3329 results for "*geneti*"

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• Genome-Wide Association Study of Hypertriglyceridemia in Mexicans

  Coronary artery disease (CAD) is the number one cause of death and mortality world-wide. High levels of serum triglycerides (TGs) and low levels of serum high-density lipoprotein cholesterol (HDL-C) are major risk factors for CAD. Previous epidemiological studies have shown that these two lipid disturbances are highly common dyslipidemias in Mexicans. However, the genetic factors underlying high serum TGs and low HDL-C are underinvestigated and poorly identified in Mexicans. As the Mexican-American and the genetically related Latin-American populations represent the fastest growing minority in the United States, elucidation of the unknown genetic factors influencing the increased susceptibility of Mexicans to these common dyslipidemias is of great relevance to these U.S. minorities and the American healthcare system. This study is a research collaboration between investigators at the University of California, Los Angeles (UCLA) and Instituto Nacional de Ciencias Médicas y Nutrición (INCMN), Mexico City, to perform a two-stage genome-wide association study (GWAS) for hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) in Mexicans (Weissglas-Volkov et al. 2013, PMID: 23505323). This study was funded by an RO1 grant from NIH/NHLBI (PI Paivi Pajukanta; PI of the subaward Teresa Tusie-Luna). In stage 1 of the GWAS, we tested all GWAS SNPs from the Illumina Infinium Human610-Quad platform that passed quality control for association in ~2,200 hypertriglyceridemia cases and controls. In stage 2, we genotyped the ~1,200 positive signals of stage 1 in additional ~2,200 hypertriglyceridemia cases and controls, and performed a combined analysis of the two stages to identify genome-wide significant variants. The subjects were recruited at the INCMN. The DNA isolation and clinical laboratory measurements of the case-control study samples were performed at INCMN using standardized procedures. Genotyping and statistical analyses of the data were performed at UCLA. A summary of this GWAS can be found in Weissglas-Volkov et al. 2013 Journal of Medical Genetics, PMID: 23505323. Briefly, using the two-stage GWAS design, we identified a novel Mexican-specific genome-wide significant locus for serum TG levels close to the Niemann-Pick type C1 protein (NPC1) gene (Weissglas-Volkov et al. 2013, PMID: 23505323). Of the European lipid GWAS loci, three TG loci (APOA5, GCKR, and LPL) and four HDL-C loci (ABCA1, CETP, LIPC and LOC55908) resulted in genome-wide significant signals in Mexicans. Furthermore, our cross-ethnic mapping narrowed three European TG GWAS loci, APOA5, MLXIPL, and CILP2 that exhibited long range LD and a large number of candidate SNPs in the European GWAS scan. In the apolipoprotein A1C3A4A5 gene cluster region, the cross-ethnic fine mapping and LD comparisons reduced the number of candidate variants to one SNP, rs964184. We also found that although 52% of the associations from European lipid GWAS meta-analysis could be generalized to Mexicans, in 82% of the European GWAS loci, a different variant other than the European lead SNP provided the statistically strongest evidence of association in the Mexican scan (Weissglas-Volkov et al. 2013, PMID: 23505323). Taken together, our Mexican GWAS for lipids identified a novel Mexican-specific locus for high serum TGs; restricted three European GWAS loci; and investigated which European lipid GWAS variants extend to the Mexican population (Weissglas-Volkov et al. 2013, PMID: 23505323). This NHLBI sponsored RO1 project aimed to identify genetic variants contributing to serum lipid levels in Mexicans. In addition to de-identified genome wide genotypic data, a selected list of de-identified phenotypic data related to hypertriglyceridemia and related metabolic traits are also available in dbGaP.

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• DNA Methylation Analysis of Peripheral Blood Cells from Siblings Discordant for ASD

  Autism is a common disorder whose causes are poorly understood. Both genetic and environmental influences are thought to act together causing autism. Epigenetics is an area that bridges genetic and environmental influencing and commonly is studied by examining dynamic methylation changes to the DNA. We have screened a total of 78 autistic boys and their fathers by this method in 807 genes and find 116 methylation changes that together can correctly identify nearly 80% of the affected boys from their fathers. We propose to confirm these exciting data in a much larger set of genes in 1,200 autistic boys and their families, including unaffected brothers. These data not only could provide new insight into the causes of autism but could also result in a screening test for autism.

