美国斯坦福大学John S. Witte研究团队近日取得一项新成果。经过不懈努力，他们的研究显示，对392,522名男性前列腺特异性抗原水平的全基因组关联研究发现了新的基因座，并提高了对祖先群体的预测。2025年2月10日，国际知名学术期刊《自然—遗传学》发表了这一成果。

课题组研究人员对296754名男性（211342名欧洲血统，58236名非洲血统，23546名西班牙/拉丁裔和3630名亚洲血统）进行了前列腺特异性抗原（PSA）水平的多祖先全基因组关联研究；96.5%的参与者来自百万退伍军人计划)。该研究组鉴定出318个独立的全基因组显著（P ≤ 5 × 10 ^-8)变异，其中184个是新的。大多数在独立队列中证实了重复的证据（n = 95,768）。荟萃分析发现和复制（n = 392,522）确定了447个变异，其中111个是新的。

全基因组多基因风险评分解释了PSA的样本外方差，欧洲血统为11.6%至16.6%，非洲血统为5.5%至9.5%，西班牙裔/拉丁裔为13.5%至18.2%，亚洲血统为8.6%至15.3%，随着年龄的增长而下降。与未调整的PSA水平相比，中年基因调整的PSA水平与总体和侵袭性前列腺癌的相关性更强。他们的研究强调了从代表性不足的人群中纳入比例更多的参与者如何改善PSA水平的遗传预测，为个性化前列腺癌筛查提供了潜力。

附：英文原文

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

Author: Hoffmann, Thomas J., Graff, Rebecca E., Madduri, Ravi K., Rodriguez, Alex A., Cario, Clinton L., Feng, Karen, Jiang, Yu, Wang, Anqi, Klein, Robert J., Pierce, Brandon L., Eggener, Scott, Tong, Lin, Blot, William, Long, Jirong, Goss, Louisa B., Darst, Burcu F., Rebbeck, Timothy, Lachance, Joseph, Andrews, Caroline, Adebiyi, Akindele O., Adusei, Ben, Aisuodionoe-Shadrach, Oseremen I., Fernandez, Pedro W., Jalloh, Mohamed, Janivara, Rohini, Chen, Wenlong C., Mensah, James E., Agalliu, Ilir, Berndt, Sonja I., Shelley, John P., Schaffer, Kerry, Machiela, Mitchell J., Freedman, Neal D., Huang, Wen-Yi, Li, Shengchao A., Goodman, Phyllis J., Till, Cathee, Thompson, Ian, Lilja, Hans, Ranatunga, Dilrini K., Presti, Joseph, Van Den Eeden, Stephen K., Chanock, Stephen J., Mosley, Jonathan D., Conti, David V., Haiman, Christopher A., Justice, Amy C., Kachuri, Linda, Witte, John S.

Issue&Volume: 2025-02-10

Abstract: We conducted a multiancestry 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 and 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (P≤5 × 10^-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 genome-wide polygenic risk scores ranged from 11.6% to 16.6% for European ancestry, 5.5% to 9.5% for African ancestry, 13.5% to 18.2% for Hispanic/Latino and 8.6% to 15.3% for Asian ancestry and decreased with increasing age. Midlife genetically adjusted PSA levels were more strongly associated with overall and aggressive prostate cancer than unadjusted PSA levels. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, offering potential to personalize prostate cancer screening.

DOI: 10.1038/s41588-024-02068-z

Source: https://www.nature.com/articles/s41588-024-02068-z