in the cancer genome that may provide new drug therapies. PARTICIPATION Eligible participants are men: With castration-resistant prostate cancer or prostate cancer not responding to hormone treatments About to begin abiraterone acetate therapy Agreeable to undergoing two tumor biopsies During the study, participants travel to Mayo Clinic for an initial biopsy (before beginning abiraterone acetate) and a second biopsy approximately three months later. The cell tissue collected is analyzed to identify gene alterations in the tumor that could eventually be targeted with treatments. Tissue is preserved for future research. Participants can continue to be treated by their local cancer care team during this period and beyond. In addition, the Mayo team carefully monitors participants' cancer via follow-up studies and the genetic signature of tumors that were biopsied so that patients may benefit from future treatments.

  Study phs001141

• The MD Anderson Colorectal Cancer Case Control Study

  Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. Driven by common disease common variants hypothesis, genome-wide association studies only identified a number of common susceptibility loci that explained a small portion of CRC heritability. We conducted a case-control study using whole exome sequencing to identify rare genetic variants with intermediate effect size that predispose individuals to colorectal cancer.

  Study phs002691

• Genetic Analysis of Limb Malformation Disorders: Freeman Sheldon Syndrome Exome Sequencing Study (LMD-FSS)

  The overall goal of this project is to investigate the etiology and pathogenesis of malformations (i.e., birth defects) of the limb, concentrating on abnormalities of limb patterning such as limb deficiency/duplications and multiple congenital contractures. The exome sequences of four unrelated individuals were obtained by massively parallel DNA sequencing. The three individuals were affected with Freeman Sheldon syndrome (OMIM: 193700).

  Study phs000204

• NHLBI GO-ESP: Family Studies (Familial Atrial Fibrillation)

  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. Large epidemiological studies have demonstrated a significant heritable component in atrial fibrillation (AF), especially the Lone forms, suggesting a monogenic syndrome. Although substantial genetic contribution has been made to the etiology of AF, the specific genes have not yet been identified. The familial form of this disease remains poorly characterized and largely undetermined. Here we seek to identify, characterize and determine the natural course of AF in our clinical practice. We identified four large multi-generation families (FAF 1-4). In FAF 1-2, most family members have symptomatic paroxysmal Atrial Fibrillation (AF) and were adequately treated with a combination of rate and rhythm therapies. By contrast, the AF substrate in FAF 3 and 4 was resistant to anti-arrhythmic drugs and ablation therapies.

  Study phs000362

• Genome-Wide Association Study of Preterm Birth

  Preterm birth (PTB, born before 37 weeks of gestation) is a leading cause of neonatal mortality and post-natal morbidity. PTB affects one in nine all live births in the U.S. Notably, the highest rate of PTB occurs among African Americans (one in six). PTB is a complex trait, likely determined by multiple environmental and genetic factors and their interactions. We demonstrated strong familial aggregation of preterm and low birthweight in the US Blacks and Whites (Wang et al, NEJM, 1995) and conducted the largest candidate gene study of preterm birth at that time (Hao et al, HMG, 2004). We showed that a subset of mothers with certain metabolic gene variants are particularly vulnerable to the adverse effects of cigarette smoking on low birthweight and preterm births (Wang et al, JAMA, 2002). We also published a number of papers that examined the effect of maternal pre-pregnancy BMI, micronutrient status, stress and environmental toxins on the risk of preterm birth and related conditions. This project, supported by a grant from the NICHD (2R01HD41702, PI, Xiaobin Wang), aimed to conduct a genome-wide association study (GWAS) and apply advanced statistical methods to identify susceptibility loci of PTB in a predominantly urban low-income African American sample, a subset of the Boston Birth Cohort. PUBLIC HEALTH REVELANCE: We anticipate that this study will lead to the identification of novel genetic loci of PTB and gene-environment interactions. Such findings not only will provide important insights into mechanisms leading to PTB, but also may help identify women at high-risk of PTB, which in turn, may lead to the development of early and targeted interventions that can prevent PTB or mitigate the severity and consequences of PTB.

  Study phs000332

• Next Generation Mendelian Genetics: Congenital Hyperinsulinism

  The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Congenital Hyperinsulinism (CHI) is the most common cause of hypoglycemia in the newborn and it is due to mutations in 8 different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and UCP2). It is a heterogeneous disease with variable onset (birth to adulthood) and a persistent, intermittent, or transient course with possible later conversion to non-autoimmune diabetes. Although mutations in the two subunits of the KATP channel (ABCC8 and KCNJ11) account for 50% of the cases, the other half is still genetically unexplained. CHI can be inherited in a dominant or recessive and can also present as a 'de novo' mutation. We became part of this study when we submitted 8 DNA samples for exome sequencing, from patients with CHI of Caucasian ancestry, which had no mutations identified in ABCC8 or KCNJ1, with the goal to identify new mutations in known genes or new mutations in new genes or genetic variants.

  Study phs000539

• The Two Sister Study: A Family-Based Study of Genes and Environment in Young-Onset Breast Cancer

  To study environmental and genetic causes of young onset breast cancer, we recruited women who had been young when recently diagnosed (under age 50 and within 4 years of enrollment), and had been identified as potentially eligible by a sister who was already participating in the ongoing Sister Study. The unaffected sister had already provided consent, questionnaire-based information and DNA (blood-based) when she enrolled in the Sister Study. Her case sister then provided comparable questionnaire-based information and DNA via a mail-back saliva collection kit. To enable family-based analyses, parents were also asked to (only) provide consent and a saliva sample. Because the cases were young-onset, most parents were alive, but unavailability of the parents was not a basis for exclusion. The study was funded in part by Susan G. Komen for the Cure.

  Study phs000678

• Gene Expression of Small Cell Carcinoma of the Ovary-Hypercalcemic Type (SCCOHT)

  Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer afflicting young women at a median age of 24 years. SCCOHTs are characterized by loss of protein expression of SWI/SNF chromatin remodeling ATPases SMARCA4 and SMARCA2 through mutation and epigenetic silencing, respectively. This study aims to establish gene expression profiles of this cancer through RNA-Seq of fourteen pathologically confirmed cases of SCCOHT tumors.

  Study phs001528

• The spectrum of somatic mutations in high-risk acute myeloid leukemia with -7/del(7q)

  Patients with myeloid malignancies bearing high-risk cytogenetic abnormalities lack effective therapies and have a poor overall survival. -7/del(7q) is identified in half of high-risk myeloid neoplasms. We recently identified CUX1 to be a haploinsufficient myeloid tumor suppressor gene located within the commonly deleted segment of 7q22. Here we identify the spectrum of somatic mutations that co-occur with loss of CUX1 and chromosome 7 in patients with de novo acute myeloid leukemia (AML) or a therapy-related myeloid neoplasm. -7/del(7q) leukemias have a distinct mutational profile characterized by low frequencies of alterations in major leukemogenic pathways, including genes encoding transcription factors, cohesin, and DNA-methylation-related proteins. In contrast, RAS pathway activating mutations occurred in 40% of -7/del(7q) samples, a significantly higher frequency than other AMLs and higher than previously reported. As targeted therapeutics advance, our data provide guidance for which pathways are most relevant in the treatment of adverse-risk myeloid leukemia.

  Study phs000759

• Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis

  This longitudinal observational study will investigate the natural history and progression of four genetic causes of intrahepatic cholestasis of childhood, including alpha-1 antitrypsin deficiency (α1-AT), Alagille syndrome (AGS), progressive familial intrahepatic cholestasis (PFIC), and bile acid synthesis defects (BAD). This study will be conducted as part of the Cholestatic Liver Disease Consortium (CLiC), an NIH-funded multi-centered Rare Disease Clinical Research Consortium. In this study, we will collect defined data elements in a uniform fashion at fixed intervals for five years over a relatively large number of patients with these rare disorders. In addition, a biobank of patient specimens and DNA samples will be established for use in ancillary studies to be performed in addition to this study. By comparing outcome measures between the four liver diseases (i.e., using each disorder as a disease-control for the other disorders), the full impact of each disorder can best be determined in comparison to the other liver diseases. Using the longitudinal database in this fashion, this study will provide an improved understanding of the effects of the cholestatic liver during childhood irrespective of the underlying etiology as well as to the pathophysiology, outcome, and complications of each of the disorders. This initial characterization will allow calculation of sample sizes for future therapeutic intervention clinical trials and provide the baseline to which interventions should be compared.

  Study phs001288

• Contribution of Genetic Polymorphisms to the Abuse Liability of Oxycodone

  The proposed study examined the prevalence of various genetic polymorphisms thought to be involved in opioid abuse among current heroin users. In addition to providing blood samples for genetics analysis, participants completed a number of questionnaires that allowed us to learn detailed information about their current and history of opioid drug use.