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• FaceBase Study of Facial Shape in Tanzania: CIDR

  The goals of this project are to identify loci that underlie major genetic determinants of orofacial shape, by means of a GWAS in a cohort of normal African children (from Tanzania) from whom we have collected 3D digitized facial morphometric scans, and a subsequent replication study of normal children from the same population. These studies are part of the NIDCR FaceBase initiative (https://www.facebase.org/). In addition to dbGaP, all study genotype and phenotype data (including primary facial scans and landmarks) will be available for data-sharing with qualified investigators via the NIDCR FaceBase Hub (www.facebase.org/), following approval by the NIDCR FaceBase Data Access Committee.

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• Rare Mendelian Disease in Old Order Amish and Mennonite Patients

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

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• The Lung Genomics Research Consortium (LGRC)

  Chronic lung diseases represent a broad spectrum of chronic fibrosing/inflammatory lung conditions that are for the most part poorly responsive to treatment and often fatal. COPD/emphysema is the fourth leading cause of death in the United States and the incidence and rate of death from pulmonary fibrosis is increasing each year. Although progress has been made in interpretation of the clinical, radiological, and pathological features of chronic lung disorders, and progress in determining the pathobiology continues, the causes, biologic mechanisms, and therapeutic options remain obscure. Moreover, predicting individuals or populations at risk for developing any of these complex diseases, at present, is not possible. To address this challenge, we plan to create a genetic, molecular, and quantitative clinical phenotyping data warehouse with bioinformatic tools that will empower investigators to make fundamental discoveries in disease pathogenesis, refine diagnostic criteria, and lead to real gains in personalized medicine. The composite genetic, genomic, and epigenetic signature combined with quantitative clinical phenotypes has the potential to characterize the dynamic biological state of a complex disease and complement existing diagnostic approaches that are reliant on traditional clinical measures of disease. In the proposed project, we plan to extend the scope and impact of the NHLBI Lung Tissue Research Consortium (LTRC) biorepository by creating the Lung Genomics Research Consortium (LGRC), a comprehensive genetic, molecular, and quantitative clinical phenotyping warehouse. Our overall hypothesis is that a genetic, molecular, and quantitative clinical phenotyping warehouse combined with a rich clinical database will enable the lung research community to make fundamental discoveries in disease pathogenesis, refine diagnostic criteria, and lead to real gains in personalized medicine. We plan to pursue this hypothesis through the following aims. Specific Aim 1: Establish a genetic, genomic, and epigenetic molecular library to complement the existing clinical database in the LTRC. Specific Aim 2: Develop a quantitative clinical phenotyping platform using existing LTRC data, as well as an enhanced data set including novel quantitative CT and histology imaging analyses. Specific Aim 3: Establish a publicly-accessible database that would integrate the genetic, molecular, and quantitative phenotyping data with the existing clinical data in the LTRC and provide query and data exploration tools that are easily accessible to the lung research community. These discoveries will enable clinicians to Identify individuals at risk of developing chronic lung diseases; Diagnose these conditions earlier; Identify novel mechanisms that cause these diseases; Reclassify disease entities into categories more representative of molecular and cellular pathogenic mechanisms regardless of traditional disease categories; develop personalized approaches to treatment.

