title: Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease.
abstract: To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P = 3.15 × 10-8, odds ratio = 1.10, 95% confidence interval = 1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r2= 0.90, D' = 0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR]) < 0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD.
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
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authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
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authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit Department of Medical and Clinical Genetics, Medicum.
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authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit Department of Medical and Clinical Genetics, Medicum.
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authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit Department of Medical and Clinical Genetics, Medicum.
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authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit Department of Medical and Clinical Genetics, Medicum.
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authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit Department of Medical and Clinical Genetics, Medicum.
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authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit Department of Medical and Clinical Genetics, Medicum.
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authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit Department of Medical and Clinical Genetics, Medicum.
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authors.affiliation: Genome-Scale Biology Research Program, Research Programs Unit Department of Medical and Clinical Genetics, Medicum.
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authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00014, Finland.
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authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00014, Finland National Institute for Health and Welfare, Helsinki 00271, Finland.
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authors.affiliation: National Institute for Health and Welfare, Helsinki 00271, Finland.
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authors.affiliation: National Institute for Health and Welfare, Helsinki 00271, Finland.
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authors.affiliation: National Institute for Health and Welfare, Helsinki 00271, Finland.
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authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00014, Finland.
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authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00014, Finland Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
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authors.affiliation: Department of Surgery, Abdominal Center, Helsinki University Hospital, Helsinki 00029, Finland.
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authors.affiliation: Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford OX3 7BN, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford OX3 7BN, UK.
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mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D044466:Asian People; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000473:pathology; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People
chemical_list: D051017:Apoptosis Regulatory Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; C495444:PNKD protein, human; C560419:TMBIM1 protein, human