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

Human Molecular Genetics, 2016, Vol. 25, No. 11 2349–2359 doi: 10.1093/hmg/ddw087 Advance Access Publication Date: 22 March 2016 Association Studies Article ASSOCIATION STUDIES ARTICLE Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease 1 Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK, 2Genome-Scale Biology Research Program, Research Programs Unit, 3Department of Medical and Clinical Genetics, Medicum and 4Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00014, Finland, 5National € lsan Research Centre, Helsinki 00250, Finland, Institute for Health and Welfare, Helsinki 00271, Finland, 6Folkha 7 Unit of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki 00014, Finland, 8Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki 00130, Finland, 9School of Health Sciences, University of Tampere, Tampere 33014, Finland, † These authors contributed equally to this work. Present address: Human Longevity Inc., La Jolla, CA 92121, USA. Received: October 16, 2015. Revised: February 5, 2016. Accepted: March 14, 2016 ‡ C The Author 2016. Published by Oxford University Press. V This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 2349 Giulia Orlando1,†, Philip J. Law1,†, Kimmo Palin2,3,†, Sari Tuupanen2,3, € nninen2,3, Tatiana Cajuso2,3, Alexandra Gylfe2,3,‡, Ulrika A. Ha Tomas Tanskanen2,3, Johanna Kondelin2,3, Eevi Kaasinen2,3, Antti-Pekka Sarin4, Jaakko Kaprio4,5, Johan G. Eriksson6,7, Harri Rissanen5, Paul Knekt5, Eero Pukkala8,9, Pekka Jousilahti5, Veikko Salomaa5, € rvinen13, Samuli Ripatti4, Aarno Palotie4,10,11,12, Heikki Ja Laura Renkonen-Sinisalo14, Anna Lepistö14, Jan Böhm15, Jukka-Pekka Mecklin16, Nada A. Al-Tassan17, Claire Palles18, Lynn Martin18, Ella Barclay18, Albert Tenesa19,20, Susan Farrington19, Maria N. Timofeeva19, Brian F. Meyer17, Salma M. Wakil17, Harry Campbell21, Christopher G. Smith22, Shelley Idziaszczyk22, Timothy S. Maughan23, Richard Kaplan24, Rachel Kerr25, David Kerr26, Daniel D. Buchanan27,28, Aung Ko Win28, John Hopper28, Mark Jenkins28, Noralane M. Lindor29, Polly A. Newcomb30, Steve Gallinger31, David Conti32, Fred Schumacher32, Graham Casey32, Jussi Taipale2,3,33, Jeremy P. Cheadle22, Malcolm G. Dunlop19, Ian P. Tomlinson18, Lauri A. Aaltonen2,3 and Richard S. Houlston1,* 2350 | Human Molecular Genetics, 2016, Vol. 25, No. 11 10 *To whom correspondence should be addressed. Tel: þ44 (0)208722 4175; Fax: þ44 (0)7224365; Email: 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 ¼ 3.15  108, odds ratio ¼ 1.10, 95% confidence interval ¼ 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 ¼ 0.90, D0 ¼ 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. Introduction Colorectal cancer (CRC), a leading cause of cancer-related death worldwide, has a heritable basis (1,2). Recent genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) influencing CRC risk thereby vindicating the assertion that part of the heritable risk is polygenic (3–7). These studies have also provided insights into the biology of CRC, highlighting the importance of bone morphogenetic protein signalling pathway genes (BMP2, BMP4, GREM1 and SMAD7) (4,5), candidate genes (CDH1), as well as genes not previously implicated in CRC (POLD3, TERC, CDKN1A, VIT1A and SHROOM2) (6,7). It is well established that inflammatory bowel disease (IBD), which primarily presents as Crohn’s disease or ulcerative colitis, is associated with an increased CRC risk (8–11). Despite IBD being strongly heritable (12), little evidence for shared genetic susceptibility or differential effects of genetic variation on IBD and CRC risk has been reported, although the presumption is that the direction of effect will be consistent between both diseases. A failure to uncover pleiotropy may be reflective of a lack of power of CRC GWAS conducted thus far. Indeed statistical modelling of GWAS data shows that although 19% of the heritability of CRC can be ascribed to common variation, only 10% of this is explained by currently identified risk SNPs (13). To empower the identification of new CRC susceptibility SNPs in persons of European ancestry, we conducted a genome-wide meta-analysis of a previously unreported GWAS with six published datasets in addition to independent replication totalling 13 810 cases and 21 754 controls. We report the identification of a new CRC risk association which also impacts on IBD risk. Extending our analysis to Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA, 11Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA, 12Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA, 13Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Helsinki 00029, Finland, 14Department of Surgery, Abdominal Center, Helsinki University Hospital, Helsinki € skyla € 40620, Finland, 00029, Finland, 15Department of Pathology, Central Finland Central Hospital, Jyva 16 € skyla € Central Hospital, University of Eastern Finland, Jyva € skyla € 40620, Finland, Department of Surgery, Jyva 17 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 12713, Saudi Arabia, 18 Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford OX3 7BN, UK, 19Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 (...truncated)