title: Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans.
abstract: Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory.
authors.forename: Ali
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authors.lastname: Amin Al Olama
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Tokhir
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authors.lastname: Dadaev
authors.affiliation: Department of Urology, Norris Comprehensive Cancer Center, Keck School of Medicine, USC, Los Angeles, CA, USA, Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, USC, Los Angeles, CA, USA.
authors.forename: Dennis J
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authors.affiliation: Medical College, Xiamen University, Xiamen, China.
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authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Daniel
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authors.lastname: Leongamornlert
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Edward J
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authors.lastname: Saunders
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.
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authors.lastname: Stephens
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Clara
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authors.lastname: Cieza-Borrella
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Ian
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authors.lastname: Whitmore
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory.
authors.forename: Sara
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authors.affiliation: Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, VIC, Australia, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health.
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authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.
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authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
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authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Fredrik
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authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden, Department of Clinical Sciences, Danderyds Hospital, Stockholm, Sweden.
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authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, USC, Los Angeles, CA, USA.
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authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, USC, Los Angeles, CA, USA.
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authors.affiliation: Department of Medical Biochemistry and Genetics Institute of Biomedicine, University of Turku, Turku, Finland, BioMediTech, University of Tampere and FimLab Laboratories, Tampere, Finland.
authors.forename: Johanna
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authors.lastname: Schleutker
authors.affiliation: BioMediTech, University of Tampere and FimLab Laboratories, Tampere, Finland.
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authors.affiliation: Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, Strangeways Laboratory, Department of Applied Health Research, University College London, London, UK.
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authors.affiliation: Department of Urology, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Munich, Germany.
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authors.affiliation: International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
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authors.affiliation: Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA, George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA.
authors.forename: Lisa
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authors.affiliation: Department of Urology and Alexandrovska University Hospital, Medical University, Sofia, Bulgaria.
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authors.affiliation: Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University, Sofia, Bulgaria.
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authors.affiliation: The University of Surrey, Guildford, Surrey, UK.
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authors.affiliation: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Department of Genetic Medicine and Development, University of Geneva, Switzerland and.
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authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory.
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authors.affiliation: Department of Urology, Norris Comprehensive Cancer Center, Keck School of Medicine, USC, Los Angeles, CA, USA, Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, USC, Los Angeles, CA, USA.
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authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK, zsofia.kote-jarai@icr.ac.uk.
authors.forename: Zsofia
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mesh_terms: D002874:Chromosome Mapping / Q000379:methods*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*; D044465:White People / Q000235:genetics*