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

Autor:	Chen DM; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA., Dong R; Department of Epidemiology and Population Health, Stanford University, Stanford, CA, 94305, USA., Kachuri L; Department of Epidemiology and Population Health, Stanford University, Stanford, CA, 94305, USA.; Stanford Cancer Institute, Stanford University, Stanford, CA, 94305, USA., Hoffmann T; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA.; Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA., Jiang Y; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA., Berndt SI; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20814, USA., Shelley JP; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA., Schaffer KR; Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA., Machiela MJ; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20814, USA., Freedman ND; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20814, USA., Huang WY; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20814, USA., Li SA; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20814, USA., Lilja H; Departments of Pathology and Laboratory Medicine, Surgery, Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.; Department of Translational Medicine, Lund University, Malmö, 21428, Sweden., Van Den Eeden SK; Division of Research, Kaiser Permanente Northern California, Oakland, CA, 94612, USA., Chanock S; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20814, USA., Haiman CA; Center for Genetic Epidemiology, Department of Population and Preventive Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90032, USA.; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA., Conti DV; Center for Genetic Epidemiology, Department of Population and Preventive Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90032, USA.; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA., Klein RJ; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA., Mosley JD; Departments of Internal Medicine and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA., Witte JS; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA.; Department of Epidemiology and Population Health, Stanford University, Stanford, CA, 94305, USA.; Departments of Biomedical Data Science and Genetics (by courtesy), Stanford University, Stanford, CA, 94305, USA., Graff RE; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2023 May 05. Date of Electronic Publication: 2023 May 05.
DOI:	10.1101/2023.05.04.23289526
Abstrakt:	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. Competing Interests: Declaration of Interests: JSW is a non-employee, cofounder of Avail Bio. HL is named on a patent for assays to measure intact prostate-specific antigen and a patent for a statistical method to detect prostate cancer commercialized by OPKO Health (4KScore). HL receives royalties from sales of the assay and has stock in OPKO Health. HL serves on the Scientific Advisory Board for Fujirebio Diagnostics Inc and owns stock in Diaprost AB and Acousort AB.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu