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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

Hoffmann, Thomas J ; Graff, Rebecca E ; Madduri, Ravi K ; Rodriguez, Alex A ; Cario, Clinton L ; Feng, Karen ; Jiang, Yu ; Wang, Anqi ; Klein, Robert J LU and Pierce, Brandon L , et al. (2025) In Nature Genetics 57(2). p.334-344
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Male, Genome-Wide Association Study, Prostate-Specific Antigen/blood, Prostatic Neoplasms/genetics, Polymorphism, Single Nucleotide, Middle Aged, Aged, Hispanic or Latino/genetics, White People/genetics, Genetic Predisposition to Disease, Cohort Studies
in
Nature Genetics
volume
57
issue
2
pages
334 - 344
publisher
Nature Publishing Group
external identifiers
  • pmid:39930085
ISSN
1546-1718
DOI
10.1038/s41588-024-02068-z
language
English
LU publication?
yes
additional info
© 2025. The Author(s).
id
b3718956-f7c7-4b93-be4e-b3e7a2653c29
date added to LUP
2025-02-16 12:17:34
date last changed
2025-02-17 08:33:55
@article{b3718956-f7c7-4b93-be4e-b3e7a2653c29,
  abstract     = {{<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 (P ≤ 5 × 10<br>
 -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.<br>
 </p>}},
  author       = {{Hoffmann, Thomas J and Graff, Rebecca E and Madduri, Ravi K and Rodriguez, Alex A and Cario, Clinton L and Feng, Karen and Jiang, Yu and Wang, Anqi and Klein, Robert J and Pierce, Brandon L and Eggener, Scott and Tong, Lin and Blot, William and Long, Jirong and Goss, Louisa B and Darst, Burcu F and Rebbeck, Timothy and Lachance, Joseph and Andrews, Caroline and Adebiyi, Akindele O and Adusei, Ben and Aisuodionoe-Shadrach, Oseremen I and Fernandez, Pedro W and Jalloh, Mohamed and Janivara, Rohini and Chen, Wenlong C and Mensah, James E and Agalliu, Ilir and Berndt, Sonja I and Shelley, John P and Schaffer, Kerry and Machiela, Mitchell J and Freedman, Neal D and Huang, Wen-Yi and Li, Shengchao A and Goodman, Phyllis J and Till, Cathee and Thompson, Ian and Lilja, Hans and Ranatunga, Dilrini K and Presti, Joseph and Van Den Eeden, Stephen K and Chanock, Stephen J and Mosley, Jonathan D and Conti, David V and Haiman, Christopher A and Justice, Amy C and Kachuri, Linda and Witte, John S}},
  issn         = {{1546-1718}},
  keywords     = {{Humans; Male; Genome-Wide Association Study; Prostate-Specific Antigen/blood; Prostatic Neoplasms/genetics; Polymorphism, Single Nucleotide; Middle Aged; Aged; Hispanic or Latino/genetics; White People/genetics; Genetic Predisposition to Disease; Cohort Studies}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{334--344}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Genetics}},
  title        = {{Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves prediction across ancestry groups}},
  url          = {{http://dx.doi.org/10.1038/s41588-024-02068-z}},
  doi          = {{10.1038/s41588-024-02068-z}},
  volume       = {{57}},
  year         = {{2025}},
}