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• Targeted Sequencing of GWAS Loci in Cleft Lip and Palate

  Nonsyndromic cleft lip and palate (NSCL/P) is a complex disorder caused by both genetic and environmental factors and has been the focus of an extensive effort to identify genetic risk factors. A number of candidate gene studies have been performed but have not been widely replicated. To date, four independent genome wide association studies have been performed as well as a meta-analysis. Together these studies have identified many loci associated with NSCL/P. The goal of this project is to use targeted sequencing to further characterize these regions and to progress from the association signals identified by GWAS to the identification of causative genes and/or variants. This study is part of the GWASeq project, a collaboration of five disease studies, which will sequence genomic regions from GWAS to characterize the genetic variation underlying these diseases and to compare study design and methods for the follow-up of GWAS studies by sequencing. The goal of this study is to sequence 1000+ NSCL/P case-parent trios from China and the Philippines and 400 trios of European ancestry. Targeted sequencing was performed on intervals ranging between 60kb to 1Mb surrounding 13 genes/loci previously associated with NSCL/P including: IRF6, MAFB, ARHGAP29, 8q24, PAX7, VAX1, NTN1, NOG, FOXE1, MSX1, BMP4, FGFR2, PTCH1.

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• CD4+ cell transcriptional profiling by RNA sequencing

  We use next generation sequencing to investigate the different transcriptomes of closely related CD4+ T-cells from healthy human donors to elucidate the genetic programs that underlie their specialized immune functions. Six cell types were included: Regulatory T-cells (CD25hiCD127low/neg with >95% FOXP3+ purity), regulatory T-cells activated using PMA/ionomycin, CD25-CD45RA+ ('naive' helper T-cells), CD25-CD45RO+ ('memory' helper T-cells), activated Th17 cells (>98% IL17A+ purity) and activated IL17-CD4+ T-cells (called 'ThPI'). Poly-T capture beads were used to isolate mRNA from total RNA, and fragment sizes of ~200 were sequenced from both ends on Illumina's genome analyzer. We confirm many of the canonical signature genes of T-cell populations, but also discover new genes whose expression is limited to specific CD4 T-cell lineages, including long non-coding RNAs. Additionally, we find that genes encoded at loci linked to multiple human autoimmune diseases are enriched for preferential expression upon T-cell activation, suggesting that an aberrant response to T-cell activation is fundamental to pathogenesis.

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• University of North Carolina at Chapel Hill (UNC) Hepatocellular Carcinoma Study by Exome Sequencing (HCCSES)

  Genetic alterations in specific driver genes lead to disruption of cellular pathways and are critical events in the instigation and progression of hepatocellular carcinoma. As a prerequisite for individualized cancer treatment, we sought to characterize the landscape of recurrent somatic mutations in hepatocellular carcinoma. We performed whole exome sequencing on 87 hepatocellular carcinomas and matched normal adjacent tissues to an average coverage of 59x. The overall mutation rate was roughly 2 mutations per Mb, with a median of 45 non-synonymous mutations that altered the amino acid sequence (range 2 to 381). We found recurrent mutations in several genes with high transcript levels: TP53 (18%), CTNNB1 (10%), KEAP1 (8%), C16orf62 (8%), MLL4 (7%) and RAC2 (5%). Significantly affected gene families include the nucleotide-binding domain and leucine rich repeat containing family, calcium channel subunits, and histone methyltransferases. In particular, the MLL family methyltransferases for histone H3 lysine 4 were mutated in 20% of tumors. Conclusion: The NFE2L2-KEAP1 and MLL pathways are recurrently mutated in multiple cohorts of hepatocellular carcinoma.

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• Genetic Epidemiology of Lung Cancer Consortium GWAS of Familial Lung Cancer

  Familial lung cancer cases were collected by the Genetic Epidemiology of Lung Cancer Consortium (GELCC) recruitment sites: University of Cincinnati, Karmanos Cancer Institute at Wayne State University, Louisiana State University Health Sciences Center-New Orleans, Mayo Clinic, and Medical College of Ohio. Familial cases for this study came from three sources: 1) one case each from families (at least 3 affected lung cancer cases in the family) included in the linkage analysis; 2) one case from linkage-eligible families (at least 3 affected lung cancer cases in the family) but where there were insufficient biospecimens available to make them informative for linkage analysis; and 3) one case from families not eligible for the linkage study with a family history of at least one first or second degree relative affected with lung cancer. Unrelated controls were selected from 1) among the spouses of family members, thus matching on socio-economic status (SES) and ethnicity (typically) of the cases or 2) from case-control studies of lung cancer conducted in the same location in which the linkage families were collected and matched on age, sex, and race. All cases and controls self-reported as European American. Biospecimens used for normal DNA extraction included blood, saliva or mouthwash. Some samples underwent whole genome amplication.

