Common variants at five new loci associated with early-onset inflammatory bowel disease

Abstract

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.

Figure 1

Overview of genome-wide association results. (a–c) Chromosomal plots of –logP against genomic location for discovery scans in the early-onset DC-CD (a), DC-UC (b) and DC-IBD (c) cohorts. Red and blue dotted lines represent thresholds for genome-wide significant (P = 1 × 10⁻⁷) and suggestive (P = 1 × 10⁻⁶) signals, respectively. Loci on 16p11, 22q12 and 2q37 emerged from these analyses as suggestive signals and were validated in the follow-up cohorts RC1 and RC2-CD. The following signals did not replicate or show significance in the meta-analysis: 1q22 (CD), 10q25 (UC), 16q21 (UC), 18q12 (UC), 8q24 (IBD) and 15q22 (IBD). The remaining loci have been previously identified in majority adult-onset genome scans of Crohn’s disease and ulcerative colitis. Loci on 22q12 and 20q13 were identified in a previous early-onset IBD scan involving a subset of the cohort analyzed in this study.

Figure 2

Colonic and LCL mRNA expression of genes in significantly associated loci. The A allele of rs1968752 confers risk in our early-onset Crohn’s disease and IBD cohorts (OR = 1.23 (1.12–1.40)). rs1968752 lies in a block of LD containing the IL27 gene. (a) Cell lines from individuals (n = 5) with the A/A genotype at rs1968752 have over 90% decrease in IL27 gene expression as compared with those with the C/C genotype. (b) IL27 colonic expression was significantly lower in samples obtained from individuals with early-onset Crohn’s disease and ulcerative colitis cases than in normal tissue. (c,d) Expression of both SULT1A1 (c) and SULT1A2 (d) genes (also in the IL27 locus) was also significantly lower in Crohn’s disease and ulcerative colitis tissue than in normal tissue. (e,f) Expression of putative IBD gene MTMR3 at 22q12 (e) and the putative ulcerative colitis gene CAPN10 at 2q37 (f) was significantly lower in ulcerative colitis tissue than in normal tissue. All significant expression effects were found to be independent of treatment and histological inflammation score (data not shown). Error bars represent s.e.m.