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• A Multiethnic Genome-wide Scan of Prostate Cancer

  Multiple GWA studies of prostate cancer conducted in European White populations are ongoing. These studies will continue to have a dramatic impact on our understanding of the contribution of common genetic variation on inter-individual susceptibility to this common cancer. Important questions that will remain unanswered, however, are whether all common risk alleles for prostate cancer will be revealed in studies limited to populations of European ancestry. A comprehensive examination of common genetic variation in men of Japanese, Latino, and African ancestry will be required to understand population differences in disease risk and to reveal the full spectrum of causal alleles that exist in these populations. Further, genetic and environmental diversity is likely to contribute to ethnic heterogeneity of genetic effects. Elucidating gene x gene and gene x environment interactions is also likely to provide knowledge that may be critical for understanding the contribution of genetic susceptibility to racial/ethnic disparities in prostate cancer incidence and for translating the findings from GWA studies into interventions. In this study we plan to undertake a genome-wide association study (GWAS) of prostate cancer in the Multiethnic Cohort (MEC) Study. We propose the following hypotheses: (a) that inherited DNA variation influences risk of prostate cancer; (b) that many of the causal alleles will be outside known "candidate genes" requiring an agnostic, comprehensive search; and (c) that performing this search in a multi-ethnic cohort is more powerful than a study limited to a single population to reveal the full range of causal alleles relevant to the U.S. population. The version 1 release of this dataset will include genotype data for the Japanese and Latino populations in the study. The version 2 release will include data for the African ancestry population along with the Japanese and Latino subjects. The version 3 release will include fully-cleaned genotype data for all three populations. 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 prostate cancer through large-scale genome-wide association studies of a well-characterized multi-ethnic cohort. Genotyping was performed at the Broad Institute of MIT and Harvard, a GENEVA genotyping center and at the University of Southern California. Data cleaning and harmonization were performed at the GEI-funded GENEVA Coordinating Center at the University of Washington. As an add-on to this GWAS we performed a targeted re-sequencing of all known prostate cancer risk loci in the samples from the MEC. Sequencing was performed in Dr. Reich's lab at Harvard Medical School.

  Study phs000306

• Scottish High Grade Serous Ovarian Cancer

  Scottish HGSOC samples were collected via local Bioresource facilities at Edinburgh, Glasgow, Dundee and Aberdeen and stored in liquid Nitrogen until required. HGSOC patients were determined from pathology records and were included in the study where there was matched tumour and whole blood samples. On receipt of tumour material the tumour was processed as follows: firstly, the tumour sample was divided into two for DNA and RNA extraction. Slivers of tissue were cut from the front and rear faces of the DNA sample, then fixed in formalin and embedded in paraffin wax. Sections from the front and rear tissues from all samples were examined by H&E staining supplemented by WT1/p53 immunohistochemistry if required. Following pathology review, samples were only included if they met the following criteria: they were confirmed as HGSOC and there was greater than 40% tumour cellularity throughout the tumour, determined using the H&E sections. Somatic DNA was extracted using the Qiagen DNeasy Blood and tissue kit (cat no 69504). The tissue was initially homogenised using a Qiagen Bioruptor, followed by the manufacturers recommended protocol (including RNase digestion step). Germline DNA was extracted from 1-3ml whole blood using the Qiagen FlexiGene kit (cat no 51206) following the manufacturers recommended protocol. The resulting DNA underwent quality control as follows: firstly, A260 and A280nm were measured on a Denovix DS-11 Fx to qualitatively illustrate A260/280nm and A260/230nm ratios as surrogate measures of DNA purity. A260/280 had to be 1.8 or greater and A260/230 had to be 2.0 or greater. Then, DNA was quantified using LifeTechnologies Qubit dsDNA BR kit (cat no Q32850) and we required a minimum of 50ul at 25ng/ul for WGS. Thirdly, DNA was diluted to 25ng/ul and a representative sample was loaded onto a 0.8% TAE gel, ran at 100v for 60mins and then imaged using a BioRad ChemiDoc imaging system to visualise the DNA quality. Only when all 4 quality control requirements were satisfied was the DNA sequenced. The DNA was sequenced at the Glasgow Precision Oncology Laboratories.