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

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

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

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. Two major goals in the study of human malignancies are (i) to understand the genetic basis that underlies the predisposition of certain individuals to develop cancer and (ii) to identify the full spectrum of acquired mutations that occur in human cancers. There has been some progress in both of these areas with respect to hematologic malignancies but much remains to be discovered. As a result of recent advantages in sequencing technologies it is now feasible to sequence multiple individual whole exomes at reasonable cost. Such technologies provide a unique opportunity to transform our understanding of the biological basis of human cancer and to identify inherited genetic variants that predispose individuals to the development of hematologic malignancies. Myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS) and acute leukemia are clonal disorders of hematopoieis. Our study involves performing whole exome sequencing of individuals with these disorders for the purpose of identifying (i) novel inherited genetic variants associated with the risk of developing of MPN/MDS/acute leukemia and (ii) novel acquired mutations associated with the development of MPN/MDS/acute leukemia.

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• National Cancer Institute (NCI) Genome Wide Association Study (GWAS) of Lung Cancer in Never Smokers

  A genomewide study of lung cancer in never smokers Abstract and specific aims In the United States, lung cancer incidence and mortality rates have been steadily declining over the past decade, following decline in the prevalence of tobacco smoking. However, lung cancer remains the leading cause of cancer death, killing more patients than breast, colon, and prostate cancers combined. Although tobacco smoke is the predominant risk factor for development of lung cancer, some patients develop the disease without a history of tobacco smoking. About 10 - 15% of all lung cancers occur in lilfetime never smokers. This figure will increase as the proportion of never smokers increases in the population. Even at present rates, lung cancer in never smokers, if considered a separate disease, is 6th to 8th top cause of cancer death. The growing number of never smokers in the USA and other countries emphasizes the importance of understanding the epidemiology and biology underlying lung cancer in this group. Genetic polymorphisms associated with the risk of lung cancer in never smokers are expected to overlap with those associated with the risk of lung cancer in ever smokers only partially. Epidemiological, molecular and clinical data suggest that molecular mechanisms of LC may differ in smokers and non-smokers, implying that lung cancer in never smokers is a different disease compared to the lung cancer in smokers. One can expect that there should be stronger genetic component in the control lung cancer in never smokers because effects of the genetic factors in never smokers are unmasked by the lack of tobacco smoke exposure. The genetic epidemiology of lung cancer in never smokers has not been well explored, largely because of difficulties in accruing the needed sample size for association studies. We propose a multicenter (total 14 sites from the US and Europe) genomewide association study of lung cancer in never smokers with the following specific aims: Aim 1: To identify candidate SNPs influencing risk for lung cancer in never smokers using Discovery sample. In the Discovery phase we will genotype 1256 Caucasian cases and 1365 age- and gender-matched never smoker controls using the Illumina Human660W-Quad platform. In addition, we will include in the analysis 284 cases and 175 matched controls already genotyped on the 610Quad platform. In this phase we will only include the study sites that have collected blood specimens (MDACC, Mayo Clinic, Karmanos Cancer Institute, The University of Liverpool Cancer research Centre, Institute of Cancer Research in Sutton, and Lunenfeld Research Institute in Toronto, Canada). All the samples will be sent to the independent lab for genotyping, to reduce site-specific technical artifacts. The final sample will consist of 1540 cases and 1540 controls matched by study site. Aim 2: To perform the second phase (validation) analysis of significant SNPs identified in aim 1 using an independent set of cases and controls. SNPs associated with risk at the significance level of 0.01 or below in the discovery set will be included in the replication phase. The proposed threshold guarantees an adequate power to retain SNPs with the typical effect size of 1.3. We plan to carry 6000-7000 SNPs for validation. The independent replication set will include 800 cases and 800 controls, mostly from sites that collected tissue (Mayo Clinic, Karmanos Cancer Institute, UT Southwestern) or buccal specimens (UCLA), but also blood samples (Imperial College London, University of Pennsylvana, German Cancer Research Center, Heidelberg, National Research Center for Environment and Health, Neuherberg, Carmel Medical Center, Haifa). We will then perform a joint analysis to test the significance of the SNPs identified in the first stage using a stringent critical p-value of 10-7. There will be 2340 cases and 2340 controls in the joint set. Based on our experience with GWAS in smokers and assuming that genetic component in lung cancer risk in never smokers can be higher than genetic component in smokers, we expect to identify about 5-10 candidate regions associated with lung cancer risk in never smokers. Aim 3: To identify and explore pathways associated with the risk of lung cancer in never smokers. Results of the number of studies on the molecular mechanisms and drug response suggest that lung cancer in never smokers is a different disease and different pathways will be associated with lung cancer risk in non-smokers and smokers. To identify pathways and molecular functions associated with lung cancer risk in never smokers we will apply Ingenuity and DAVID bioinformatics tools. We will use at least 300 top candidate genes identified in joint and discovery analysis. The reason why we select rather large number of candidate genes for functional annotation is two-fold: 1. Both algorithms are looking for enrichment of pathways and function by most significant genes and they produce statistically robust results only when number of genes is relatively high. 2. Despite the fact that this study will be largest possible for never smokers we still are underpowered to detect SNPs with relatively small effect size. But though those SNPs will not reach genome wide level of significance they will tend to be on the top of the list. In other words genes from the gray zone (significant on individual level and non-significant for genome wide level) are expected to be enriched by true discoveries. True discoveries are likely to be associated with limited number of pathways / functions while false positives are expected to be uniformly distributed across functions and pathways. Therefore significant clustering of the gene to a given function will suggest that that those genes are true discoveries. This is the first GWAS aiming at identifying the genetic control of susceptibility to lung cancer in Caucasian never smokers. We will combine the available resources from the multiple sites to achieve the sample size sufficient for this study. The study will identify genetic architecture of the predisposition to the lung cancer in never smokers.

