Title

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Authors

Tokhir Dadaev, The Institute of Cancer Research, London, SW7 3RP, UK.
Edward J. Saunders, The Institute of Cancer Research, London, SW7 3RP, UK.
Paul J. Newcombe, MRC Biostatistics Unit, University of Cambridge, Robinson Way, Cambridge, CB2 0SR, UK.
Ezequiel Anokian, The Institute of Cancer Research, London, SW7 3RP, UK.
Daniel A. Leongamornlert, The Institute of Cancer Research, London, SW7 3RP, UK.
Mark N. Brook, The Institute of Cancer Research, London, SW7 3RP, UK.
Clara Cieza-Borrella, The Institute of Cancer Research, London, SW7 3RP, UK.
Martina Mijuskovic, The Institute of Cancer Research, London, SW7 3RP, UK.
Sarah Wakerell, The Institute of Cancer Research, London, SW7 3RP, UK.
Ali Amin Olama, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, CB1 8RN, UK.
Fredrick R. Schumacher, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, 44106-7219, USA.
Sonja I. Berndt, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
Sara Benlloch, The Institute of Cancer Research, London, SW7 3RP, UK.
Mahbubl Ahmed, The Institute of Cancer Research, London, SW7 3RP, UK.
Chee Goh, The Institute of Cancer Research, London, SW7 3RP, UK.
Xin Sheng, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.
Zhuo Zhang, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.
Kenneth Muir, Institute of Population Health, University of Manchester, Manchester, M13 9PL, UK.
Koveela Govindasami, The Institute of Cancer Research, London, SW7 3RP, UK.
Artitaya Lophatananon, Institute of Population Health, University of Manchester, Manchester, M13 9PL, UK.
Victoria L. Stevens, Epidemiology Research Program, American Cancer Society, 250 Williams Street, Atlanta, GA, 30303, USA.
Susan M. Gapstur, Epidemiology Research Program, American Cancer Society, 250 Williams Street, Atlanta, GA, 30303, USA.
Brian D. Carter, Epidemiology Research Program, American Cancer Society, 250 Williams Street, Atlanta, GA, 30303, USA.
Catherine M. Tangen, SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
Phyllis Goodman, SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
Ian M. Thompson, CHRISTUS Santa Rosa Hospital - Medical Center, San Antonio, TX, 78229, USA.
Jyotsna Batra, Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, 4059, Australia.
Suzanne Chambers, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, 4222, Australia.
Leire Moya, Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, 4059, Australia.
Judith Clements, Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, 4059, Australia.
Lisa Horvath, Chris O'Brien Lifehouse (COBLH), Camperdown, Sydney, NSW, 2010, Australia.
Wayne Tilley, Dame Roma Mitchell Cancer Research Centre, University of Adelaide, Adelaide, SA, 5005, Australia.
Gail Risbridger, Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia.

Document Type

Article

Publication Date

6-11-2018

Abstract

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

Publication Source (Journal or Book title)

Nature communications

First Page

2256

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