  Study EGAS00001004410

• INSIGHT (Intervention Nurses Start Infants Growing on Healthy Trajectories) Cohort

  This is a study of the biological risk factors for children enrolled in the INSIGHT (Intervention Nurses Start Infants Growing on Healthy Trajectories) study. INSIGHT is a randomized, controlled trial testing a responsive parenting intervention designed for the primary prevention of childhood obesity against a safety control. These first-born children were deeply studied in this time period with data collected on a wide variety of variables including mode of delivery, gender, weight and height (collected at 7 time points), medication usage, diet information, and maternal health information (gestational weight gain, gestational diabetes, smoking during pregnancy). This study includes a survey of the oral and gut microbiota from 226 mother-child dyads. It was designed to investigate the relationship between a cross-sectional view of the child's microbiome (at two years of age) and the patterns of growth between birth and 2 years. Microbiome samples from children (buccal swab and stool sample) and their mothers (buccal swab) are collected at the children's 2-year clinical research visit. Stool metabolites have also been assayed for a subset of the 226 children using 1H-NMR. Additionally, we genotyped the same individuals for SNPs across the genome. For a subset of 48 individuals we have added second-born siblings. For these additional 48 children, we characterized the methylation pattern across the genome using cord blood and placenta samples.

  Study phs001498

• Relationship between low LDL cholesterol concentrations not due to statin therapy and risk of type 2 diabetes: a US-based cross-sectional observational study using electronic medical records

  Lipid lowering therapy using HMG-CoA reductase inhibitors (statins) is associated with an approximately 9-12% increase in the risk of new-onset type 2 diabetes (T2DM). The risk of diabetes could be increased by statins directly; however, genetic approaches have also implicated low LDL cholesterol (LDL-C) concentrations as a risk factor for T2DM. Mendelian randomization studies using functional variants in both HMGCR (GeneID:3156) and PCSK9 (GeneID:255738) genes found a higher risk of T2DM in individuals with variants associated with lower LDL-C concentrations. Since PCSK9 and HMGCR are involved in lipid metabolism through distinct molecular pathways, the altered glycemic effect associated with variants in both genes is likely to be the result of their common effect on LDL-C concentrations. Despite the findings from statin clinical trials and genetic studies, there is little direct evidence implicating low LDL-C concentrations with increased risk of T2DM. Individuals who have very low LDL-C concentrations not due to lipid lowering therapy can provide insights into the relationship between low LDL-C concentrations and T2DM. Here, we used de-identified electronic health records (EHRs) to test the hypothesis that low LDL-C concentrations are associated with T2DM.

  Study phs001588

• Birth Defects: Moebius Syndrome and Related Congenital Facial Weakness Disorders