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• Whole Exome Sequencing for Familial Intracranial Aneurysm (FIA I-II) Study

  The goal of this study is to identify the genes underlying the risk of intracranial aneurysm (IA). The FIA Study initially recruited families appropriate for linkage analysis. Therefore, the recruitment focus was not only on probands with a family history of IA but also required that biological samples be obtained for at least two affected family members. Family members underwent detailed interviews for medical, social and family history, and provided blood samples for DNA extraction. Over 400 multiplex IA families were recruited and enrolled. The whole exome sequencing project aims to identify novel and rare (in the general population) genetic variants that are enriched in seven extended multiplex families with a strong familial aggregation of intracranial aneurysms.

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• Genome-Wide Association Study of Relapse of Childhood Acute Lymphoblastic Leukemia

  Using risk-directed therapy for childhood acute lymphoblastic leukemia (ALL), outcome has improved dramatically in the last 40 years. However, a substantial portion of patients experience relapse, many of whom have no known risk factors. Taking a genome-wide approach, we sought to evaluate the relationships between germline SNP genotypes and the risk of relapse in 2,535 children with newly diagnosed ALL after adjusting for genetic ancestry and treatment regimen. We examine prognostic value of selected SNPs in the context of known relapse risk factors (molecular subtypes, minimal residual disease, age and leukocyte count at diagnosis). Associations of relapse-related SNPs with pharmacokinetic and pharmacodynamics of antileukemic drugs offer plausible mechanism by which they are linked to treatment outcome. Finally, we aim to identify SNPs that are related to both genetic ancestry and relapse which are likely to contribute to racial disparities in ALL survival.

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• Whole Exome Sequencing Identifies

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

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• Genetic Epidemiology of Chronic Lymphocytic Leukemia

  Chronic lymphocytic leukemia (CLL) is a subtype of B-cell lymphoproliferative disorders (LPD), and is the most common form of adult leukemia in Caucasians in the United States. Small lymphocytic lymphoma (SLL) is also a B-cell LPD and is typically considered to be the same disease as CLL, based on pathology. We consider CLL and SLL as the same disease entity, and hereafter refer to both simply as "CLL". Using genealogical databases and cancer records, the familial clustering for CLL is one of the strongest for all cancer sites, strongly implicating germline genetic risk. We ascertained CLL cases and controls for a genomewide association study (GWAS) that was undertaken as part of the International Lymphoma Epidemiology (InterLymph) consortium GWAS. Some CLL cases are also part of extended high-risk CLLpedigrees.

