Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions.
- Department of Preventive Medicine, Keck School of Medicine.
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
- Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center.
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, Cancer Genomics Research Laboratory, NCI-DCEG, SAIC-Frederick Inc., Frederick, MD, USA.
- Cancer Genomics Research Laboratory, NCI-DCEG, SAIC-Frederick Inc., Frederick, MD, USA.
- Program for Personalized Cancer Care and Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA.
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
- Department of Genomics of Common Disease, School of Public Health.
- Genomic Epidemiology Group, German Cancer Research Center, Heidelberg, Germany.
- Laboratory for Statistical Analysis.
- Laboratory for Genotyping Development.
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
- Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
- Department of Epidemiology.
- Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
- The Institute of Cancer Research, London, UK.
- The Institute of Cancer Research, London, UK, Royal Marsden National Health Services (NHS) Foundation Trust, London and Sutton, UK.
- Korle Bu Teaching Hospital, Accra, Ghana, University of Ghana Medical School, Accra, Ghana.
- Westat, Rockville, MD, USA.
- School of Public Health, University of California, Berkeley, CA, USA.
- James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institution, Baltimore, MD, USA.
- Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology.
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
- Department of Nutrition, Department of Epidemiology.
- Department of Medical Oncology.
- Department of Medical Oncology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
- Cancer Prevention Institute of California, Fremont, CA, USA, Division of Epidemiology, Department of Health Research and Policy, and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
- University of Arizona College of Medicine and University of Arizona Cancer Center, Tucson, AZ, USA.
- Department of Urology, Northwestern University, Chicago, IL, USA.
- International Epidemiology Institute, Rockville, MD, USA, Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
- Department of Preventive Medicine, Stony Brook University, Stony Brook, NY, USA.
- The Translational Genomics Research Institute, Phoenix, AZ, USA.
- Department of Preventive Medicine, Stony Brook University, Stony Brook, NY, USA, Chronic Disease Research Centre and Faculty of Medical Sciences, University of the West Indies, Bridgetown, Barbados.
- Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA.
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.
- Center for Cancer Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.
- Department of Epidemiology and Biostatistics, Institute for Human Genetics, University of California, San Francisco, CA, USA and.
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK.
- Medical College, Xiamen University, Xiamen 361102, China.
- Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
- Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.
- Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
- Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, haiman@usc.edu.
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.