Karina Dalsgaard Sørensen

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Tokhir Dadaev, The Institute of Cancer Research: Royal Cancer Hospital, 123 Old Brompton Road, London SW7 3RP, UK.
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  • Edward J Saunders, The Institute of Cancer Research: Royal Cancer Hospital, 123 Old Brompton Road, London SW7 3RP, UK.
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  • Paul J Newcombe, MRC Biostatistics Unit, University of Cambridge, Robinson Way, Cambridge, CB2 0SR, UK.
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  • Ezequiel Anokian, The Institute of Cancer Research: Royal Cancer Hospital, 123 Old Brompton Road, London SW7 3RP, UK.
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  • Daniel A Leongamornlert, Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
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  • Mark N Brook, The Institute of Cancer Research: Royal Cancer Hospital, 123 Old Brompton Road, London SW7 3RP, UK.
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  • Clara Cieza-Borrella, The Institute of Cancer Research: Royal Cancer Hospital, 123 Old Brompton Road, London SW7 3RP, UK.
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  • Martina Mijuskovic, The Institute of Cancer Research: Royal Cancer Hospital, 123 Old Brompton Road, London SW7 3RP, UK.
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  • Sarah Wakerell, The Institute of Cancer Research: Royal Cancer Hospital, 123 Old Brompton Road, London SW7 3RP, UK.
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  • Ali Amin Al Olama, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK.
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  • Fredrick R Schumacher, Seidman Cancer Center, University Hospitals, Cleveland, OH, 44106, USA.
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  • Sonja I Berndt, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
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  • Sara Benlloch, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, CB1 8RN, UK.
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  • Mahbubl Ahmed, The Institute of Cancer Research: Royal Cancer Hospital, 123 Old Brompton Road, London SW7 3RP, UK.
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  • Chee Goh, The Institute of Cancer Research: Royal Cancer Hospital, 123 Old Brompton Road, London SW7 3RP, UK.
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  • Xin Sheng, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.
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  • Zhuo Zhang, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.
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  • Kenneth Muir, Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom.
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  • Koveela Govindasami, The Institute of Cancer Research: Royal Cancer Hospital, 123 Old Brompton Road, London SW7 3RP, UK.
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  • Artitaya Lophatananon, Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom.
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  • Victoria L Stevens, Epidemiology Research Program, American Cancer Society, 250 Williams Street, Atlanta, GA, 30303, USA.
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  • Susan M Gapstur, Epidemiology Research Program, American Cancer Society, 250 Williams Street, Atlanta, GA, 30303, USA.
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  • Brian D Carter, Epidemiology Research Program, American Cancer Society, 250 Williams Street, Atlanta, GA, 30303, USA.
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  • Catherine M Tangen, SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
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  • Phyllis Goodman, SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
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  • Ian M Thompson, CHRISTUS Santa Rosa Hospital - Medical Center, San Antonio, TX, 78229, USA.
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  • Jyotsna Batra, Translational Research Institute, Brisbane, QLD, 4102, Australia.
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  • Suzanne Chambers, Cancer Council Queensland, 553 Gregory Tce, Fortitude Valley, QLD 4006, Australia. Electronic address: dannyyoulden@cancerqld.org.au.
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  • Leire Moya, Translational Research Institute, Brisbane, QLD, 4102, Australia.
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  • Judith Clements, Translational Research Institute, Brisbane, QLD, 4102, Australia.
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  • Lisa Horvath, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia.
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  • Wayne Tilley, Dame Roma Mitchell Cancer Research Centre, University of Adelaide, Adelaide, SA, 5005, Australia.
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  • Gail Risbridger, Prostate Cancer Translational Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
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  • Henrik Gronberg, Department of Epidemiology and Biostatistics, Drexel University School of Public Health, Philadelphia, Pennsylvania 19104 and Department of Medical Epidemiology and Biostatistics and Department of Public Health Sciences, Karolinska Institute, SE 171-77 Stockholm, Sweden.
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  • Markus Aly, Department of Molecular Medicine and Surgery, Karolinska Institutet, and Department of Urology, Karolinska University Hospital, 171 76, Stockholm, Sweden.
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  • Tobias Nordström, Department of Clinical Sciences at Danderyd Hospital, Karolinska Institutet, 182 88, Stockholm, Sweden.
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  • Paul Pharoah, Centre for Cancer Genetic Epidemiology, Department of Oncology, Strangeways Laboratory, University of Cambridge, Cambridge, CB1 8RN, UK.
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  • Nora Pashayan, Department of Applied Health Research, University College London, London, WC1E 7HB, UK.
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  • Johanna Schleutker, Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, 20521, Turku, Finland.
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  • Teuvo L J Tammela, Department of Urology, Tampere University Hospital, University of Tampere, Kalevantie 4, FI-33014, Tampere, Finland.
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  • Csilla Sipeky, Institute of Biomedicine, University of Turku, FI-20014, Turku, Finland.
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  • Anssi Auvinen, Department of Epidemiology, School of Health Sciences, University of Tampere, FI-33014, Tampere, Finland.
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  • Demetrius Albanes, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
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  • PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium

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.

Original languageEnglish
Article number2256
JournalNature Communications
Volume9
Issue1
Number of pages19
ISSN2041-1723
DOIs
Publication statusPublished - 1 Dec 2018

    Research areas

  • ANNOTATION, BAYESIAN FRAMEWORK, ELEMENTS, GENETIC ASSOCIATION, GENOME-WIDE ASSOCIATION, JOINT ANALYSIS, MODEL SELECTION, RISK LOCI, STATISTICS, VARIABLE-SELECTION

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