  It is estimated that about 1 in every 33 infants in the United States is born with a birth defect. Among these, the subset of birth defect syndromes associated with facial weakness and lack of facial expression can have profound implications for social interactions and psychosocial development. Moebius syndrome is defined by congenital and non-progressive facial weakness and limited eye abduction, and most cases are believed to result from dysfunction of cranial nuclei/nerves VI and VII. Although rare, this syndrome causes significant impairment because of facial weakness and associated intellectual disabilities, autism, hearing loss, difficulty swallowing and breathing, peripheral neuropathy, muscle hypotonia, heart defects, chest wall abnormalities, and limb malformations. The phenotypic spectrum and the associated genetic and environmental factors underlying Moebius syndrome are poorly understood. The goal of this research is to identify causative gene mutations for Moebius syndrome and related conditions, such as Moebius-Poland or -Robin sequence, hereditary congenital facial paresis (HCFP), and oculoauriculovertebral dysplasia (Goldenhar syndrome). This proposal builds on an ongoing collaboration among researchers at Mount Sinai Medical Center, Boston Children's Hospital, NHGRI intramural program, and the Moebius Syndrome Foundation, but aims to greatly extend that work by collaboration with investigators in the NIH Clinical Center (CC). Our groups have already defined a new autosomal dominant syndrome with Moebius syndrome, Kallmann syndrome, cyclic vomiting resulting from a TUBB3 E410K substitution. We have also identified a new autosomal recessive Moebius-related syndrome with bilateral facial palsy, hearing loss, and strabismus resulting from a HOXB1 R207C substitution. Through collaborative efforts of these extramural teams with intramural investigators, whole exome sequencing (WES) has been conducted for four families with Moebius-like features, and data analyses are ongoing. The overall goal of this new grant application will be to conduct extensive phenotype analysis on approximately 24 families per year with Moebius and other undefined syndromes with facial weakness. Studies to be conducted at the CC include neurology, psychiatry, neurocognitive, rehabilitation medicine (muscle strength, speech/language pathology), ophthalmology, audiology, and genetics evaluations; autism screening; electromyography, nerve conduction, and blink reflex studies; videoscopy of quantitative eye movement recordings; 3D-CT craniofacial imaging; MRI of the brain, orbit, internal auditory canals, posterior fossa including brain diffusion tensor imaging for tractography; and genetic counseling. Jointly with the extramural teams, WES analysis and variant confirmation will be performed. A more comprehensive definition of the phenotypic and genotypic spectrum of these birth defects will have a significant impact on our understanding of the molecular pathways underlying dysmorphologies, cranial nerve development, and more common childhood disorders such as autism. Thus, this project will lead to strategies for prevention and treatment of birth defects.

  Study phs001383

• Investigation of a method for generating cells for regenerative medicine using comprehensive nucleic acid analysis of iPS cell-derived cardiomyocytes.

  Regenerative medicine for heart failure is expected to restore cardiac function by using human iPS cells (hiPSCs). In our laboratory, it was shown that transplantation of cardiomyocytes (CMs) derived from hiPSCs into a pig model of myocardial infarction improves the disease condition. However, the instability of differentiation efficiency and tumorigenicity after transplantation are still issues to be resolved. We attempt to identify and analyze the genes and DNA methylation associated with the induction of differentiation of hiPSCs into CMs with the aim of achieving stable induction of CMs differentiation. Furthermore, we aim to analyze genes involved in tumorigenesis in CMs, and to develop a predictive marker for tumorigenesis to ensure the safety of cells before transplantation.

  Study JGAS000665

• Molecular characteristics in Burkitt lymphoma over age groups

  Treatment optimization has improved the overall survival in Burkitt lymphoma (BL) patients but there are still relevant outcome differences between pediatric and adult patients. In both age groups survival remains poor for patients who suffer relapse. Therefore, new treatment approaches are warranted to improve survival. Thus, we conducted a comparative study in the largest pediatric cohort to date including 191 cases and 97 samples from adult patients and analyzed the mutational landscape. We detected overlapping molecular profiles but also significant differences in the mutational pattern. Samples from pediatric patients show a higher frequency of mutations in ID3, DDX3X and BAF-complex components ARID1A and SMARCA4, while YY1AP1 and BCL2 are more frequently mutated in cases from adult BL patients. Correlation of the mutational profile with clinical data was available for the pediatric cohort and identified TP53 mutations to be highly significantly associated with the incidence of relapse thus identifying the first molecular marker to be associated with the incidence of relapse in pediatric BL. As the hotspot analysis of TP53 mutations showed mostly gain of function mutations, it is tempting to speculate that drugs decreasing the amount of malignant TP53 or increase the abundance of wildtype TP53 could be a promising approach for future treatment regimens to further improve prognosis.

