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

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility to screen for prostate cancer (PCa). We thus conducted a transcriptome-wide association study (TWAS) of PSA levels using genome-wide summary statistics from 95,768 PCa-free men, the MetaXcan framework, and gene prediction models trained in Genotype-Tissue Expression (GTEx) project data. Tissue-specific analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10e-6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61e-6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses that combined associations across 45 tissues identified 155 genes that were statistically significantly (p < 0.05/22,249 = 2.25e-6) associated with PSA levels. Based on conditional analyses that assessed whether TWAS associations were attributable to a lead GWAS variant, we found 20 novel genes (11 single-tissue, 9 cross-tissue) that were associated with PSA levels in the TWAS. Of these novel genes, five showed evidence of colocalization (colocalization probability > 0.5): EXOSC9, CCNA2, HIST1H2BN, RP11-182L21.6 , and RP11-327J17.2 . Six of the 20 novel genes are not known to impact PCa risk. These findings yield new hypotheses for genetic factors underlying PSA levels that should be further explored toward improving our understanding of PSA biology.

Dong, RuochengStanford University (författare)
Kachuri, LindaStanford University (författare)
Hoffmann, ThomasUniversity of California, San Francisco (författare)
Jiang, YuUniversity of California, San Francisco (författare)
Berndt, Sonja INational Cancer Institute, USA (författare)
Shelley, John PVanderbilt University Medical Center (författare)
Schaffer, Kerry RVanderbilt University Medical Center (författare)
Machiela, Mitchell JNational Cancer Institute, USA (författare)
Freedman, Neal DNational Cancer Institute, USA (författare)
Huang, Wen-Yi (författare)
Li, Shengchao A (författare)
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 (författare)
Van Den Eeden, Stephen K (författare)
Chanock, Stephen (författare)
Haiman, Christopher A (författare)
Conti, David V (författare)
Klein, Robert J (författare)
Mosley, Jonathan D (författare)
Witte, John S (författare)
Graff, Rebecca E (författare)
University of California, San FranciscoStanford University (creator_code:org_t)

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