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Hum Mol Genet. 2016 Jun 1;25(11):2349-2359. Epub 2016 Mar 22.

Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease.

Author information

1
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
2
Genome-Scale Biology Research Program, Research Programs Unit Department of Medical and Clinical Genetics, Medicum.
3
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00014, Finland.
4
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00014, Finland National Institute for Health and Welfare, Helsinki 00271, Finland.
5
Folkhälsan Research Centre, Helsinki 00250, Finland Unit of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki 00014, Finland.
6
National Institute for Health and Welfare, Helsinki 00271, Finland.
7
Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki 00130, Finland School of Health Sciences, University of Tampere, Tampere 33014, Finland.
8
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.
9
Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Helsinki 00029, Finland.
10
Department of Surgery, Abdominal Center, Helsinki University Hospital, Helsinki 00029, Finland.
11
Department of Pathology, Central Finland Central Hospital, Jyväskylä 40620, Finland.
12
Department of Surgery, Jyväskylä Central Hospital, University of Eastern Finland, Jyväskylä 40620, Finland.
13
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 12713, Saudi Arabia.
14
Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford OX3 7BN, UK.
15
Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK The Roslin Institute, University of Edinburgh, Easter Bush, Roslin EH25 9RG, UK.
16
Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK.
17
Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK.
18
Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
19
CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
20
MRC Clinical Trials Unit, Aviation House, London WC2B 6NH, UK.
21
Department of Oncology, Oxford Cancer Centre, Churchill Hospital.
22
Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 7LE, UK.
23
Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, Vic. 3010, Australia.
24
Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, Vic. 3010, Australia.
25
Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ 85259, USA.
26
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
27
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
28
Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA.
29
Genome-Scale Biology Research Program, Research Programs Unit Department of Medical and Clinical Genetics, Medicum Department of Biosciences and Nutrition, SciLife Center, Karolinska Institute, Stockholm, SE 141 83, Sweden.
30
Genome-Scale Biology Research Program, Research Programs Unit Genome-Scale Biology Research Program, Research Programs Unit.
31
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK richard.houlston@icr.ac.uk.

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.

PMID:
27005424
PMCID:
PMC5081051
DOI:
10.1093/hmg/ddw087
[Indexed for MEDLINE]
Free PMC Article

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