Multiethnic GWAS and TWAS to Inform Risk Prediction for Prostate Cancer

多种族 GWAS 和 TWAS 为前列腺癌风险预测提供信息

• 批准号: 10613934
• 负责人: David V Conti
• 金额: $ 63.15万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613934
• 关键词: African; African American; African American population; African ancestry; Age; Asian; Asian ancestry; Asian population; Biological; Biological Assay; Biology; Data; Disease; Ethnic Origin; Ethnic Population; European; European ancestry; Freezing; Gene Expression; Genes; Genetic; Genetic Databases; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genetic study; Histologic; Incidence; Latino; Malignant neoplasm of prostate; Maps; Measures; Medical; Modeling; Phenotype; Physicians; Population; Prostate; RNA Sequences; Race; Regulator Genes; Regulatory Element; Risk; Risk Marker; Sample Size; Sampling; Scanning; Signal Transduction; Specimen; Susceptibility Gene; Testing; Tissues; Trans-Omics for Precision Medicine; Transcript; Validation; Variant; Work; case control; causal variant; cohort; design; ethnic difference; genetic association; genome wide association study; genome-wide; improved; innovation; insertion/deletion mutation; man; men; multi-ethnic; novel; polygenic risk score; prostate cancer risk; racial difference; racial diversity; racial population; risk prediction; risk variant; screening; secondary analysis; transcriptome; transcriptome sequencing; transcriptomics; whole genome; African; African American; African American population; African ancestry; Age; Asian; Asian ancestry; Asian population; Biological; Biological Assay; Biology; Data; Disease; Ethnic Origin; Ethnic Population; European; European ancestry; Freezing; Gene Expression; Genes; Genetic; Genetic Databases; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genetic study; Histologic; Incidence; Latino; Malignant neoplasm of prostate; Maps; Measures; Medical; Modeling; Phenotype; Physicians; Population; Prostate; RNA Sequences; Race; Regulator Genes; Regulatory Element; Risk; Risk Marker; Sample Size; Sampling; Scanning; Signal Transduction; Specimen; Susceptibility Gene; Testing; Tissues; Trans-Omics for Precision Medicine; Transcript; Validation; Variant; Work; case control; causal variant; cohort; design; ethnic difference; genetic association; genome wide association study; genome-wide; improved; innovation; insertion/deletion mutation; man; men; multi-ethnic; novel; polygenic risk score; prostate cancer risk; racial difference; racial diversity; racial population; risk prediction; risk variant; screening; secondary analysis; transcriptome; transcriptome sequencing; transcriptomics; whole genome

Abstract Prostate cancer (PCa) incidence is highest in African Americans and lowest in Asians. These long-standing racial/ethnic differences have yet to be explained. Genome-wide association studies of PCa have provided support for common and population-specific genetic effects for PCa and for a genetic basis of the underlying population differences in risk. To further progress in understanding the genetic basis of PCa across populations, we propose to substantially augment the size of genetic association studies in men of European, African, Asian and Latino ancestry to create the largest genetic database of PCa ever assembled in these populations, with substantially greater statistical power for novel discovery of risk alleles for PCa as well as aggressive disease. More specifically, we will expand studies in men of African ancestry from 10,368 cases and 10,986 controls to 34,000 cases and 74,000 controls, in men of Asian ancestry from 8,610 cases and 18,809 controls to 20,000 cases and 40,000 controls, in men of Latino ancestry from 2,714 cases and 5,239 controls to 10,000 cases and 20,000 controls, and in men of European ancestry from 82,000 cases and 61,000 controls to 117,000 cases and 517,000 controls, with all studies imputed to a multiethnic whole-genome sequence reference panel (e.g. TOPMed). In Aim 1, we will search for novel common risk alleles for overall and aggressive PCa in ethnic-specific and multiethnic analyses. Within known and newly discovered risk regions, we will conduct multiethnic fine- mapping using novel Bayesian statistical approaches that incorporate functional annotations and biology with statistical evidence to identify independent markers of risk as well as the most promising functional candidates. In Aim 2, we will create the first multiethnic genome-wide SNP-eQTL prostate reference panel for men of European, African, Asian and Latino ancestry using whole-transcriptome RNA sequencing of ~1,000 histologically normal, fresh-frozen prostate tissue specimens. We will characterize eQTLs in the sample and impute gene expression in men of European, African, Asian, and Latino ancestry to perform a multiethnic transcriptome-wide association scan (TWAS). In Aim 3, we will construct and evaluate a polygenic risk score (PRS) across populations, using known and novel risk variants from Aim 1 and TWAS loci from Aim 2. PRS validation testing will be conducted in three independent multiethnic cohorts (>38,000 PCa cases from ATLAS, All of Us and CCPM). We expect findings from this study will make a major contribution to our understanding of genetic susceptibility to PCa and lead to better risk models that more accurately predict a man's risk of developing PCa and are efficacious across racial/ethnic populations.

抽象的 在非洲裔美国人中，前列腺癌（PCA）发病率最高，在亚洲人中最低。这些长期存在 种族/种族差异尚未解释。 PCA全基因组关联研究提供了 支持PCA的常见和人群特异性遗传效应以及基础的遗传基础 风险的人口差异。为了进一步了解跨种群PCA的遗传基础的进展， 我们建议大大增加欧洲，非洲，亚洲男性的遗传关联研究的规模 和拉丁裔血统，创建了有史以来最大的PCA遗传数据库 新发现的PCA风险等位基因以及侵略性疾病的新统计能力大大更大。 更具体地说，我们将将非洲血统男性的研究从10,368例和10,986个对照组扩大到 34,000例和74,000例对照，亚洲血统的男性从8,610例和18,809个对照到20,000 案件和40,000个对照，拉丁裔血统的男性从2,714例案件和5,239个对照到10,000例 20,000个对照，以及欧洲血统的男性，从82,000例和61,000例控制到117,000例 517,000个对照，所有研究都归纳为多种族全基因组序列参考面板（例如， 顶）。在AIM 1中，我们将寻找新颖的普通风险等位基因，以特定于种族的PCA总体和侵略性PCA 和多民族分析。在已知和新发现的风险区域内，我们将进行多种族的精细 - 使用新颖的贝叶斯统计方法映射，将功能性注释和生物学结合到 统计证据以识别风险的独立标记以及最有前途的职能候选者。 在AIM 2中，我们将创建第一个多民族基因组全基因组SNP-EQTL前列腺参考面板 欧洲，非洲，亚洲和拉丁裔血统使用全本书组RNA测序〜1,000 组织学正常，新鲜的前列腺组织标本。我们将在样本中表征EQTL，并 在欧洲，非洲，亚洲和拉丁裔血统的男性中估算基因表达 整个转录组的关联扫描（TWA）。在AIM 3中，我们将构建和评估多基因风险评分 （PR）在跨种群中，使用AIM 1和AIM 2的已知和新型风险变体。PRS 验证测试将在三个独立的多民族队列中进行（来自Atlas的38,000个PCA案例， 我们所有人和CCPM）。我们希望这项研究的发现将为我们的理解做出重大贡献 对PCA的遗传敏感性并导致更好的风险模型，以更准确地预测男人的风险 在种族/民族人群中开发PCA并有效。