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Chen, Dorothy MUniversity of California System
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Transcriptome-Wide Association Analysis Identifies Candidate Susceptibility Genes for Prostate-Specific Antigen Levels in Men Without Prostate Cancer
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LIBRIS-ID:oai:lup.lub.lu.se:82a47f36-ff9e-4c56-9074-0b9d7cbcf269
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https://lup.lub.lu.se/record/82a47f36-ff9e-4c56-9074-0b9d7cbcf269URI
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https://doi.org/10.1016/j.xhgg.2024.100315DOI
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Language:English
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Summary in:English
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Subject category:art swepub-publicationtype
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Subject category:ref swepub-contenttype
Notes
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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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Dong, RuochengStanford University
(author)
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Kachuri, LindaStanford University
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Hoffmann, ThomasUniversity of California System
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Jiang, YuUniversity of California System
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Berndt, Sonja INational Cancer Institute, USA
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Shelley, John PVanderbilt University Medical Center
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Schaffer, Kerry RVanderbilt University Medical Center
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Machiela, Mitchell JNational Cancer Institute, USA
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Freedman, Neal DNational Cancer Institute, USA
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Huang, Wen-YiNational Cancer Institute, USA
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Li, Shengchao ANational Cancer Institute, USA
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Lilja, HansLund University,Lunds universitet,Klinisk kemi, Malmö,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Clinical Chemistry, Malmö,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Memorial Sloan-Kettering Cancer Center(Swepub:lu)klke-hli
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Justice, AmyArgonne National Laboratory
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Madduri, RaviArgonne National Laboratory
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Rodriguez, AlexArgonne National Laboratory
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Van Den Eeden, Stephen KKaiser Permanente
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Chanock, StephenNational Cancer Institute, USA
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Haiman, Christopher AUniversity of Southern California
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Conti, David VUniversity of Southern California
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Klein, Robert JIcahn School of Medicine at Mount Sinai
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Mosley, Jonathan DVanderbilt University Medical Center
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Witte, John SStanford University
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Graff, Rebecca EUniversity of California System
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University of California SystemStanford University
(creator_code:org_t)
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In:Human Genetics and Genomics Advances2666-2477
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Chen, Dorothy M
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Dong, Ruocheng
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Kachuri, Linda
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Hoffmann, Thomas
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Jiang, Yu
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Berndt, Sonja I
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Shelley, John P
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Schaffer, Kerry ...
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Machiela, Mitche ...
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Freedman, Neal D
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Huang, Wen-Yi
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Li, Shengchao A
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Lilja, Hans
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Justice, Amy
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Madduri, Ravi
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Rodriguez, Alex
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Van Den Eeden, S ...
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Chanock, Stephen
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Haiman, Christop ...
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Conti, David V
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Klein, Robert J
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Mosley, Jonathan ...
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Witte, John S
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Graff, Rebecca E
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