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• Study of Adaptation to Hypoxia in Ethiopian Highlanders via Whole Genome Sequencing

  Although it has long been proposed that genetic factors contribute to adaptation to high altitude, such factors remain largely unverified. Recent advances in high-throughput sequencing have made it feasible to analyze genome-wide patterns of genetic variation in human populations. Since traditionally such studies surveyed only a small fraction of the genome (either exons or a subset of SNPs) or a group of candidate genes, interpretation of the results was limited. We focused our study on Ethiopian highlander populations, which have been found to be well adapted to high altitudes (~3500m). We sequenced and analyze the genomes of 13 high altitude native Ethiopians: 6 individuals of Oromo heritage living on Bale Plateau (labeled "Oromos"), and 7 individuals residing on the Chennek field in the Simien Mountains (labeled "Amhara"). Our study revealed evolutionarily conserved genes that modulate hypoxia tolerance.

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• 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).

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• Pediatric Investigation of Genetic Factors Linked with Renal Progression (PediGFR): Chronic Kidney Disease in Children Cohort (CKiD)

  The Pediatric Investigation for Genetic Factors Associated with Renal Progression (PediGFR) (RO1-DK082394) is an international collaborative study among three large prospective cohort studies of children with chronic kidney disease. The participating parent cohort studies are the "Chronic Kidney Disease in Children (CKiD)", the "Effect of Strict Blood Pressure Control and ACE Inhibition on CRF Progression in Pediatric Patients (ESCAPE)", and the "Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C)" study. In these cohorts, pediatric subjects with CKD have been prospectively followed with standardized measurements for renal progression. The current version of the upload includes the genotype and baseline phenotype for the CKiD cohort. In brief the CKiD study is a prospective study of children with chronic kidney disease (CKD) between the ages of 1 year to 16 years of age and an estimated glomerular filtration rate (eGFR) by Schwartz equation between 30 and 75 ml/min per 1.73m2. Included in this upload are the phenotypic data for anemia traits utilized for the sub-study, "Role of Genetic Variation in the Anemia of Chronic Kidney Disease" (K24DK078737), with the RBC trait and anemia data pertaining to CKiD as well.

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• Epi4K: Gene Discovery in 4,000 Epilepsy Genomes

  The Epi4K project began in 2011 as an international, multi-center study that seeks to identify and characterize the genetic bases of complex epilepsies. The Center without Walls Epi4K project includes three cores and four scientific projects, as well as a steering committee comprised of the primary study investigators and representatives from the National Institute of Neurological Disorders and Stroke (NINDS). The three cores include: (1) The Administrative Core which handles the overall coordination of Epi4K activities; (2) The Sequencing, Biostatistics and Bioinformatics Core which is responsible for generating the next-generation sequence data, inferring the genetic variation in each of the study participants, and performing the primary analyses to identify epilepsy genes; and (3) The Phenotyping and Clinical Informatics Core which verifies and archives all the phenotypic data from each study participant. The proposed number of patients to be sequenced and analyzed in the scientific projects is a minimum of 4,000; thus the Center was named "Epi4K: Gene Discovery in 4,000 Genomes". Project 1 addresses the genetics of rare and severe childhood epilepsies, including epileptic encephalopathies (infantile spasms and Lennox-Gastaut syndrome), and malformations of cortical development (periventricular nodular heterotopia and polymicrogyria). Exome and genome sequence data generated from DNA collected from patients will be screened for mutations (single nucleotide substitutions, small insertion-deletions, and copy number variations) that cause or contribute to the diseases. Project 2 is focused on genetic discovery in multiplex families. This study will use next-generation sequencing to identify genomic variation that influences risk for common subtypes of epilepsy including idiopathic generalized epilepsy and nonlesional focal epilepsy. Project 3 seeks to identify genetic determinants of prognosis in patients with a range of epilepsy disorders. This study will study established epilepsy cohorts with well-characterized data on seizure outcome to look for relationships between genetic variation and pharmacological control of seizures. Project 4 will use next-generation sequencing data (exome and genome) to screen for epilepsy-associated copy number variation across all Epi4K projects using novel computational algorithms.

