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

Giulia Orlando, Philip J. Law, Kimmo Palin, Sari Tuupanen, Alexandra Gylfe, Ulrika A. Hänninen, Tatiana Cajuso, Tomas Tanskanen, Johanna Kondelin, Eevi Kaasinen, Antti Pekka Sarin, Jaakko Kaprio, Johan G. Eriksson, Harri Rissanen, Paul Knekt, Eero Pukkala, Pekka Jousilahti, Veikko Salomaa, Samuli Ripatti, Aarno PalotieHeikki Järvinen, Laura Renkonen-Sinisalo, Anna Lepistö, Jan Böhm, Jukka Pekka Mecklin, Nada A. Al-Tassan, Claire Palles, Lynn Martin, Ella Barclay, Albert Tenesa, Susan Farrington, Maria N. Timofeeva, Brian F. Meyer, Salma M. Wakil, Harry Campbell, Christopher G. Smith, Shelley Idziaszczyk, Timothy S. Maughan, Richard Kaplan, Rachel Kerr, David Kerr, Daniel D. Buchanan, Aung Ko Win, John Hopper, Mark Jenkins, Noralane M. Lindor, Polly A. Newcomb, Steve Gallinger, David Conti, Fred Schumacher, Graham Casey, Jussi Taipale, Jeremy P. Cheadle, Malcolm G. Dunlop, Ian P. Tomlinson, Lauri A. Aaltonen, Richard S. Houlston

Research output: Contribution to journalArticle

21 Scopus citations

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=3.15x10-8, 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.

Original languageEnglish (US)
Pages (from-to)2349-2359
Number of pages11
JournalHuman molecular genetics
Volume25
Issue number11
DOIs
StatePublished - Jun 1 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease'. Together they form a unique fingerprint.

  • Cite this

    Orlando, G., Law, P. J., Palin, K., Tuupanen, S., Gylfe, A., Hänninen, U. A., Cajuso, T., Tanskanen, T., Kondelin, J., Kaasinen, E., Sarin, A. P., Kaprio, J., Eriksson, J. G., Rissanen, H., Knekt, P., Pukkala, E., Jousilahti, P., Salomaa, V., Ripatti, S., ... Houlston, R. S. (2016). Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease. Human molecular genetics, 25(11), 2349-2359. https://doi.org/10.1093/hmg/ddw087