Multiethnic GWAS and TWAS to Inform Risk Prediction for Prostate Cancer

摘要 前列腺癌（PCa）的发病率在非洲裔美国人中最高，亚洲人最低。这些长期存在的 种族/民族差异尚未得到解释。PCa的全基因组关联研究提供了 支持PCa的共同和群体特异性遗传效应，并支持潜在的 风险的人群差异。为了进一步了解PCa在人群中的遗传基础， 我们建议在欧洲、非洲、亚洲男性中大幅增加遗传关联研究的规模， 和拉丁美洲血统，以创建有史以来在这些人群中组装的最大的PCa基因数据库， 对于PCa以及侵袭性疾病的风险等位基因的新发现，具有显著更大的统计功效。 更具体地说，我们将扩大对非洲血统男性的研究，从10,368例病例和10,986例对照， 34，000例病例和74，000例对照，亚洲血统男性从8，610例病例和18，809例对照增加到20，000例 病例和40，000例对照，拉丁裔男性从2，714例病例和5，239例对照增加到10，000例， 20，000例对照，欧洲血统的男性从82，000例病例和61，000例对照增加到117，000例病例， 517，000个对照，所有研究均采用多种族全基因组序列参考组（例如， TOPMed）。在目标1中，我们将在种族特异性PCa中寻找整体和侵袭性PCa的新的共同风险等位基因。 多民族分析。在已知和新发现的风险地区，我们将进行多民族的精细- 映射使用新的贝叶斯统计方法，结合功能注释和生物学， 统计学证据，以确定独立的风险标记以及最有前途的功能候选人。 在目标2中，我们将创建第一个多种族全基因组SNP-eQTL前列腺参考组， 欧洲、非洲、亚洲和拉丁美洲血统，使用全转录组RNA测序约1，000 组织学正常的新鲜冷冻前列腺组织标本。我们将对样品中的eQTL进行表征， 在欧洲人、非洲人、亚洲人和拉丁美洲人祖先中输入基因表达， 全转录组关联扫描（TWAS）。在目标3中，我们将构建和评估多基因风险评分 (PRS)在人群中，使用来自Aim 1的已知和新的风险变体和来自Aim 2的TWAS基因座。PRS 验证测试将在三个独立的多种族群组中进行（来自ATLAS的> 38，000个PCa病例， 我们所有人和CCPM）。我们希望这项研究的结果将对我们理解 遗传易感性PCa，并导致更好的风险模型，更准确地预测男性的风险 发展PCa并且对种族/民族人群有效。

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.