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

Hum Mol Genet
Authors
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 (r(2) = 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.

Year of Publication
2016
Journal
Hum Mol Genet
Volume
25
Issue
11
Pages
2349-2359
Date Published
2016 Jun 01
ISSN
1460-2083
DOI
10.1093/hmg/ddw087
PubMed ID
27005424
PubMed Central ID
PMC5081051
Links
Grant list
HHSN261201000035C / PC,CA / None / None
U01 CA074799 / CA / NCI NIH HHS / United States
MC_PC_U127527198 / Medical Research Council / United Kingdom
U24 CA074783 / CA / NCI NIH HHS / United States
N01 CN067009 / CN / NCI NIH HHS / United States
12076 / Cancer Research UK / United Kingdom
U24 CA074794 / CA / NCI NIH HHS / United States
N01PC35137 / CA / NCI NIH HHS / United States
U24 CA074806 / CA / NCI NIH HHS / United States
HHSN261201300009C / CA / NCI NIH HHS / United States
U24 CA097735 / CA / NCI NIH HHS / United States
U01 CA074794 / CA / NCI NIH HHS / United States
HHSN261201300011C / RC / CCR NIH HHS / United States
HHSN261201300012I / CA / NCI NIH HHS / United States
R01 CA143237 / CA / NCI NIH HHS / United States
N01PC35142 / CA / NCI NIH HHS / United States
MR/K018647/1 / Medical Research Council / United Kingdom
K02 AA018755 / AA / NIAAA NIH HHS / United States
HHSN261201300021C / CA / NCI NIH HHS / United States
HHSN261201000035I / CA / NCI NIH HHS / United States
K05 AA000145 / AA / NIAAA NIH HHS / United States
HHSN261201000034C / CA / NCI NIH HHS / United States
U01 CA097735 / CA / NCI NIH HHS / United States
R01 AA012502 / AA / NIAAA NIH HHS / United States
UM1 CA167551 / CA / NCI NIH HHS / United States
U01 CA122839 / CA / NCI NIH HHS / United States
U58 DP003862 / DP / NCCDPHP CDC HHS / United States
U01 CA074783 / CA / NCI NIH HHS / United States
U24 CA074799 / CA / NCI NIH HHS / United States
U01 CA074806 / CA / NCI NIH HHS / United States
U24 CA074800 / CA / NCI NIH HHS / United States
HHSN261201000121C / CP / NCI NIH HHS / United States
U01 CA074800 / CA / NCI NIH HHS / United States
R37 AA012502 / AA / NIAAA NIH HHS / United States