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<p>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 (<i>P</i> ≤ 5 × 10<sup>−8</sup>) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (<i>n</i> = 95,768). Meta-analyzing discovery and replication (<i>n</i> = 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月10日

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

摘要

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.