Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction

We conducted a multi-ancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry; 58,236 African ancestry; 23,546 Hispanic/Latino; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p[≤]5e-8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n=95,768). Meta-analyzing discovery and replication (n=392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our new polygenic risk score reached 16.9% (95% CI=16.1%-17.8%) in European ancestry, 9.5% (95% CI=7.0%-12.2%) in African ancestry, 18.6% (95% CI=15.8%-21.4%) in Hispanic/Latino, and 15.3% (95% CI=12.7%-18.1%) in Asian ancestry, and lower for higher age. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, with potential to personalize prostate cancer screening.

我们对296754名男性的前列腺特异性抗原（PSA）水平进行了多血统全基因组关联研究（其中211342名欧洲血统；58236名非洲血统；23546名西班牙裔/拉丁裔；3630名亚洲血统；96.5%的参与者来自百万退伍军人计划）。我们确定了318个独立的全基因组显著（p≤5×10⁻⁸）变异体，其中184个是新的。大多数在一个独立队列（n = 95768）中显示出复制的证据。对发现队列和复制队列（n = 392522）进行荟萃分析确定了447个变异体，其中又有111个是新的。我们新的多基因风险评分对PSA的样本外方差解释在欧洲血统中达到16.9%（95%置信区间 = 16.1% - 17.8%），在非洲血统中达到9.5%（95%置信区间 = 7.0% - 12.2%），在西班牙裔/拉丁裔中达到18.6%（95%置信区间 = 15.8% - 21.4%），在亚洲血统中达到15.3%（95%置信区间 = 12.7% - 18.1%），且年龄越大解释率越低。我们的研究强调了纳入更多比例的来自代表性不足人群的参与者如何提高PSA水平的遗传预测能力，具有实现前列腺癌筛查个性化的潜力。