  Study phs001559

• Genomic Landscape of Cutaneous Diffuse Large B Cell Lymphoma

  Cutaneous diffuse large B cell lymphomas (DLBCL) are aggressive lymphomas with a poor prognosis. To elucidate their genetic bases, we performed whole exome capture and massively parallel sequencing on 19 tumor samples of diffuse large B cell lymphoma, leg type (DLBCL-LT) and 6 samples of secondary cutaneous diffuse large B cell lymphoma, not otherwise specified (DLBCL-NOS). Tumor specimens and their associated sequencing data were from multiple institutions, including Northwestern University (Chicago, IL), Massachusetts General Hospital (Boston, MA), and Medical University of Graz (Graz, Austria).

  Study phs001645

• E5103 Correlative Studies

  ECOG-ACRIN E5103 (E5103) was a phase III adjuvant breast cancer trial that randomized 4994 patients with node-positive or high-risk node-negative breast cancer to intravenous doxorubicin and cyclophosphamide every 2 or 3 weeks (at the discretion of treating physician), for four cycles of adriamycin and cyclophosphamide (AC) followed by 12 weeks of weekly paclitaxel (80 mg/m2) alone (Arm A), or to the same chemotherapy with either concurrent bevacizumab (Arm B), or concurrent plus sequential bevacizumab (Arm C). To develop predictive genetic biomarkers for chemotherapy efficacy and toxicities, we have successfully performed genome-wide genotyping and whole exome sequencing in the germline (blood) DNA of 3215 and 672 patients, respectively, from the E5103 trial to investigate the association of genetic variants with chemotherapy efficacy and toxicities. Case and control studies were performed with genome-wide analyses (GWAS) and whole exome analyses (WES) across all arms of E5103 to identify genotypes at single-nucleotide polymorphisms (SNPs) and deleterious gene mutations that were associated with paclitaxel-induced peripheral neuropathy (TIPN). Through GWAS, we have identified a SNP, rs3125923, and through WES, Cytochrome P450 oxidoreductase (POR), that was significantly associated with grade 3-4 TIPN.

  Study phs003201

• Disorders/Differences of Sex Development (DSD) Study Performed at UCLA in Collaboration with the DSD-Translational Research Network (DSD-TRN), with the Support of the Gabriella Miller Kids First Pediatric Research Program

  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). Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. Whole Genome Sequence (WGS) and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Disorders/Differences of Sex Development (DSD) are congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical. DSD are chronic medical conditions collectively affecting ~1% of the population, frequently requiring life-long care by multiple specialists, and carrying a significant public health burden. Some are associated with life-threatening events, such as adrenal crises in Congenital Adrenal Hyperplasia (CAH). DSD are also associated with increased infertility, cancer, gender dysphoria risks, psychosocial distress and pervasive challenges to health-related quality of life (HRQoL) for patients and families. DSD are broadly classified into three categories: sex chromosome DSD, 46,XY DSD and 46,XX DSD, and further classified according to the type of gonad found in the patient (ovary, testis, ovotestis). We were able to increase significantly the diagnostic success for DSD using Whole Exome Sequencing (WES), with the identification of disease-causing and likely pathogenic variants in a third of a cohort of 46,XY patients. We have therefore proposed a shift in the diagnostic approach to DSD to use next-gen sequencing as a first-line clinical test, which could lead to faster and more accurate diagnosis, and orient further clinical management, limiting unnecessary, costly, and often invasive endocrine testing and imaging. However many remain unexplained (over half of the XY cases, a significant minority of XX cases, including most ovotesticular DSD, and most syndromic cases). In addition, the very large phenotypic variability in cases with known variants in the same gene is unexplained. We here propose to use Whole-Genome Sequencing (WGS), which dramatically improves upon exome sequencing, covering both coding and non-coding parts of the genome more uniformly, as an approach to not only improve diagnostic yield, but also to identify novel genes and regulatory elements involved in DSD.

  Study phs001178

• CIP: Differential Response to Hydroxyurea and Incidence of Stroke in Sickle Cell Disease

  Sickle cell disease (SCD) is a severe debilitating hematological disorder associated with a high degree of morbidity and mortality. There are approximately 200,000 babies born with sickle cell disease each year, with the disease predominately affecting individuals in Africa. The overall global burden of the disease is tremendous, with more than 100,000 patients currently in the US and further millions worldwide. The governing bodies of the World Health Organization have recently adopted a resolution to strengthen the response to sickle disease in all affected countries and there is a definite need for high quality sickle cell disease research that has the potential to improve the treatment and prognosis of patients with this devastating disease. The clinical manifestations of SCD arise from a complex pathophysiology that includes hemolysis, acute vaso-occlusion, endothelial dysfunction, inflammation, and chronic organ damage. While the individual clinical course of this disease is highly variable, many of the associated complications demonstrate some degree of heritability. Intensive research into identifying genetic modifiers that can affect the pathophysiology of SCD has been limited to date and there is an urgent need to improve of our knowledge the molecular mechanisms underlying the clinical complications of SCD. The Sickle cell CIP project is investigating complication of stroke and pharmacogenomics of hydroxyurea response in patients with sickle cell anemia. The major benefit of hydroxyurea comes from its ability to induce fetal hemoglobin (HbF) and higher HbF levels are associated with reduced morbidity and mortality in SCA patients. We will perform whole exome and whole genome sequencing of SCA patients in order to identify genome variants associated with incidences of stroke and HbF response to hydroxyurea.

  Study phs000691

• Genetics of Schizophrenia in an Ashkenazi Jewish Case-Control Cohort

  Schizophrenia is characterized by high heritability (~80%), yet the identification of susceptibility genes has proven extremely challenging. The Ashkenazi Jewish population, derived from a limited number of founders, may be enriched for a subset of susceptibility alleles, which may also have higher odds ratios than those detected by previous studies. GWAS was conducted in a large Ashkenazi case-control cohort, derived from the Hebrew University Genetic Resource, using the Illumina HumanOmni1-Quad BeadChip.

  Study phs000448

• Next Generation Mendelian Genetics: Neonatal Diabetes

  The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Neonatal diabetes mellitus (ND) is a rare form of monogenic diabetes (90,000-260,000 live births) that is diagnosed in the first 6 months of life. The disease has been classified as transient or permanent and although it can be inherited, more frequently is sporadic as a result of 'de novo' mutations. Defects in 12 genes have been found as responsible for the disease (defects in the paternally imprinted chromosomal region 6q24, IPF1, SLCA2A, INS, EIF2AK3, GCK, FOXP3, GLIS3, PTF1A, HNF1Beta, KCNJ11 and ABCC8). The two subunits of the ATP-sensitive K channel (ABCC8 and KCNJ11) and the insulin gene (INS), account for almost half of the cases and similar to CHI, the other half, remains genetically unexplained. We became part of this study when we submitted 4 DNA samples for exome sequencing, from patients with NDM of Caucasian ancestry, which had no mutations identified in ABCC8 or KCNJ1, with the goal to identify new mutations in known genes or new mutations or genetic variants in new genes.

  Study phs000542

• Copy-Number Analysis of Understudied Black Women Ovarian Cancers

  Two general types of genetic alterations drive cancer progression: mutations and copy number alterations (CNAs). With the exception of p53, single nucleotide variant mutations (here, simply "mutations") are not drivers of 80% of tumors within the most frequent and deadly histotype of ovarian cancer: serous ovarian cancer (SOC). Rather, CNAs are more prevalent in SOC than any other cancer type studied by phs000178 The Cancer Genome Atlas (TCGA). Fully two-thirds of genes are altered by CNAs in the average SOC. Bioinformatic methods have shown that these CNAs modulate specific molecular pathways, such as autophagy, and this finding enabled effective pathway-targeted therapies1. Unfortunately, TCGA ovarian cancer data lacks racial diversity. Only 6% of SOC tumors (n=32) studied are from African origin. Black women diagnosed with ovarian cancer are more likely to die from their disease than white women. Five-year survival after diagnosis is 31% among blacks versus 42% among whites, and this disparity is seen in every age group and tumor stage distribution. Dr. Kelemen examined data from 365 white and 95 black ovarian cancer patients from the Hollings Cancer Center (HCC) Cancer Registry between 2000 and 2015 and found that black women had an 81% higher risk of death after diagnosis compared to white women (HR 1.81, 95% CI 1.35-2.43), independent of diagnosis center (98% were treated at HCC but half were diagnosed elsewhere), tumor stage, histology, extent of residual tumor remaining following surgery, insurance status, smoking, type of treatment for ovarian cancer, and age-adjusted Charlson comorbidity index. This disparity remained even when restricted to women who received the standard of care, surgery-chemotherapy sequence (HR 1.79, 95% CI 1.10-2.89). Despite receiving the same treatment, black race was still associated with inferior survival. A similar disparity has been reported by others, indicating that the HCC experience is representative of national data. Here, an additional set of high-grade serous ovarian cancer primary tumors were acquired from biorepositories with a focus on expanding data originating from African American women. Data were analyzed for copy-number alterations using exome sequencing and control-FREEC software.

