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

Hum Mol Genet. 2016 Jun 1;25(11):2349-2359. doi: 10.1093/hmg/ddw087. Epub 2016 Mar 22.

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.

Publication types

  • Meta-Analysis

MeSH terms

  • Apoptosis Regulatory Proteins / genetics*
  • Asian People
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Female
  • Genetic Pleiotropy
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Inflammatory Bowel Diseases / genetics*
  • Inflammatory Bowel Diseases / pathology
  • Linkage Disequilibrium
  • Male
  • Membrane Proteins / genetics*
  • Muscle Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • White People

Substances

  • Apoptosis Regulatory Proteins
  • Membrane Proteins
  • Muscle Proteins
  • PNKD protein, human
  • TMBIM1 protein, human

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