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

Hoffmann, Thomas J ; Graff, Rebecca E ; Madduri, Ravi K ; Rodriguez, Alex A ; Cario, Clint L ; Feng, Karen ; Jiang, Yu ; Wang, Anqi ; Klein, Robert J and Pierce, Brandon L , et al. (2023)
Abstract

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,... (More)

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.

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organization
publishing date
type
Working paper/Preprint
publication status
published
subject
publisher
medRxiv
external identifiers
  • pmid:37961155
DOI
10.1101/2023.10.27.23297676
language
English
LU publication?
yes
id
cccc9c2c-88ad-45b4-a7bc-cb15fc785091
date added to LUP
2023-11-28 10:13:22
date last changed
2023-11-28 16:24:41
@misc{cccc9c2c-88ad-45b4-a7bc-cb15fc785091,
  abstract     = {{<p>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.</p>}},
  author       = {{Hoffmann, Thomas J and Graff, Rebecca E and Madduri, Ravi K and Rodriguez, Alex A and Cario, Clint 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 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 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}},
  language     = {{eng}},
  month        = {{10}},
  note         = {{Preprint}},
  publisher    = {{medRxiv}},
  title        = {{Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction}},
  url          = {{http://dx.doi.org/10.1101/2023.10.27.23297676}},
  doi          = {{10.1101/2023.10.27.23297676}},
  year         = {{2023}},
}