  Study phs002313

• GWAS in African Americans, Latinos and Japanese

  The Multiethnic Cohort Study is a population-based prospective cohort study (n=215,251) that was initiated between 1993 and 1996 and includes subjects from various ethnic groups - African Americans and Latinos primarily from Californian (great Los Angeles area) and Native Hawaiians, Japanese-Americans, and European Americans primarily from Hawaii. State drivers' license files were the primary sources used to identify study subjects in Hawaii and California. Additionally, in Hawaii, state voter's registration files were used, and, in California, Health Care Financing Administration (HCFA) files were used to identify additional African American study subjects. In the cohort, incident cancer cases are identified annually through cohort linkage to population-based cancer Surveillance, Epidemiology, and End Results (SEER) registries in Hawaii and Los Angeles County as well as to the California State cancer registry. Information on estrogen receptor status is also obtained through these registries. Blood sample collection in the MEC began in 1994 and targeted incident breast cancer cases and a random sample of study participants to serve as controls for genetic analyses. Subjects are frequency matched on age at blood draw and ethnicity. The following number of breast cancer cases and controls were genome-wide scanned as part of this study: African Americans, 473 cases and 464 controls; Japanese: 885 cases and 822 controls; Latinos, 520 cases and 544 controls.

  Study phs000517

• A panel of reference haplotypes for imputing complement component 4 (C4) gene structural variation

  Neuropsychiatric and autoimmune disorders have substantial epidemiological correlations (Benros et al., JAMA Psychiatry 2013, PMID: 23760347) and broad, genome-wide patterns of shared genetic risk (Pouget et al., Hum Mol Genet, PMID: 31211845; Tylee et al., Am J Med Genet B Neuropsychiatr Genet 2018, PMID: 30325587). Some cases of psychosis involve autoantibodies against the NMDA receptor, AMPA receptor, or other synaptic proteins (reviewed in Dalmau et al, Lancet Neurol 2011, PMID: 21163445). The related autoimmune conditions lupus and Sjogren's Syndrome also involve the development of autoantibodies. The possibility that neuropsychiatric disorders can have molecular mechanisms in common with autoimmune disorders - for example, that psychosis involves an inflammatory or autoimmune component in some patients, or that immune molecules are re-used in the brain to underlie other important biological activities (Stevens et al., Cell 2007, PMID: 18083105) - could open novel therapeutic possibilities for neuropsychiatric disorders. At a genetic level, the strongest genetic associations of schizophrenia, lupus, and Sjogren's Syndrome to common genetic variation involve associations to genetic markers in the Major Histocompatibility Complex (MHC) locus. Bipolar disorder in some studies also associates with variation in or near the MHC locus, though less strongly than schizophrenia does. Intriguingly, the same specific SNPs appear to associate strongly with schizophrenia, lupus, and Sjogren's; these strongly associating SNPs span a genomic segment that includes the HLA class II genes (which have an important role in antibody production) and the complement component 4 (C4) genes. The specific genes and alleles responsible for these associations need to be completely defined, and the extent to which they represent shared or distinct genetic influences in neuropsychiatric and autoimmune illnesses needs to be clarified. The complement component 4 (C4A and C4B) genes are present in the MHC locus, between the class I and class II HLA genes. C4A and C4B commonly vary in genomic copy number and encode complement proteins with distinct affinities for molecular targets. The complex genetic variation at C4 - arising from many alleles with different numbers of C4A and C4B genes - has been challenging to analyze in large cohorts. We recently developed an approach to this problem based on imputation: people share long haplotypes with the same combinations of SNP and C4 alleles, such that C4A and C4B gene copy numbers can be imputed from SNP data (Sekar et al., Nature 2016, PMID: 26814963). In the current work, to analyze C4 in large cohorts, we developed a way to identify C4 alleles from whole-genome sequence (WGS) data, then analyzed WGS data from 1,234 individuals to create a large multi-ancestry panel of 2,530 reference haplotypes of MHC SNPs and C4 alleles that can then be imputed into still-larger cohorts for which SNP data are available. With this dbGaP submission, we make this reference panel available for other studies. Protocols and software for imputing C4 alleles into genome-wide SNP data, and for performing molecular analyses on the C4 genes (such as direct measurement of copy number from genomic DNA), can be found on the McCarroll Lab web site (http://mccarrolllab.org/resources). We are also working to create additional reference panels for imputation of C4 alleles that will be based on still-larger and more diverse population samples; links to these will also be available on the McCarroll Lab web site as we create and validate them.

  Study phs001992

• Brigham and Women's Hospital Multiple Sclerosis Genetic Collection

  The main objective of this GWA study is to identify Multiple Sclerosis (MS) susceptibility loci. Whole-genome association analysis was performed on 924 individuals genotyped on the Affymetrix 6.0 Genechip. The cohort consisted of 860 clinically diagnosed MS patients and 64 control subjects.

  Study phs000275

• The Etiological Bases of Giftedness: Epidemiological Study of Cognitive Ability in Children in Saudi Arabia

  Recent studies of genetic foundations of cognitive ability rely on large samples (hundreds of thousands) of individuals from relatively outbred populations of mostly European ancestry. Hypothesizing that the genetic foundation of cognitive ability depends on the broader population-specific genetic context, we performed a genome-wide association study and homozygosity mapping of cognitive ability estimates obtained through latent variable modeling in a sample of 354 children from the consanguineous population of Saudi Arabia. Approximately half of the sample demonstrated significantly elevated homozygosity levels indicative of inbreeding, and among those with elevated homozygosity, it was negatively associated with cognitive ability. Further homozygosity mapping identified a specific run, inclusive of the GRIA4 gene, that survived corrections for multiple testing for association with cognitive ability. The results suggest that in a consanguineous population, a notable proportion of the variance in cognitive ability in the normal range in children might be regulated by population-specific mechanisms such as patterns of elevated autozygosity.

  Study phs001884

• Polycystic Ovary Syndrome (PCOS) Genetics

  PCOS is a complex genetic disease reflecting the interplay of susceptibility genes and environmental factors. The cardinal reproductive feature of the syndrome, hyperandrogenemia, appears to play a direct role in the pathogenesis of the associated metabolic abnormalities. Male as well as female first-degree relatives have reproductive and metabolic phenotypes including increased prevalence rates of type 2 diabetes (T2D), metabolic syndrome (MBS) and other risk factors for cardiovascular disease (CVD). Northwestern University (NU) investigators lead a team that has extensive experience in phenotyping PCOS and in the genetic analysis of complex diseases including genome-wide association study (GWAS). Together with an expert group of collaborators from the Hershey Medical Center, and The University of Chicago, we have conducted a GWAS to identify PCOS susceptibility alleles using a large cohort of extensively and consistently phenotyped PCOS cases. Population controls for this study come from the NUgene project described below. NUgene project: In 2002, Northwestern committed to the development of a DNA repository to serve as a platform for the identification and validation of genotype-phenotype associations that will impact healthcare. 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 questionnaire (2 versions were used, 1 before and 1 after February 2006, both are included) 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.

  Study phs000368

• 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

• Genomic Analysis of Extra-Nodal Natural Killer/T-Cell Lymphoma (ENKTCL)

  In this study, we performed extensive genetic profiling on 209 extra-nodal natural killer/T-cell lymphoma (ENKTCL) nasal-type cases, including 174 Chinese from four hospitals in China, and 31 Hispanic and 4 Caucasian patients from City of Hope and Eberhard Karls University of Tübingen. All of the cases were reviewed by experienced hematopathologists to confirm diagnosis. Written informed consents from patients were reviewed and approved by the institutional review board of each institution. We deposited targeted exon sequencing data of a selected 333-gene panel on the ENKTCL cases in dbGaP. DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissues with an AllPrep DNA/RNA FFPE Kit. A custom platform (Agilent SureSelect) was used to capture target exons from genomic DNA of ENKTCL tumors. DNA was fragmented to 200bp using a Covaris S220 Focused-ultrasonicator and was end-repaired and ligated to Illumina adaptors with a KAPA Hyper Prep Kit. Ligated products were purified and amplified with a 7-cycle PCR. Exome capture from the PCR products was performed using a SureSelect Target Enrichment Kit. The captured exomes were further amplified with an 8-cycle PCR and purified for cluster generation using the cBot cluster generation system with a HiSeq PE Cluster Kit V4. 100bp paired-end reads were generated from an Illumina HiSeq 2500 system with a HiSeq SBS Kit V4.

