Exonic variants and their relation to complex traits in minorities of the WHI

外显子变异及其与 WHI 少数群体复杂性状的关系

• 批准号: 9527426
• 负责人: Charles L Kooperberg
• 金额: $ 37.99万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9527426
• 关键词: Affect; African American; Age; Aging; American; Architecture; Asian Americans; Asians; Behavioral; Blood Pressure; Body Composition; Body mass index; Cardiovascular Diseases; Cause of Death; Characteristics; Chronic Disease; Clinical; Code; Collaborations; Collection; Communities; Complex; Creatinine; Data; Databases; Diet; Disease; Enrollment; Environmental Risk Factor; Epidemiologist; Ethnic Origin; European; Frequencies; Funding; Gene Frequency; Genetic; Genetic Variation; Genome; Genomics; Genotype; Glucose; Goals; Heritability; Hispanic Americans; Hispanics; Hormone use; Insulin; Investigation; Laboratories; Lead; Link; Lipids; Malignant Neoplasms; Maps; Measures; Methods; Minority; Molecular; National Heart, Lung, and Blood Institute; Native Americans; Non-Insulin-Dependent Diabetes Mellitus; Open Reading Frames; Outcome; Participant; Pathogenesis; Pathway interactions; Pharmacotherapy; Phenotype; Physicians; Population; Population Heterogeneity; Prevention strategy; Productivity; Public Health; Race; Regulatory Element; Research; Resources; Risk; Risk Factors; Sampling; Smoking; Susceptibility Gene; System; Untranslated RNA; Variant; Waist-Hip Ratio; Woman; Women' s Health; blood lipid; burden of illness; cohort; cost efficient; database of Genotypes and Phenotypes; drug discovery; exome; exome sequencing; follow-up; frailty; gene environment interaction; genetic risk factor; genetic variant; genome wide association study; improved; inflammatory marker; insight; multidisciplinary; novel; phenome; phenotypic data; pleiotropism; prevent; prospective; public health relevance; rare variant; screening; success; trait; treatment strategy

DESCRIPTION (provided by applicant): In the current PAGE study (PAGE 1) we investigated many genetic loci identified through genome-wide association studies (GWAS) in ancestrally diverse populations, and successfully generalized and fine-mapped many GWAS loci from studies of European-descent populations. These successes support extending the genomic search to less frequent and rare variants, which have not been captured in GWAS, but represent the largest fraction of genetic variation in the genome and contribute to the heritabilit of many complex traits. Most GWAS have been conducted in Europeans; yet studies investigating the impact of genetic risk factors, including low frequency variants, on common complex traits in diverse populations are needed including understudied US minorities having high burden of disease. The goal of this project is to comprehensively investigate less frequent and rare non-synonymous variants across the protein coding regions of the genome, i.e. the "exome", and their associations with common complex traits, such as cardiovascular disease, cancer, body composition, blood lipids, glucose, insulin, and many other outcomes in a multi-ethnic population. Specifically, we propose to use a newly developed ExomeChip genotyping platform, augmented with additional content focused on ancestral diversity and putative regulatory elements in non-coding regions. This platform is highly cost-efficient and will provide genotyping data on about 350,000 variants with allele frequencies as low as 0.1%. Most of these low frequency variants are neither genotyped nor well tagged on existing GWAS arrays. We will use this ExomeChip in an ancestrally diverse population including African Americans (n=7,510), Hispanics (n=5,394) and Native Americans (n=596) from the Women's Health Initiative (WHI). These data will be combined with ExomeChip genotypes and exome sequencing data from 23,303 European Americans and 3,631 African Americans from ongoing WHI studies, for a total of 40,434 WHI participants. This resource will permit us to investigate relationships between low frequency and rare genetic variants with complex diseases of public health importance as well as with well-curated intermediate traits and over 4,800 phenotypic variables available in the WHI. We will develop new methods and apply them in this rich resource to estimate heritability and to identify effects of variants across multiple phenotypes (pleiotropy) and gene-environment interaction which are motivated by our PAGE 1 findings for common variants. Through these efforts, we expect to identify multiple susceptibility loci that may better quantify the proportion of variation in complex diseases explained by genetic variants, identify population-specific loci and provide insights into shared molecular pathways that will more efficiently direct subsequent prevention and treatment strategies in the diverse US population. All genotype and associated phenotypic data will be made publically available through databases, such as dbGaP and as part of the WHI system, building a resource for the scientific community.

