Transcriptome-wide association analysis identifies candidate susceptibility genes for prostate-specific antigen levels in men without prostate cancer Journal Article
| Authors: | Chen, D. M.; Dong, R.; Kachuri, L.; Hoffmann, T. J.; Jiang, Y.; Berndt, S. I.; Shelley, J. P.; Schaffer, K. R.; Machiela, M. J.; Freedman, N. D.; Huang, W. Y.; Li, S. A.; Lilja, H.; Justice, A. C.; Madduri, R. K.; Rodriguez, A. A.; Van Den Eeden, S. K.; Chanock, S. J.; Haiman, C. A.; Conti, D. V.; Klein, R. J.; Mosley, J. D.; Witte, J. S.; Graff, R. E. |
| Article Title: | Transcriptome-wide association analysis identifies candidate susceptibility genes for prostate-specific antigen levels in men without prostate cancer |
| Abstract: | Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide association study (GWAS) 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 a 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 GWAS. Ten of these 20 genes replicated, and two of the replicated genes had colocalization probability of >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. © 2024 The Authors |
| Keywords: | signal transduction; major clinical study; genetics; review; colorectal cancer; prostate specific antigen; quality control; chromosome; gene; ovary cancer; gene expression; statistics; genotype; genome-wide association study; lung cancer; data base; transcriptomics; prostate cancer; prostate-specific antigen; blood; prostate; screening; blood analysis; literature; fisher exact test; transcriptome; meta analysis; veteran; ethics; hispanic; data collection method; african; tissue culture; genotyping; gene ontology; european; data processing; replication study; human; article; prostate tissue; biobank; kegg; data accuracy; nf kb signaling; data availability; biological phenomena and functions concerning the entire organism; transcriptome-wide association study; data classification |
| Journal Title: | Human Genetics and Genomics Advances |
| Volume: | 5 |
| Issue: | 3 |
| ISSN: | 2666-2477 |
| Publisher: | Cell Press |
| Date Published: | 2024-07-18 |
| Start Page: | 100315 |
| Language: | English |
| DOI: | 10.1016/j.xhgg.2024.100315 |
| PUBMED: | 38845201 |
| PROVIDER: | scopus |
| PMCID: | PMC11262184 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- Source: Scopus |