  Study phs002925

• Michigan Polybrominated Biphenyl (PBB) Exposure Registry

  Humans are exposed to chemicals such as brominated flame retardants (BFRs) at unprecedented levels, and a wide variety of health effects are attributed to such exposures. However, the biological mechanisms that link exposures to its consequences remain unknown. An industrial accident in the 1970's exposed over 4000 individuals in rural Michigan to polybrominated biphenyl (PBB), a BFR that was present in the food supply for years prior to detection and management. Health effects are still evident in these individuals and their children. Because this population has been assessed regularly since the exposure, it is an ideal group in which to examine the molecular mechanisms that contribute to susceptibility, vulnerability and health effects. The goal of this project is to identify the genetic variants that associate with the rate of PBB elimination over time and integrate genetic and epigenetic datasets and identify complex gene-environment relationships in PBB exposed individuals. We will leverage data generated as part of past and ongoing studies in the Michigan Polybrominated Biphenyl Registry. We anticipate that this study will provide insight into how genetic variants and the environment interact in relation to PBB exposure and its health effects. We also anticipate the results of this study will be informative for studies of BFRs and other endocrine disrupting compounds with similar chemical properties. Note that methylation array data is available from NCBI GEO under GSE116339: Exposure to Polybrominated Biphenyl (PBB) Associates with DNA Methylation Differences Across the Genome

  Study phs001862

• Genomic Psychiatry Cohort (GPC) Whole Genome Sequencing and Genotyping Study

  The Center for Genomic Psychiatry at the University of Southern California (USC), SUNY Downstate and an extensive network of academic medical centers have created the Genomic Psychiatry Cohort (GPC). The GPC consists of a large clinical cohort of patients with schizophrenia, bipolar disorder, and healthy controls. The data generation of genotyping and whole genome sequencing of the GPC has been done in collaboration with the USC and the Broad Institute of MIT and Harvard. Genome-wide association studies are being performed with the samples to identify genetic risks for psychiatric disease. Genotyping is also being used to determine ancestry informative markers and replication of candidate genes. Whole genome sequencing identifies functional variants associated with disease risk.

  Study phs001020

• CIDR: The Role of Rare Coding Variation in Prostate Cancer in Men of African Ancestry - RESPOND Project 2

  In RESPOND Project 2, we seek to identify rare genetic factors that are associated with prostate cancer (PCa) risk and aggressiveness in men of African ancestry (AA). We will conduct exome sequencing of 15,000 prostate cancer cases and 5,000 controls from the RESPOND cohort and the African Ancestry Prostate Cancer Consortium (AAPC) with cases selected based on risk categories: high-risk (stage T3/T4 or Gleason 8+ or PSA>20 ng/ml), intermediate-risk (stage T2b/T2c or Gleason 7 or PSA 10-20 ng/ml) and low-risk disease (stage T1/T2a and Gleason ≤ 6 and PSA<10 ng/ml). We expect the findings from this Project to significantly advance knowledge of susceptibility to aggressive PCa and racial/ethnic disparities in PCa risk, and to guide the development of future preventive, early detection and prognostic measures for AA men. The first phase of the study will include exome sequence data for approximately 7,500 cases and 5,000 controls from AAPC. The second phase of the study will include exome data for 5,000 cases from RESPOND and AAPC.ACKNOWLEDGMENTS and CONTRIBUTING SITES Multiethnic Cohort (MEC): The MEC and the genotyping in this study were supported by National Institutes of Health (NIH) grants CA63464, CA54281, CA1326792, CA148085, and HG004726. Cancer incidence data for the MEC and Los Angeles Study of Aggressive Prostate Cancer (LAAPC) studies have been collected by the Los Angeles Cancer Surveillance Program of the University of Southern California with federal funds from the National Cancer Institute (NCI)/NIH/Department of Health and Human Services (DHHS) under Contract No. N01-PC-35139, and the California Department of Health Services as part of the state-wide cancer reporting program mandated by California Health and Safety Code Section 103885, and grant 1U58DP000807-3 from the Centers for Disease Control and Prevention (CDC). Ghana Prostate Study (GPS): The Ghana Prostate Study was funded by the Intramural Program of the NCI/NIH/DHHS under Contract No. HHSN261200800001E. Men of African Descent and Carcinoma of the Prostate (MADCaP): We thank all MADCaP study participants. This work is a product of the MADCaP network. This work was supported by NCI/NIH grant U01CA184374 to Timothy Rebbeck and National Institute of General Medical Sciences (NIGMS) MIRA grant R35GM133727 to Joseph Lachance. Additional funding includes a seed grant from the Integrated Cancer Research Center at Georgia Institute of Technology. UGANDA: The UGANDA study was supported by NIH grant R01CA165862. Southern Community Cohort (SCCS) is funded by NIH grant CA092447. SCCS sample preparation was conducted at the Epidemiology Biospecimen Core Lab that is supported in part by the Vanderbilt Ingram Cancer Center (CA68485). Data on SCCS cancer cases were provided by Alabama Statewide Cancer Registry, Kentucky Cancer Registry, Office of Cancer Surveillance at Tennessee Department of Health, Florida Cancer Data System, Central Cancer Registry at North Carolina Division of Public Health, Georgia Comprehensive Cancer Registry, Louisiana Tumor Registry, Mississippi Cancer Registry, South Carolina Central Cancer Registry, Virginia Cancer Registry at Virginia Department of Health, and Cancer Registry at Arkansas Department of Health. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries (NPCR)/Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the NPCR/CDC. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. Karuprostate: The Karuprostate study was supported by the French National Health Directorate and by the Association pour la Recherche sur les Tumeurs de la Prostate. Séverine Ferdinand, Marc Romana. The North Carolina - Louisiana Prostate Cancer Project (PCaP) is carried out as a collaborative study supported by the Department of Defense contract DAMD 17-03-2-0052. The authors thank the staff, advisory committees and research subjects participating in the PCaP study for their important contributions. We would also like to acknowledge the UNC BioSpecimen Facility and the LSUHSC Pathology Lab for our DNA extractions, blood processing, storage and sample disbursement (https://genome.unc.edu/bsp). Gene-Environment Interaction in Prostate Study (GECAP) was supported by NIH grant ES011126. King County Prostate Cancer Study (KCPCS) was supported by NIH grants CA056678, CA082664, and CA092579, with additional support from the Fred Hutchinson Cancer Research Center. We thank the participants in these studies, and Ms. Suzanne Kolb for help with study management. The Los Angeles Study of Aggressive Prostate Cancer (LAAPC) was funded by grant 99-00524V-10258 from the Cancer Research Fund, under Interagency Agreement #97-12013 (University of California contract #98-00924V) with the Department of Health Services Cancer Research Program. Cancer incidence data for the MEC and LAAPC studies have been collected by the Los Angeles Cancer Surveillance Program of the University of Southern California with Federal funds from the NCI/NIH/DHHS under Contract No. N01-PC-35139, and the California Department of Health Services as part of the state-wide cancer reporting program mandated by California Health and Safety Code Section 103885, and grant 1U58DP000807-3 from the CDC. Prostate Cancer Studies at MD Anderson (MDA) was supported by grants CA68578, ES007784, DAMD W81XWH-07-1-0645, and CA140388.

  Study phs002637

• Health and Retirement Study (HRS)

  Introduction to V2: This data release comprises data from the V1 release combined with approximately 3,000 additional samples, collected during the HRS 2010 field period. The 2010 data include samples from a random half of the new cohort enrolled in 2010 along with a significant expansion of the minority sample. Description: The University of Michigan Health and Retirement Study (HRS) is a longitudinal panel study that surveys a representative sample of approximately 20,000 people in America over the age of 50 every two years. Supported by the National Institute on Aging (NIA U01AG009740) and the Social Security Administration, the HRS explores the changes in labor force participation and the health transitions that individuals undergo toward the end of their work lives and in the years that follow. The study collects information about income, work, assets, pension plans, health insurance, disability, physical health and functioning, cognitive functioning, and health care expenditures. Through its unique and in-depth interviews, the HRS provides an invaluable and growing body of multidisciplinary data that researchers can use to address important questions about the challenges and opportunities of aging. Because of its innovation and importance, the HRS has become the model and hub for a growing network of harmonized longitudinal aging studies around the world. Origins of the HRS. As the population ages it is increasingly important to obtain reliable data about aging and topics that are relevant to a range of policy issues in aging. To address this need, the National Institutes on Aging (NIA) established a cooperative agreement with the University of Michigan Institute for Social Research to collect such data. The HRS launched data collection in 1992 and has re-interviewed the original sample of respondents every two years since then. By adding new cohorts and refreshing the sample, the HRS has grown to become the largest, most representative longitudinal panel study of Americans 50 years and older. HRS Study Design. The target population for the original HRS cohort includes all adults in the contiguous United States born during the years 1931-1941 who reside in households, with a 2:1 oversample of African-American and Hispanic populations. The original sample is refreshed with new birth cohorts (51-56 years of age) every six years. The sample has been expanded over the years to include a broader range of birth cohorts as well. The target population for the AHEAD survey consists of United States household residents who were born in 1923 or earlier. Children of the Depression (CODA) recruits households born 1924-1930, War Babies 1942-47, Early Boomers 1948-53, and Mid-Boomers 1954-59. Data collection includes a mixed mode design combining in-person, telephone, mail, and Internet. For consenting respondents, HRS data are linked at the individual level to administrative records from Social Security and Medicare claims. Genetic Research in the HRS. The HRS has genotyped 2.5 million single nucleotide polymorphisms (SNPs) on respondents using Illumina's Human Omni2.5-Quad (Omni2.5) BeadChip. The genotyping was performed by the NIH Center for Inherited Disease Research (CIDR). Saliva was collected on half of the HRS sample each wave starting in 2006. In 2006, saliva was collected using a mouthwash collection method. From 2008 onward, the data collection method switched to the Oragene kit. Saliva completion rates were 83% in 2006, 84% in 2008, and 80% in 2010 among new cohort enrollees. HRS Phenotypic data. Phenotypic data are available on a variety of dimensions. Health measures include physical/psychological self-report, various health conditions, disabilities, cognitive performance, health behaviors (smoking, drinking, exercise), physical performance and anthropomorphic measures, and biomarkers (HbA1c, Total Cholesterol, HDL, CRP, Cystatin-C). Data are also available on health services including utilization, insurance and out-of-pocket spending with linkage to Medicare records. Economic measures include employment status/history, earnings, disability, retirement, type of work, income by source, wealth by asset type, capital gains/debt, consumption, linkage to pensions, Social Security earnings/benefit histories. There is also extensive information on family structure, proximity, transfers to/from of money, time, social and psychological characteristics, as well as a wide range of demographics. Performance on a cognitive test combining immediate and delayed word recall was selected as an example trait for the dbGaP data release. In the immediate word recall task the interviewer reads a list of 10 nouns to the respondent and asks the respondent to recall as many words as possible from the list in any order. After approximately five minutes of asking other survey questions, the respondent is asked to recall the nouns previously presented as part of the immediate recall task. The total recall score is the sum of the correct answers to these two tasks, with a range of 0 to 20. Researchers who wish to link to other HRS measures not in dbGaP will be able to apply for access from HRS. A separate Data Use Agreement (DUA) will be required for linkage to the HRS data. See the HRS website (http://hrsonline.isr.umich.edu/gwas) for details.

