Multiethnic GWAS and TWAS to Inform Risk Prediction for Prostate Cancer

摘要 前列腺癌(PCA)的发病率在非裔美国人中最高，在亚洲人中最低。这些历史悠久的 种族/民族差异尚未得到解释。对前列腺癌的全基因组关联研究提供了 支持PCA的共同和特定于人群的遗传效应以及潜在的遗传基础 风险方面的人群差异。为了进一步了解群体间前列腺癌的遗传基础， 我们建议大幅扩大欧洲、非洲、亚洲男性的基因关联研究的规模 和拉丁裔血统创建了有史以来在这些群体中组装的最大的PCA基因数据库， 为新发现前列腺癌和侵袭性疾病的风险等位基因提供更大的统计能力。 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例对照扩大到 34,000例病例和74,000名对照，亚裔男性从8,610例和18,809名对照增加到20,000名 在拉丁裔男性中，从2,714例和5,239例对照增加到10,000例和10,000例对照 20,000例对照，欧洲血统男性从82,000例和61,000例对照增加到117,000例和 517,000个对照，所有研究都归入多种族全基因组序列参考小组(例如： TOPMed)。在目标1中，我们将在种族特定的总体和侵袭性前列腺癌中寻找新的共同的风险等位基因 和多种族分析。在已知和新发现的风险区域内，实行多民族罚款-- 使用新的贝叶斯统计方法进行映射，该方法将功能注释和生物学与 确定独立的风险标志物以及最有希望的功能候选者的统计证据。 在目标2中，我们将为以下男性创建第一个多种族基因组范围的SNP-eQTL前列腺参考板 使用约1,000个完整转录组RNA测序的欧洲、非洲、亚洲和拉丁裔血统 组织学正常、新鲜冷冻的前列腺组织标本。我们将在样本中表征eQTL，并 归因于欧洲、非洲、亚洲和拉丁裔血统男性的基因表达表现出多种族 全转录组联合扫描(TWAS)。在目标3中，我们将构建和评估多基因风险评分。 使用来自AIM 1的已知和新的风险变异，以及来自AIM 2的TWAS基因座。 验证测试将在三个独立的多种族队列中进行(来自ATLAS的38,000例PCA病例， 我们所有人和CCPM)。我们期待这项研究的发现将对我们理解 对前列腺癌的遗传易感性并导致更好的风险模型，更准确地预测男性患前列腺癌的风险 发展PCA，并在种族/民族人群中有效。

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.