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 PAGE 研究（第 1 页）中，我们研究了通过全基因组关联研究 (GWAS) 在祖先多样化人群中鉴定的许多遗传位点，并成功概括和精细绘制了来自欧洲研究的许多 GWAS 位点- 后裔人口。这些成功支持将基因组搜索扩展到不太常见和罕见的变异，这些变异尚未在 GWAS 中捕获，但代表了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。大多数 GWAS 是在欧洲人中进行的；然而，需要研究遗传风险因素（包括低频变异）对不同人群中常见复杂性状的影响，包括研究不足的疾病负担高的美国少数族裔。该项目的目标是全面研究基因组蛋白质编码区域（即“外显子组”）中不太常见和罕见的非同义变异，以及它们与常见复杂特征的关联，例如心血管疾病、癌症、身体成分、多种族人群中的血脂、血糖、胰岛素和许多其他结果。具体来说，我们建议使用新开发的 ExomeChip 基因分型平台，并添加关注祖先多样性和非编码区域推定调控元件的附加内容。该平台具有极高的成本效益，将提供约 350,000 个等位基因频率低至 0.1% 的变异的基因分型数据。大多数这些低频变异在现有的 GWAS 阵列上既没有进行基因分型也没有很好的标记。我们将在来自妇女健康倡议 (WHI) 的祖先多样化人群中使用此外显子组芯片，包括非裔美国人 (n=7,510)、西班牙裔 (n=5,394) 和美洲原住民 (n=596)。这些数据将与来自正在进行的 WHI 研究的 23,303 名欧洲裔美国人和 3,631 名非洲裔美国人的 ExomeChip 基因型和外显子组测序数据相结合，总共 40,434 名 WHI 参与者。该资源将使我们能够研究低频和罕见遗传变异与具有公共卫生重要性的复杂疾病之间的关系，以及与精心策划的中间性状和 WHI 中提供的 4,800 多个表型变量之间的关系。我们将开发新方法并将其应用于这一丰富的资源中，以估计遗传力并识别跨多个表型（多效性）的变异的影响以及基因-环境相互作用，这是由我们对常见变异的第 1 页发现推动的。通过这些努力，我们期望确定多个易感位点，这些位点可以更好地量化由遗传变异解释的复杂疾病的变异比例，确定人群特异性位点并提供对共享分子途径的见解，从而更有效地指导后续的预防和治疗策略。多元化的美国人口。所有基因型和相关表型数据将通过 dbGaP 等数据库公开，并作为 WHI 系统的一部分，为科学界构建资源。

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