  Study phs000428

• The Genetic Landscape of Metastasis and Recurrence in Head and Neck Squamous Cell Carcinoma

  Recurrence and/or metastasis occur in more than half of patients with head and neck squamous cell carcinoma (HNSCC) and pose the greatest threats to long-term survival. The genetic alterations underlying recurrent/metastatic HNSCC are unknown. This study represents the first whole exome sequencing (WES) cohort study of patient-matched tumor pairs in recurrent or metastatic HNSCC. Synchronous lymph node metastases are genetically more similar to their paired index primary tumors than metachronous recurrent tumors are. Newly arisen mutations in recurrent or metastatic tumors, may have therapeutic implications. Several genes were found to be mutated in multiple metastatic or recurrent tumors, but not in their respective primaries, including C17orf104, ITPR3, and DDR2. DDR2 mutations have been shown to confer enhanced sensitivity to Src-family kinase (SFK) inhibitors in other malignancies. Similarly, we found HNSCC cell lines harboring endogenous and engineered DDR2 mutations to be more sensitive to the SFK inhibitor dasatinib, than those with WT DDR2. This study outlines the first compendium of somatic mutations in primary, metastatic and/or recurrent HNSCC cancers that arise in individual patients; and demonstrates how such data can be used to interrogate potential predictive/prognostic biomarkers to inform and guide personalized therapy.

  Study phs001007

• Systems genetics in human endothelial cells identifies non-coding variants modifying enhancers, expression, and complex disease traits

  Identification of causal variants and mechanisms underlying complex disease traits in humans requires strategies to locate and fine-map functional regulatory variants in disease-relevant cell types. To discover functional regulatory variants in primary aortic endothelial cells (ECs) from humans, we collected genetic, transcriptomic, and four epigenomic phenotypes in a population of 153 human donors representing individuals of both sexes and three major ancestries. We found thousands of EC eQTLs that were not present in GTEx at all ranges of effect sizes, indicating novel functional variants not observable from tissue data. We performed several epigenetic assays across 53 donors' EC to enable molecular QTL mapping, which included chromatin accessibility, histone modification, and transcription factor binding of proteins ERG and NF-kB/p65 in two activation states. We discovered over 3000 regulatory elements where cis-regulatory variants associated to significant differences in epigenetic marks. Co-localization with our eQTLs, TF motif mutations, and 3D confirmation capture data in ECs enabled our discovery of hundreds of high-confidence functional regulatory elements that perturb endothelial molecular phenotypes. Furthermore, this set of variants is enriched at GWAS loci for Coronary Artery disease and other disease traits, with some SNPs demonstrating pleiotropic effects. Together, our dataset and analytical approach provide the genetics and vascular biology communities with specific variants affecting EC biology and serves as a proof-of-principle for how to detect functional regulatory variants in human cells with relevance to complex traits.

  Study phs002057

• The Genomic Landscape of Tuberous Sclerosis Complex (TSC)

  In this study, we characterized the genomic landscape of tuberous sclerosis complex (TSC), a rare genetic disease causing multisystem growth of benign tumors and other hamartomatous lesions. We analyzed 127 human tissues, including 111 TSC-associated samples and 16 non-TSC negative controls, using multiple genomic platforms including whole exome sequencing, targeted sequencing of known disease-causative loci (TSC1 and TSC2), mRNA sequencing, high-density SNP arrays, and DNA methylation arrays.

  Study phs001357

• Patient-Specific Factors Influence Somatic Variation Patterns in Von Hippel-Lindau Disease Renal Tumors

  Patients affected with von Hippel-Lindau disease are at risk of developing multiple independent clear cell renal carcinomas. This study performed whole genome sequencing on 40 tumors from 6 VHL patients to compare somatic variation patterns within and between patients. Although tumors from the same patient showed many differences, within-patient patterns were discernible. Single-nucleotide substitution type rates were significantly different between patients and showed biases in trinucleotide mutation context. We also observed biases in chromosome copy number aberrations. These results show that genetic background and/or environment can influence the types of mutations that occur.

  Study phs001107

• Genomic Analysis of Fibrolamellar Hepatocellular Carcinoma

  Fibrolamellar hepatocellular carcinoma (FL-HCC) is a very rare and distinct subtype of hepatocellular carcinoma that occurs in the previously healthy livers of adolescents and young adults. The low incidence rate has kept FL-HCC an understudied cancer, thus the list of FL-HCC markers is limited and the genetic alterations driving its growth have remained unknown. In order to gain a better understanding of the molecular mechanisms underlying FL-HCC initiation and progression, we performed an in-depth genomic analyses of one tumor followed by immunohistochemistry validation on seven other tumors. We showed the expression of neuroendocrine markers in FL-HCC. In addition, DNA/RNA sequencing revealed that common cancer pathways are not visibly altered in FL-HCC but identified two novel structural variants, both resulting in fusion transcripts. Through in vitro studies, we demonstrated the oncogenic properties of these fusion transcripts. These experiments further highlight the tumorigenic role of gene fusions in the etiology of pediatric solid tumors and identify both candidate biomarkers and possible therapeutic targets for this lethal pediatric disease.

  Study phs000828

• Study of Addiction: Genetics and Environment (SAGE)