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• 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.

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• Genetic measurement of memory B-cell recall using antibody repertoire sequencing

  We developed an improved high throughput sequencing approach to measure the quantities and sequences of the repertoire of antibody heavy chain RNA in a blood sample. Using this approach we analyzed the antibody repertoire in response to yearly vaccinations with influenza vaccines TIV and LAIV in healthy adults in two subsequent years. We determined vaccine response patterns specific to LAIV and TIV and found antibody sequences that were shared between two samples of the same individuals following influenza vaccination in subsequent years, thereby providing a genetic measurement of B-cell memory recall.

  Study phs000656

• Chinese Alternating Hemiplegia of Childhood (AHC) Disease Study

  AHC is a rare and severe neurological disorder, and characterized by episodic hemiplegia or quadriplegia attacks, accompanied by other paroxysmal symptoms of oculomotor abnormalities, dystonia, seizures and autonomic disturbances; the age of onset usually occurrs before 18 months of life. Sodium-potassium ATPase alpha3 subunit (ATP1A3) has recently been identified as a causal gene for sporadic AHC by three groups. However, there has not been any large genetic study on a Chinese cohort. In the submitted data, whole-exome sequencing of three trios and three sporadic cases in a Chinese cohort produced an average of 18.8 gigabases of raw sequence. Through our analysis pipeline including BWA mapping, GATK recalibration, variant calling and filtering, all six patients contained missense mutations in ATP1A3 which were further confirmed as de novo mutations. Along with validation in additional patients, this study confirmed ATP1A3 as a causal gene in Chinese AHC patients, and reported six novel mutations.

  Study phs000660

• Germline Sequencing for Aggressive Prostate Carcinoma

  This study aims to elucidate the genetic determinants of susceptibility to aggressive prostate carcinoma. To this end, germ line whole exome sequence has been generated from patients with aggressive prostate cancer. Whole genome sequence for a representative subset of tumors from patients whose cancer was resistant to primary therapy is included as well. This deep genomic interrogation will allow the identification of rare, functionally disruptive variants that may play a role in disease progession and response to treatment.

  Study phs000661

• National Children's Study Vanguard Study Formative Research Study (NCS)

  The National Children's Study (NCS) is a multi-year prospective epidemiological study tasked with identifying a nationally representative sample of 100,000 children and following them from pregnancy through age 21 to study environmental impacts on growth, development, and health. Determination of NCS enrollee ancestry is important for assessing the diversity of study enrollees and for examining the effect of ancestry on various health outcomes. We estimated the genetic ancestry of a convenience sample of 641 parents enrolled at the 7 original NCS Vanguard sites by analyzing 29,972 markers on exome arrays, using the participants of the 1000 Genomes Project (1KG) super populations (e.g. European, East Asian) as reference populations, and compared this to self-reported ethnicity and race. Self-reported ethnicity and race agreed with predicted super population in 98.9% of individuals. NCS individuals identified as Asian by self-report had genetic ancestry of either South Asian or Asian groups, while those reporting as either Hispanic White or Hispanic Other had similar genetic ancestry. Of the 33 individuals who self-reported as Multiracial or Non-Hispanic Other, 11 (33%) matched the South Asian and Asian groups, while these groups were less represented in the other reported categories (27/609, 4.4%). Our data suggest that self-reported ethnicity and race categories have some limitations in accurately capturing this information for Hispanic and South Asian populations. Overall, our data indicate that despite the complexity of the U.S. population, individuals know their ancestral origins and that self-reported ethnicity and race is a reliable indicator of genetic ancestry.

  Study phs000662