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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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- Chen, Dorothy M (author)
- University of California System
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- Dong, Ruocheng (author)
- Stanford University
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- Kachuri, Linda (author)
- Stanford University
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- Hoffmann, Thomas (author)
- University of California System
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- Jiang, Yu (author)
- University of California System
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- Berndt, Sonja I (author)
- National Cancer Institute, USA
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- Shelley, John P (author)
- Vanderbilt University Medical Center
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- Schaffer, Kerry R (author)
- Vanderbilt University Medical Center
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- Machiela, Mitchell J (author)
- National Cancer Institute, USA
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- Freedman, Neal D (author)
- National Cancer Institute, USA
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- Huang, Wen-Yi (author)
- National Cancer Institute, USA
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- Li, Shengchao A (author)
- National Cancer Institute, USA
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- Lilja, Hans (author)
- Lund 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
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- Justice, Amy (author)
- Argonne National Laboratory
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- Madduri, Ravi (author)
- Argonne National Laboratory
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- Rodriguez, Alex (author)
- Argonne National Laboratory
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- Van Den Eeden, Stephen K (author)
- Kaiser Permanente
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- Chanock, Stephen (author)
- National Cancer Institute, USA
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- Haiman, Christopher A (author)
- University of Southern California
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- Conti, David V (author)
- University of Southern California
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- Klein, Robert J (author)
- Icahn School of Medicine at Mount Sinai
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- Mosley, Jonathan D (author)
- Vanderbilt University Medical Center
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- Witte, John S (author)
- Stanford University
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- Graff, Rebecca E (author)
- University of California System
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(creator_code:org_t)
- English.
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In: Human Genetics and Genomics Advances. - 2666-2477.
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http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
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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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
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- By the author/editor
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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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show more...
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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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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Human Genetics a ...
- By the university
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Lund University