  This study is part of the Gene Environment Association Studies initiative (GENEVA) funded by the National Human Genome Research Institute. The overarching goal is to identify novel genetic factors that contribute to addiction through a large-scale genome-wide association study of DSM-IV alcohol dependent (and frequently illicit drug dependent) cases and non-dependent, unrelated control subjects of European and African American descent. The focus of this proposal is a case-control design of unrelated individuals for a genetic association study of addiction. Cases are defined as individuals with DSM-IV alcohol dependence (lifetime) and potentially other illicit drug dependence. In addition to the categorical diagnosis, we have data on ordinal measurements of number of DSM-IV symptoms for alcohol, nicotine, marijuana, cocaine, opiates and other drugs so that we will able to construct quantitative measurements of addiction severity over a wide range of substances. Controls are defined as individuals who have been exposed to alcohol (and possibly to other drugs), but have never met lifetime diagnosis for alcohol dependence or dependence on other illicit substances. Analyses that include refinement of the phenotype and incorporation of important demographic and environmental factors into association studies will be pursued. Cases and controls were selected from three large, complementary datasets: the Collaborative Study on the Genetics of Alcoholism (COGA), the Family Study of Cocaine Dependence (FSCD), and the Collaborative Genetic Study of Nicotine Dependence (COGEND). COGA: COGA was initiated in 1989 and is a large-scale family study that has had as its primary aim the identification of genes that contribute to alcoholism susceptibility and related characteristics. COGA is funded through the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Subjects were recruited from 7 sites across the U.S. Alcohol dependent probands were recruited from treatment facilities and assessed by personal interview. After securing permission, other family members were also assessed. A set of comparison families was drawn from the same communities as the families recruited through the alcohol dependent probands. Assessment involved a comprehensive personal interview developed for this project, the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), which gathers detailed information on alcoholism related symptoms along with other drugs and psychiatric symptoms. Families with three or more first-degree relatives who were alcohol dependent were invited for more extensive testing, including neurophysiology evaluations (ERPs and EEGs) and a battery of neuropsychological assessments. Blood was obtained for genetic studies. Institutional Review Boards at all sites approved the protocols, including sharing in the NIAAA national repository. COGA has four Co-Principal Investigators Bernice Porjesz, Victor Hesselbrock, Howard Edenberg, and Laura Bierut. COGA includes nine different centers where data collection, analysis, and storage take place. The nine sites and Principal Investigators and Co-investigators are: University of Connecticut (Victor Hesselbrock); Indiana University (Howard Edenberg, John Nurnberger, Jr., Tatiana Foroud); University of Iowa (Samuel Kuperman); SUNY Downstate (Bernice Porjesz); Washington University in St. Louis (Laura Bierut, Alison Goate, John Rice); University of California at San Diego (Marc Schuckit); Howard University (Robert Taylor); Rutgers University (Jay Tischfield); Southwest Foundation (Laura Almasy). Q. Max Guo serves as the NIAAA Staff Collaborator. This national collaborative study is supported by the NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). Family Study of Cocaine Dependence (FSCD): This project was initiated in 2000 as a case-control family study of cocaine dependence funded through the National Institute on Drug Abuse (NIDA; PI: Laura Bierut). The primary goal was to increase the understanding of the familial and non-familial antecedents and consequences of cocaine dependence. Cocaine dependent individuals were systematically recruited from chemical dependency treatment units (both public and private; residential and outpatient) in the greater St. Louis metropolitan area. Community based control subjects were identified through a Missouri Driver's License Registry (maintained at Washington University for research purposes) and matched by age, race, gender, and residential zip code. As a supplement to this project, blood samples were collected for future genetic analysis and were included in the NIDA Genetics Consortium. Phenotypic data, DNA, and cell lines are in the NIDA Center for Genetics Studies. Collaborative Genetic Study of Nicotine Dependence (COGEND): COGEND was initiated in 2001 as a three-part program project grant funded through the National Cancer Institute (NCI; PI: Laura Bierut). The three projects included a study of the familial transmission of nicotine dependence, a genetic study of nicotine dependence, and a study of the relationship of nicotine dependence with nicotine metabolism. The primary goal is to detect, localize, and characterize genes that predispose or protect an individual with respect to heavy tobacco consumption, nicotine dependence, and related phenotypes and to integrate these findings with the family transmission and nicotine metabolism findings. The primary design is a community based case-control family study. All subjects were recruited from Detroit and St. Louis. Nicotine dependent cases and non-dependent smoking controls were identified and recruited. In addition, one sibling for each case and control subject was recruited in a subset of the sample. Over 56,000 subjects aged 25-44 years were screened by telephone, over 3,100 subjects were personally interviewed, and over 2,900 donated blood samples for genetic studies. All three studies (COGA, COGEND, FSCD) include measures of basic socio-demographic variables, including age, sex, race/ethnicity, family income, educational attainment, religious participation, and family structure. Other important covariates and/or potential moderators of genetic effects include comorbid addictions and age at initiation of use for cigarettes, alcohol and drugs. The assessments also include measures of various life stressors, such as physical and sexual abuse, which have been implicated in gene-environment interactions for several disorders. Coding for both individual variables and indices has been standardized across studies. All subjects were assessed in person by trained research assistants. Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR), was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease"(HHSN268200782096C). Note for Publications Related to Study: The Study of Addiction: Genetics and Environment (SAGE) has not yet generated publications. Below is a listing of publications related to the three studies from which the SAGE sample was selected. COGA has over 228 publications listed at www.niaaagenetics.org This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to addiction through a large-scale genome-wide association study of DSM-IV alcohol dependent (and frequently illicit drug dependent) cases and non-dependent, unrelated control subjects of European and African American descent. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000092

• Elucidating Transcription Regulation by Epigenetics in Neuroblastoma

  PURPOSE Whole-genome profiles of the epigenetic modification 5-hydroxymethylcytosine (5-hmC) are robust diagnostic biomarkers in adult patients with cancer. We investigated if 5-hmC profiles would serve as novel prognostic markers in neuroblastoma, a clinically heterogeneous pediatric cancer. Because this DNA modification facilitates active gene expression, we hypothesized that 5-hmC profiles would identify transcriptomic networks driving the clinical behavior of neuroblastoma. PATIENTS AND METHODS Nano-hmC-Seal sequencing was performed on DNA from Discovery (n = 51), Validation (n = 38), and Children's Oncology Group (n = 20) cohorts of neuroblastoma tumors. RNA was isolated from 48 tumors for RNA sequencing. Genes with differential 5-hmC or expression between clusters were identified using DESeq2. A 5-hmC model predicting outcome in high-risk patients was established using linear discriminant analysis. RESULTS Comparison of low- versus high-risk tumors in the Discovery cohort revealed 577 genes with differential 5-hmC. Hierarchical clustering of tumors from the Discovery and Validation cohorts using these genes identified two main clusters highly associated with established prognostic markers, clinical risk group, and outcome. Genes with increased 5-hmC and expression in the favorable cluster were enriched for pathways of neuronal differentiation and KRAS activation, whereas genes involved in inflammation and the PRC2 complex were identified in the unfavorable cluster. The linear discriminant analysis model trained on high-risk Discovery cohort tumors was prognostic of outcome when applied to high-risk tumors from the Validation and Children's Oncology Group cohorts (hazard ratio, 3.8). CONCLUSION 5-hmC profiles may be optimal DNA-based biomarkers in neuroblastoma. Analysis of transcriptional networks regulated by these epigenomic modifications may lead to a deeper understanding of drivers of neuroblastoma phenotype. "Reprinted from Applebaum et. JCO Precision Oncology, 2019, with permission from creative commons license."

  Study phs001831

• NHLBI TOPMed: SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS)

  Subpopulations and Intermediate Outcome Measures in COPD Study Description Subpopulations and intermediate outcome measures in COPD study (SPIROMICS) supports the prospective collection and analysis of phenotypic, biomarker, genetic, genomic, and clinical data from subjects with COPD for the purpose of identifying subpopulations and intermediate outcome measures. It is funded by the National Heart, Lung, and Blood Institute and is coordinated by the University of North Carolina at Chapel Hill. Molecular fingerprinting and extensive subject phenotyping will be performed to identify disease subpopulations and to identify and validate surrogate markers of disease severity, which will be useful as intermediate outcome measures for future clinical trials. Secondary aims are to clarify the natural history of COPD, to develop bioinformatic resources that will enable the utilization and sharing of data in studies of COPD and related diseases, and to create a collection of clinical, biomarker, radiographic, and genetic data that can be used by external investigators for other studies of COPD. Participating Institutions: Research participants for SPIROMICS will be enrolled, phenotyped, and followed at twelve SPIROMICS Clinical Centers: Columbia University, Temple University, Johns Hopkins University, Wake Forest University, University of Michigan, University of Illinois at Chicago, University of Iowa, University of Utah, National Jewish Health, University of California at San Francisco, and University of California at Los Angeles. The University of North Carolina at Chapel Hill serves as the Genomics and Informatics Center. The Radiology Reading Center is based at the University of Iowa. The PFT Reading Center is based at the University of California at Los Angeles. Study Design: SPIROMICS is a prospective cohort study that enrolled approximately 2,981 participants at twelve clinical centers over five years. Participants are distributed across four enrollment strata (i.e., Never-smokers, Smokers without COPD, Mild/Moderate COPD, and Severe COPD). Study Visits: Participants have up to four in-person visits (Baseline and Annual Clinic Visits at years 1, 2, 3 after Baseline). Study questionnaires and spirometry are completed at all main study visits. Blood and urine samples are collected at visits 1, 2, and 4. Sputum samples are collected at Visit 1. The CT scans are completed and Baseline and Visit 2. Participants also receive quarterly follow-up calls to assess health status and determine if an exacerbation has occurred. Substudies Bronchoscopy and Immunophenotyping Substudy The Bronchoscopy Substudy will enroll 50 subjects per site, for a total of 300 participants. These participants will be recruited across all four study strata. This substudy includes two study visits. During the first visit, sputum samples are collected for Immunophenotyping analysis at the Immunophenotyping Core Lab based at the University of Michigan. Participants then return for a second visit during which samples are collected via bronchoscopy, including bronchoalveolar lavage, epithelial brushings and bronchial biopsies. Immunophenotyping analysis is also conducted on BAL and blood collected during the bronchoscopy study visit. Repeatability Substudy The entire baseline clinic visit was repeated on 98 volunteers to determine reliability of measurement procedures. All baseline study-related procedures and questionnaires, including the CT scan, were re-administered and new samples of blood, urine, saliva, and sputum were collected. Field center staff processed these biospecimen samples according to the same protocol. Exacerbation Substudy The Exacerbation Substudy is a prospective, longitudinal observational study of up to 400 participants, which will allow the assessment of participant-driven health care utilization (HCU) events and symptom-defined exacerbation events over time. HCU-driven events are defined by change in medical treatment in response to a perceived COPD Exacerbation. Symptom-based events will be defined by using EXACT-PRO (EXacerbations of Chronic Pulmonary Disease Tool - Patient Reported Outcome), a daily symptom diary developed to measure the frequency, severity, and duration of exacerbations in clinical trials. All participants are provided with a PDA on which to complete the diary. Participants reporting a possible COPD exacerbation will be brought into the study clinic for a study visit to collect biological specimens and questionnaire data. The overall objectives of the Exacerbation Substudy are to: Obtain clinical data and specimens on SPIROMICS participants before and during an acute COPD exacerbation defined by Health care utilization triggered by the subject, or Symptomatic change (triggered by an EXACT defined threshold) Describe symptomatic changes occurring around HCU and symptom-defined (EXACT) events and their relationship to clinical and specimen data, Characterize the non-exacerbation "stable" state in COPD using the EXACT, including: Symptom variability (EXACT), Clinical data and specimen parameters during a stable state (baseline), The relationship between clinical and specimen data and symptom severity and variability. Explore the characteristics of stable patients, defined as those who do not experience HCU or symptom-defined (EXACT) events during the sub-study period, using baseline clinical data and specimens, and compare these characteristics with patients who experience HCU and/or symptom-defined events. Examine the relationship between HCU and symptom-defined exacerbation frequency during the first one-year period of follow-up for exacerbations and health outcomes, including 12-month change in lung function and COPD health status, and longer-term morbidity and mortality, with the latter derived from long-term data from the larger SPIROMICS study.

  Study phs001927

• Genetic Factors associated with Conversion from Active Surveillance to Treatment for Prostate Cancer

  This is a genome-wide association study (GWAS) of conversion from active surveillance (AS) for prostate cancer (PC) to treatment. AS is the monitoring with screening tests and/or biopsies over time of men usually with low-risk, early-stage PC to avoid harmful side effects of PC treatment. "Conversion" refers to patients who withdraw from AS (switch to active treatment) due to changes in their cancer development, anxiety about delayed treatment, or other reasons. Patients who converted because of anxiety alone were censored in the GWAS analysis. The overall goal of this study is to develop an easily measurable, germline-based panel of genetic variants to aid in selecting PC patients appropriate for AS and/or the intensity of monitoring. In total, 6,324 PC patients from 28 collaborating institutions are included in this study. Patients are those with PC who are either on AS or who have previously converted from AS to treatment. In this study, 70% of all subjects were diagnosed with very low-risk, low-risk, or low-volume intermediate-risk PC (Kryvenko and Epstein, 2016; PMID: 26709152) and have been enrolled in an AS program. DNA was extracted from blood, saliva, or formalin-fixed, paraffin-embedded (FFPE) tissue collected from the study subjects at the participating sites. Genotyping, quality control processes, and imputation were performed at the Center for Inherited Disease Research (CIDR) at Johns Hopkins University. CIDR used the Illumina Infinium Multi-Ethnic Global Array (MEGA) version 1, which included genome-wide tag SNPs and 10,000 SNPs selected with custom content. Quality control and assurance (QC/QA) checks on genotyped data involved four domains: sample-level checks, batch effects, SNP-level checks, and preliminary association tests. Samples and SNPs passing the QC/QA checks were imputed to appropriate reference panels (HRC r1.1 for patients of European ancestry) using the Michigan Imputation Server (PMID: 27571263). Unmeasured genetic variants were imputed using the Trans-Omics for Precision Medicine (TOPMed) Imputation Server, with 97,256 reference samples and 308,107,085 SNPs. Variants with imputation quality (INFO) score < 0.3 were excluded, leaving a total of 22,691,641 SNPs successfully imputed. After QC steps, a total of 5,936 samples genotyped at CIDR remained for inclusion in the GWAS.

  Study phs002056

• Mayo-Perlegen LEAPS (Linked Efforts to Accelerate Parkinson's Solutions) Collaboration

  We performed a two-tiered, whole-genome association study of Parkinson disease (PD). For tier 1, we individually genotyped 198,345 uniformly spaced and informative single-nucleotide polymorphisms (SNPs) in 443 sibling pairs discordant for PD. For tier 2a, we individually genotyped 1,793 PD-associated SNPs (P<.01 in tier 1) and 300 genomic control SNPs in 332 matched case-unrelated control pairs. We identified 11 SNPs that were associated with PD (P<.01) in both tier 1 and tier 2 samples and had the same direction of effect. For these SNPs, we combined data from the case-unaffected sibling pair (tier 1) and case-unrelated control pair (tier 2) samples and employed a liberalization of the sibling transmission/disequilibrium test to calculate odds ratios, 95% confidence intervals, and P values. A SNP within the semaphorin 5A gene (SEMA5A) had the lowest combined P value (P=7.62E-6). The protein encoded by this gene plays an important role in neurogenesis and in neuronal apoptosis, which is consistent with existing hypotheses regarding PD pathogenesis. A second SNP tagged the PARK11 late-onset PD susceptibility locus (P=1.70E-5). In tier 2b, we also selected for genotyping additional SNPs that were borderline significant (P<.05) in tier 1 but that tested a priori biological and genetic hypotheses regarding susceptibility to PD (n=941 SNPs). In analysis of the combined tier 1 and tier 2b data, the two SNPs with the lowest P values (P=9.07E-6; P=2.96E-5) tagged the PARK10 late-onset PD susceptibility locus. Independent replication across populations will clarify the role of the genomic loci tagged by these SNPs in conferring PD susceptibility. Note: The following instruments were used: 1)clinical assessments form and manual; 2) sibling screening form and manual; 3) unrelated control screening and manual; and 4) risk factors questionnaire and manual. All cases underwent #1, as did sibling controls screening positive (see below). Unrelated controls were not examined. All siblings underwent #2. All unrelated controls underwent #3. All subjects (cases, sibling controls, and unrelated controls) underwent #4. Any publications using the data are to cite the original American Journal of Human Genetics article (Maraganore et al., 2005). Investigators using the data collection instruments are to acknowledge Drs. Maraganore and Rocca, and cite grants ES-10751 and NS-33978.

  Study phs000048

• BrainSpan Atlas of the Human Brain

  The NIH-funded BrainSpan (www.brainspan.org) and PsychENCODE (www.psychencode.org). Consortia sought to generate and analyze multi-dimensional genomics data from the developing and adult human brain in healthy and disease states. One of the main goals has been to perform large-scale and integrated analysis of the genome, transcriptome, and epigenome of the human brain to broaden our understanding of human neurodevelopment. This dataset consists of sixteen regions, including eleven neocortical areas, of human donors of both sexes and various ethnic groups. In the first stage of this project, we provide the genome-wide exon-level transcriptome data generated using the Affymetrix GeneChip Human Exon 1.0 ST Arrays, and the genome-wide genotyping data for 2.5 million markers using the Illumina Human Omni 2.5-Quad Bead Chips. In the second stage of this project, we provide whole-genome sequencing data, transcriptome data by mRNA-Seq, small RNA data by smRNA-seq, DNA cytosine methylation by Infinium HumanMethylation450 BeadChip, and epigenomic/epigenetic data by ChIP-Seq for H3K4me3, H3K27me3, H3K27ac and CTCF.

  Study phs000755

• The Immunogenetics of Measles Immunity - Measles (MMR) vaccination (NIAID/NIH)

  To examine the role of gene polymorphisms (including functional studies of SNPs) on variations in vaccine-induced immune responses, in approximately 3,000 healthy school-age children, adolescents and young adults/adults, who were vaccinated with measles-containing vaccine (MMR). To achieve greatest power to detect SNPs associated with measles-specific immune response phenotypes, we pooled our data across three genotyping platforms and three cohorts (US cohort, San Diego cohort and Rochester cohort).

  Study phs001630

• Genetics of Inherited Muscle Disease

  The samples are drawn from a collection of patients with a heterogeneous set of neuromuscular disorders, including congenital muscular dystrophy, congenital myopathy, limb-girdle muscular dystrophy, Emery-Dreifuss muscular dystrophy, and arthrogryposis, along with unaffected parents and siblings in some cases. The samples were collected by the following clinicians affiliated with the associated institutes: Kathryn North and Nigel Clarke (Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Australia) Hanns Lochmuller and Kate Bushby (The Newcastle Muscle Centre, Newcastle University, UK) Peter Kang (Boston Children's Hospital) Carsten Bonnemann (National Institutes of Health, Bethesda, MD, USA) Nigel Laing (University of Western Australia) All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using Agilent SureSelect Human All Exon Kit v2 or Illumina's Rapid Capture Exome enrichment kit and sequencing was performed on an Illumina HiSeq 2000. In addition some samples were whole genome sequenced on Illumina HiSeq X Ten.