描述（由申请人提供）：在当前的页面研究（第1页）中，我们研究了许多通过全基因组关联研究（GWAS）在祖先多样化的人群中确定的遗传基因座，并成功地概括了许多GWAS基因座，这些GWAS基因座是从欧洲繁殖人群的研究中进行的。这些成功支持将基因组搜索扩展到尚未在GWAS中捕获的频率较低和稀有变体，而是基因组中遗传变异的最大部分，并有助于许多复杂性状的遗传性。大多数GWA都是在欧洲人进行的。然而，需要研究遗传危险因素（包括低频变异）对各种种群中常见复杂性状的影响的研究，包括研究疾病负担很高的美国少数民族。该项目的目的是全面研究基因组蛋白质编码区域的频繁和罕见的非同义变体，即“外部”及其与常见的复杂性状的关联，例如心血管疾病，癌症，身体成分，血脂，糖脂，葡萄糖，胰岛素，胰岛素，胰岛素，许多其他人群。具体而言，我们建议使用新开发的外部基因分型平台，并增强了其他内容，这些内容侧重于祖先多样性和非编码区域的推定监管元素。该平台的成本效益高，将提供大约350,000种等位基因频率低至0.1％的基因分型数据。这些低频变体中的大多数既不是基因分型，也不是在现有的GWA阵列上标记的。我们将在包括非洲裔美国人（n = 7,510），西班牙裔（n = 5,394）和美洲原住民（n = 596）（妇女健康倡议（WHI））中，在包括非洲裔美国人（n = 7,510），西班牙裔美国人（n = 5,394）（n = 5,394）（n = 5,394）中，将这种外国志用。这些数据将与来自正在进行的WHI研究的23,303名欧洲人和3,631名非裔美国人的外部基因型和外显子组测序数据相结合，共有40,434名参与者。该资源将使我们能够研究低频与稀有遗传变异之间的关系，以及与公共健康重要性的复杂疾病，以及经过良好策划的中间性状以及WHI中有4,800多个表型变量的关系。我们将开发新方法，并将它们应用于这种丰富的资源中，以估算遗传力，并确定多种表型（多效性）和基因环境相互作用的变体的影响，这是由我们的第1页对共同变体的发现激发的。通过这些努力，我们希望确定多个易感基因座，可以更好地量化遗传变异解释的复杂疾病变异的比例，识别特定人群特异性的基因座，并提供对共享分子途径的见解，这些途径将更有效地直接直接直接直接在美国人群中进行后续的预防和治疗策略。所有基因型和相关的表型数据将通过数据库（例如DBGAP）和作为WHI系统的一部分公开提供，并为科学界建立资源。

项目成果

Cardiovascular Disease and Mortality in Black Women Carrying the Amyloidogenic V122I Transthyretin Gene Variant.

携带淀粉样变性 V122I 运甲状腺素蛋白基因变体的黑人女性的心血管疾病和死亡率。

• DOI: 10.1016/j.jchf.2023.02.003
• 发表时间: 2023
• 期刊: JACC. Heart failure
• 作者: Haring,Bernhard;Hunt,RebeccaP;Shadyab,AladdinH;Eaton,Charles;Kaplan,Robert;Martin,LisaWarsinger;Panjrath,Gurusher;Kuller,LewisH;Assimes,Themistocles;Kooperberg,Charles;Wassertheil-Smoller,Sylvia
• 通讯作者: Wassertheil-Smoller,Sylvia