  Study EGAS00001005270

• Whole Genome Sequencing of Asian Lung Cancers: Second Hand Smoke is Not Responsible for Higher Incidence of Lung Cancer Among Asian Never-Smokers

  Background Asian nonsmoking populations have a higher incidence of lung cancer compared to their European counterparts. There is a long-standing hypothesis that the increase of lung cancer in Asian never-smokers is due to environmental factors such as second-hand smoke. Results We analyzed whole-genome sequencing of 30 Asian lung cancers. Unsupervised clustering of mutational signatures separated the patients into two categories: i) all of the never-smokers, and ii) only smokers or ex-smokers. Half of the ex-smokers / smokers were in the never-smoker-like cluster. The overall somatic variant profiles of Asian lung cancers were similar to that of European origin with G.C>T.A being predominant in smokers. We found EGFR and TP53 are the most frequently mutated genes with mutations in 50% and 27% of individuals, respectively. Among these Asian never-smokers, 71% had an EGFR mutation compared to 20% of the smokers in the smoking cluster. Other frequently mutated genes include RYR2, SATB2, C1orf88, FERMT1 and CTNNB1. Somatic alterations occurred in WNT signaling pathway genes, suggesting this pathway plays a role in both Western and Asian lung cancers. Conclusions Asian never-smokers have lung cancer signatures distinct from the smoker signature and their mutation profiles are similar to that of European never-smokers. The profiles of Asian and European smokers are also similar. This suggests that the same mutational mechanisms underlie the etiology for both ethnic groups, and the high incidence of lung cancer in Asian never-smokers might not be due to second hand smoke or other carcinogens that cause oxidative DNA damage. Half of the ex-smokers/smokers have a molecular phenotype similar to never-smokers; of which, 50% had EGFR mutations. This suggests that routine EGFR testing is warranted in the Asian population, regardless of smoking status.

  Study EGAS00001000621

• Genome-wide association study identifies common variants associated with breast cancer in South African Black women

  Genome-wide association studies (GWAS) have characterized the contribution of common variants to the development of breast cancer (BC) in populations of European descent, however no GWAS have been reported in resident African populations. This GWAS included 2,485 resident African BC cases and 1,101 population matched controls. Two risk loci were identified, one on chromosome 15, located between UNC13C and RAB27A (rs7181788, p = 1.01x10-08) and a second in an intron of USP22 on chromosome 17 (rs899342, p = 4.62x10-08). RAB27A is a member of the RAS oncogene family associated with invasive growth and metastasis, and UNC13C is involved in tumor progression. The rs899342 SNP is an eQTL for expression of USP22 in a wide range of tissues. Several genome-wide significant signals were detected in a hormone receptor subtype analysis. Comparison of a meta-analysis of other African ancestry BC GWAS datasets predominantly of West African ancestry with our South African data showed limited evidence of shared risk loci, suggesting potential heterogeneity in genetic risk factors for breast cancer in different African populations. A European ancestry derived polygenic risk model for BC was applied to our data, explaining only 0.79% of variance, with an area under the curve of 0.56. This study identified genetic risk factors for BC in a resident African population, but larger studies in this and other African populations are needed to further define the contribution of common variants to BC risk.

  Study EGAS00001008032

• NHLBI TOPMed - NHGRI CCDG: The Vanderbilt University BioVU Atrial Fibrillation Genetics Study

  Atrial fibrillation (also called AFib or AF) is a quivering or irregular heartbeat (arrhythmia) that can lead to blood clots, stroke, heart failure and other heart-related complications. At least 2.7 million Americans are living with AFib. Individuals with early onset atrial fibrillation (AF) are included in this study of cases from the BioVU sample repository. BioVU is Vanderbilt's biobank of DNA extracted from leftover and otherwise discarded clinical blood specimens. BioVU operates as a consented biorepository; all individuals must sign the BioVU consent form in order to donate future specimens. BioVU subjects are de-identified and linked to the Synthetic Derivative enabling researchers to access genetic data/DNA material as well as dense, longitudinal electronic medical record (EMR) information.

  Study phs001624