  Study phs000655

• NHLBI TOPMed - NHGRI CCDG: Early-onset Atrial Fibrillation in the CATHeterization GENetics (CATHGEN) Cohort

  The CATHeterization GENetics (CATHGEN) biorepository collected biospecimens and clinical data on individuals age ≥18 undergoing cardiac catheterization for concern of ischemic heart disease at a single center (Duke University Medical Center) from 2000-2010; a total of N=9334 individuals were collected. Samples were matched at the individual level to clinical data collected at the time of catheterization and stored in the Duke Databank for Cardiovascular Diseases (DDCD). Clinical data included subject demographics, cardiometabolic risk factors, cardiac history including symptoms, age-of-onset of cardiovascular diseases, coronary anatomy and cardiac function at catheterization, laboratory data, and yearly follow-up for hospitalizations, vital status, medication use and lifestyle factors. AF cases were defined as individuals who had ever had AF based on any ECG available at Duke University or ICD-9 code for AF used for inpatient or outpatient billing.

  Study phs001600

• Identification of Structural Variants Relevant to Autism by Pacific Biosciences HiFi Whole-Genome Sequencing

  The purpose of this research study was to perform long-read whole-genome sequencing on a family with autism. This family had no known genetic cause based on clinical array and whole-exome sequencing analysis. Utilizing PacBio HiFi long-read whole-genome sequencing, we identified a relevant missense variant in the KCNC2 gene. This variant was likely to be a germline mosaic in the paternal germline.

  Study phs002698

• Whole Exome Sequencing of Primary Mediastinal B-cell Lymphoma

  Primary mediastinal large B-cell lymphomas (PMBLs) are aggressive tumors that typically present as large mediastinal masses in young women. PMBLs share clinical, transcriptional, and molecular features with classical Hodgkin lymphoma (cHL), including constitutive activation of nuclear factor kappaB (NF-kappaB), JAK/STAT signaling, and programmed cell death protein 1 (PD-1)-mediated immune evasion. The demonstrated efficacy of PD-1 blockade in relapsed/refractory PMBLs led to recent approval by the US Food and Drug Administration and underscored the importance of characterizing targetable genetic vulnerabilities in this disease. Here, we report a comprehensive analysis of recurrent genetic alterations -somatic mutations, somatic copy number alterations, and structural variants-in a cohort of 37 newly diagnosed PMBLs. We identified a median of 9 genetic drivers per PMBL, including known and newly identified components of the JAK/STAT and NF-kappaB signaling pathways and frequent B2M alterations that limit major histocompatibility complex class I expression, as in cHL. PMBL also exhibited frequent, newly identified driver mutations in ZNF217 and an additional epigenetic modifier, EZH2. The majority of these alterations were clonal, which supports their role as early drivers. In PMBL, we identified several previously uncharacterized molecular features that may increase sensitivity to PD-1 blockade, including high tumor mutational burden, microsatellite instability, and an apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutational signature. The shared genetic features between PMBL and cHL provide a framework for analyzing the mechanism of action of PD-1 blockade in these related lymphoid malignancies.

  Study phs000450

• SNPs and Extent of Atherosclerosis (SEA) Study

  The SEA study is a genome-wide association study to identify genetic variants associated with premature atherosclerosis in subjects included in the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) repository - a unique NHLBI resource including data, DNA and arterial specimens from over 3000 multi-ethnic subjects 15-34 years of age who died of non-atherosclerotic causes (mostly trauma). All PDAY subjects had post-mortem quantitative assessment of raised atherosclerotic lesions in their aorta and coronary arteries - making this the largest and most carefully phenotyped cohort for premature atherosclerosis in the world. The goal of the current project was to use the quantitative measure of raised atherosclerotic lesions in the PDAY cohort as the target phenotype for a genome-wide association study and to use quantitative measures of subclinical atherosclerosis (coronary calcium and carotid IMT) in the Multi-Ethnic Study of Atherosclerosis (MESA) to confirm or refute candidate loci identified from the PDAY analysis. Identifying genetic factors that predispose individuals to premature atherosclerosis could lead to more effective screening and early treatment of high risk individuals and suggest novel molecular targets for treatment and prevention interventions.

  Study phs000349

• National Cancer Institute - Population Structure and Natural Selection in the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) study in Uganda

  A genome-wide analysis of genetic structure, gene flow, and natural selection was conducted in populations in the endemic Burkitt lymphoma (eBL) belt in Ghana and Northern Uganda, both subject to a high incidence of falciparum malaria and eBL. These populations have different ethnolinguistic ancestries and are located 2400 miles apart in sub-Saharan Africa. We characterized genetic composition of these populations in the context of 22 additional African populations and present evidence for gene flow events that occurred in the last 3000 years, possibly related to regional migrations in Western Africa and major migrations involving Nilotic, Cushitic, and Bantu groups. The Ugandan population was comprised of 758 children (mean age ~7 years) from 17 Western Nilo-Saharan tribes. The current dataset includes 561 healthy children and 197 children with eBL from northern Uganda.

  Study phs001705

• Multimodal Genomic Features Predict Outcome of Immune Checkpoint Blockade in Non-small Cell Lung Cancer

  This study evaluates integrated genomic models of response to immune checkpoint blockade for lung cancer patients. A computationally adjusted tumor mutation burden was combined with HLA class I genetic variation, mutational smoking signature and activating mutations in receptor tyrosine kinase genes to generate a prognostic classifier that outperforms tumor mutation burden.

  Study phs001940

• Ulcerative Colitis Human Microbiome Project (UCHMP)

  The aims of the multi-center Ulcerative Colitis Human Microbiome Project (UCHMP) are to examine the role of the enteric microbiome in causing human ulcerative colitis, specifically the development of pouchitis. Pouchitis is an inflammatory condition of the surgically-created ileoanal pouch that serves as a pseudo-rectum in patients with ulcerative colitis who have undergone a total colectomy. It is a condition unique to ulcerative colitis (UC), as it rarely occurs in non-UC patients who have the same procedure. Within one year, about 50% of patients will develop pouchitis. The condition is almost certainly due to aspects of the pouch microbiota on a background of genetic susceptibility, as most patients respond to treatment with antibiotics. While there have been reports on the microbiota in pouchitis patients, all have been performed after the inflammatory process is initiated, rendering interpretation of the results difficult, as the inflammatory process itself will change the microbiota. Our project is therefore unique and possibly the only opportunity in the role of the enteric microbiome in IBD in a prospective manner, thereby establishing potentially important causal relationships between microbiota structure or function and development of UC.The studies also offer two additional advantages. First, the development of the pouch microbiota can be observed prospectively. Second, the cause of antibiotic treatment failure in some patients with pouchitis may be revealed. The two aims are (1) to identify causal factors in the structure and/or function of the enteric microbiota in the development of pouchitis, and (2) to determine the basis of treatment failure in UC pouchitis patients. Our analyses will include serial measurements of enteric microbial structure (16S rRNA gene-based), function (metagenomics and functional candidate genes), and cultivation, the latter to enhance interpretation of gene sequences derived from metagenomes and targeted gene surveys (either functional or 16S genes). The insights gained from these studies will help us understand the fundamental and causative roles of the enteric microbiome in human inflammatory bowel diseases (IBD). This information will be the basis for developing strategies to restore host-microbial relationships to prevent and treat IBD.

  Study phs000262

• HudsonAlpha Institute for Biotechnology Clinical Sequencing Exploratory Research (CSER): Genomic Diagnosis in Children with Developmental Delay

  The overarching goal of this project is to explore the ability for whole exome and genome sequencing technologies to identify the genetic causes of unexplained developmental delay, intellectual disability (DD/ID), and related congenital anomalies in children. Such information may be useful as an endpoint to the otherwise fruitless "diagnostic odyssey" that many DD/ID affected families undergo and in some cases, identification of these genetic variants may point to better therapeutic or educational options by precisely defining the root cause(s) of the child's condition. We seek to identify causal, diagnostically relevant, genetic variants in children with developmental delay and/or intellectual disability (DD/ID). In addition, because our analytical approach includes sequencing probands and their parents (parent-offspring trios and duos; parents are sequenced when available), secondary findings will be returned to adults (parents) at their request. The aims of this research project include: 1) Use exome and whole genome sequencing to identify genetic variation that results in DD/ID. 2) Return primary genetic results (DD/ID causative) as well as secondary findings to probands and their parents, respectively. 3) Understand how the return of genomic test results affects the health and well-being of study participants. The children participating in this study are patients at, or referrals to, North Alabama Children's Specialist (NACS) in Huntsville, Alabama. All blood samples from probands and their parents will be collected at NACS (project 1). Sequencing will be completed at the HudsonAlpha Institute for Biotechnology, with validation (via Sanger sequencing) conducted at Emory University for all returned variants (project 2). The University of Louisville will oversee questionnaires, surveys and interviews aimed at understanding study participants' perception of, and response to, genetic test results, in addition to assessment of secondary findings preferences (project 3).A subset of variants, largely those determined to be diagnostic or variants of uncertain significance for study participants at the time of disclosure, have been submitted to ClinVar. These variants are listed as part of the "CSER-HudsonAlpha" study within the database.

  Study phs001089