Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions
Year: 2015
Type: article
Study design: Observational Study
Abstract: Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10(-4)-5.6 × 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10(-6)) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddv269
Authors: Ying Han, Dennis J. Hazelett, Fredrik Wiklund, Fredrick R. Schumacher, Daniel O. Stram, Sonja I. Berndt, Zhaoming Wang, Kristin A. Rand, Robert N. Hoover, Mitchell J. Machiela, Merideth Yeager, Laurie Burdette, Charles C. Chung, Amy Hutchinson, Kai Yu, Jianfeng Xu, Ruth C. Travis, Timothy J. Key, Afshan Siddiq, Federico Canzian, Atsushi Takahashi, Michiaki Kubo, Janet L. Stanford, Suzanne Kolb, Susan M. Gapstur, W. Ryan Diver, Victoria L. Stevens, Sara S. Strom, Curtis A. Pettaway, Ali Amin Al Olama, Zsofia Kote-Jarai, Rosalind A. Eeles, Edward D. Yeboah, Yao Tettey, Richard B. Biritwum, Andrew A. Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Anand P. Chokkalingam, William B. Isaacs, Constance Chen, Sara Lindstrom, Loic Le Marchand, Edward L. Giovannucci, Mark Pomerantz, Henry Long, Fugen Li, Jing Ma, Meir Stampfer, Esther M. John, Sue A. Ingles, Rick A. Kittles, Adam B. Murphy, William J. Blot, Lisa B. Signorello, Wei Zheng, Demetrius Albanes, Jarmo Virtamo, Stephanie Weinstein, Barbara Nemesure, John Carpten, M. Cristina Leske, Suh-Yuh Wu, Anselm J. M. Hennis, Benjamin A. Rybicki, Christine Neslund-Dudas, Ann W. Hsing, Lisa Chu, Phyllis J. Goodman, Eric A. Klein, S. Lilly Zheng, John S. Witte, Graham Casey, Elio Riboli, Qiyuan Li, Matthew L. Freedman, David J. Hunter, Henrik Gronberg, Michael B. Cook, Hidewaki Nakagawa, Peter Kraft, Stephen J. Chanock, Douglas F. Easton, Brian E. Henderson, Gerhard A. Coetzee, David V. Conti, Christopher A. Haiman
Institutions: Karolinska Institutet, USC Norris Comprehensive Cancer Center, National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Science Applications International Corporation (United States), Endeavor Health, University of Oxford, German Cancer Research Center, University of Washington, Fred Hutch Cancer Center, American Cancer Society, The University of Texas MD Anderson Cancer Center, University of Cambridge, Institute of Cancer Research, National Health Service, Royal Marsden NHS Foundation Trust, University of Ghana, Korle Bu Teaching Hospital, Westat (United States), University of California, Berkeley, Johns Hopkins University, Johns Hopkins Hospital, University of Hawaii Cancer Center, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard University, Cancer Prevention Institute of California, Stanford Cancer Institute, Stanford University, University of Arizona, University of Arizona Cancer Center, Northwestern University, Vanderbilt University, International Epidemiology Institute, Finnish Institute for Health and Welfare, Stony Brook University, Translational Genomics Research Institute, University of the West Indies, Henry Ford Health, Henry Ford Hospital, Cleveland Clinic, Wake Forest University Health Sciences, Wake Forest University, University of California, San Francisco, Imperial College London, Xiamen University, RIKEN Center for Integrative Medical Sciences, University of Southern California
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funders: U.S. Department of Health and Human Services, Petrus och Augusta Hedlunds Stiftelse, Swedish Cancer Foundation, Cancer Research UK, Ministerio de Economía y Competitividad, Stockholms Läns Landsting, Vetenskapsrådet, National Institutes of Health, U.S. Public Health Service, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Environmental Health Sciences, National Center for Chronic Disease Prevention and Health Promotion
Awards: G1148307873, Southern Community Cohort Study, G1364610698, ENVIRONMENTAL &GENETIC DETERMINANTS OF PROSTATE CANCER, G1590068161, The Howard University SCORE Program, G1621215609, G1632577609, G1740625458, G1798569254, PROSTATE CANCER IN RELATION TO VASECTOMY, G1932976417, G2036036603, G2076485198, G2079028289, G2089819271, G216524704, G2242167451, G2313542652, #14: Residual Tissue Repository to Create HIV Cancer Tumor Tissue Microrarrays , G2349108260, MD Anderson Cancer Center Prostate Cancer SPORE, GENETIC POLYMORPHISMS AND PROSTATE CANCER RISK, G2548880556, G268454541, G2787837681, FOLLOW-UP OF THE ALPHA-TOCOPHEROL, BETA-CAROTENE CANCER PREVENTION (ATBC) STUDY , G2851966638, G286522202, G2985633519, GENETIC SUSCEPTIBILITY TO CANCER IN MULTIETHNIC COHORTS, PCPT and SELECT cohorts: Core Infrastructure Support for Cancer Research, G315517791, G3157549237, G3276551827, G3312934439, G3336502132, Genetic Epidemiology of Prostate Cancer Risk and Progression, G3398637311, G3430965699, G3437244150, G3491934775, U S-FINLAND STUDIES OF NUTRITION AND CANCER, G3569180201, Elucidating Loci Involved in Prostate Cancer Suceptibility, G3843026767, G3948222162, G395156118, G4015216323, G4063614301, G4146105916, G4192692896, G4309359879, G4407166175, G4450071017, G4494057802, G4513176822, Genome Wide Association Coordinating Center, Characterizing Genetic Susceptibility to Breast and Prostate Cancer; the BPC3, G4954491483, G5070257806, G5101912108, A NESTED CASE-CONTROL STUDY OF PROSTATE CARCINOGENESIS, G519175825, Prostate Cancer Risk Enhancers, G5357596128, G543148253, Mechanisms and Prevention of Environmental Disease, G557084418, G5654214539, G5664723454, G589878898, G6124801312, G6191305262, G6195211026, G6386128873, G639206035, NSAIDS and Other Medications in Prostate Cancer Etiology, G650037044, G6703222393, G6723261869, G675132270, G6838805842, G697149933, G7238814555, G725763919, G7278087418, Characterizing Genetic Susceptibility to Breast and Prostate Cancer; the BPC3, G7605512422, G767466929, G7697152668, G828535024, G8286131369, G8561355530, G8850026470, G894009200, G9000216949, G9000286278, G9000307018, The Robert H. Lurie Comprehensive Cancer Center
OpenAlex ID: W1928032004