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Transcriptome-Wide Association Analysis Identifies Candidate Susceptibility Genes for Prostate-Specific Antigen Levels in Men Without Prostate Cancer

Chen, Dorothy M ; Dong, Ruocheng ; Kachuri, Linda ; Hoffmann, Thomas ; Jiang, Yu ; Berndt, Sonja I ; Shelley, John P ; Schaffer, Kerry R ; Machiela, Mitchell J and Freedman, Neal D , et al. (2024) In Human Genetics and Genomics Advances
Abstract

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10×10
-6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61×10
-6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses identified 155 statistically significantly (p < 0.05/22,249 = 2.25×10
-6) genes. Out of 173 unique PSA-associated genes across... (More)

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10×10
-6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61×10
-6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses identified 155 statistically significantly (p < 0.05/22,249 = 2.25×10
-6) genes. Out of 173 unique PSA-associated genes across analyses, we replicated 151 (87.3%) in TWAS of 209,318 PCa-free individuals from the Million Veteran Program. Based on conditional analyses, we found 20 genes (11 single-tissue, nine cross-tissue) that were associated with PSA levels in the discovery TWAS that were not attributable to a lead variant from a genome-wide association study (GWAS). Ten of these 20 genes replicated, and two of the replicated genes had colocalization probability > 0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.

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organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
Human Genetics and Genomics Advances
article number
100315
publisher
Elsevier
external identifiers
  • pmid:38845201
ISSN
2666-2477
DOI
10.1016/j.xhgg.2024.100315
language
English
LU publication?
yes
additional info
Copyright © 2024. Published by Elsevier Inc.
id
82a47f36-ff9e-4c56-9074-0b9d7cbcf269
date added to LUP
2024-06-09 11:18:29
date last changed
2024-06-10 11:40:53
@article{82a47f36-ff9e-4c56-9074-0b9d7cbcf269,
  abstract     = {{<p>Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p &lt; 0.05/12,192 = 4.10×10<br>
 -6) associations in whole blood and 39 statistically significant (p &lt; 0.05/13,844 = 3.61×10 <br>
 -6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses identified 155 statistically significantly (p &lt; 0.05/22,249 = 2.25×10 <br>
 -6) genes. Out of 173 unique PSA-associated genes across analyses, we replicated 151 (87.3%) in TWAS of 209,318 PCa-free individuals from the Million Veteran Program. Based on conditional analyses, we found 20 genes (11 single-tissue, nine cross-tissue) that were associated with PSA levels in the discovery TWAS that were not attributable to a lead variant from a genome-wide association study (GWAS). Ten of these 20 genes replicated, and two of the replicated genes had colocalization probability &gt; 0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.<br>
 </p>}},
  author       = {{Chen, Dorothy M and Dong, Ruocheng and Kachuri, Linda and Hoffmann, Thomas and Jiang, Yu and Berndt, Sonja I and Shelley, John P and Schaffer, Kerry R and Machiela, Mitchell J and Freedman, Neal D and Huang, Wen-Yi and Li, Shengchao A and Lilja, Hans and Justice, Amy and Madduri, Ravi and Rodriguez, Alex and Van Den Eeden, Stephen K and Chanock, Stephen and Haiman, Christopher A and Conti, David V and Klein, Robert J and Mosley, Jonathan D and Witte, John S and Graff, Rebecca E}},
  issn         = {{2666-2477}},
  language     = {{eng}},
  month        = {{06}},
  publisher    = {{Elsevier}},
  series       = {{Human Genetics and Genomics Advances}},
  title        = {{Transcriptome-Wide Association Analysis Identifies Candidate Susceptibility Genes for Prostate-Specific Antigen Levels in Men Without Prostate Cancer}},
  url          = {{http://dx.doi.org/10.1016/j.xhgg.2024.100315}},
  doi          = {{10.1016/j.xhgg.2024.100315}},
  year         = {{2024}},
}