Genome-wide association study of Crohn's disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations

Abstract

Objective: Crohn's disease (CD) is an intractable inflammatory bowel disease (IBD) of unknown cause. Recent meta-analysis of the genome-wide association studies (GWAS) and Immunochip data identified 163 susceptibility loci to IBD in Caucasians, however there are limited studies in other populations.

Methods: We performed a GWAS and two validation studies in the Korean population comprising a total of 2311 patients with CD and 2442 controls.

Results: We confirmed four previously reported loci: TNFSF15, IL23R, the major histocompatibility complex region, and the RNASET2-FGFR1OP-CCR6 region. We identified three new susceptibility loci at genome-wide significance: rs6856616 at 4p14 (OR=1.43, combined p=3.60×10(-14)), rs11195128 at 10q25 (OR=1.42, combined p=1.55×10(-10)) and rs11235667 at 11q13 (OR=1.46, combined p=7.15×10(-9)), implicating ATG16L2 and/or FCHSD2 as novel susceptibility genes for CD. Further analysis of the 11q13 locus revealed a non-synonymous single nucleotide polymorphism (SNP) (R220W/rs11235604) in the evolutionarily conserved region of ATG16L2 with stronger association (OR=1.61, combined p=2.44×10(-12)) than rs11235667, suggesting ATG16L2 as a novel susceptibility gene for CD and rs11235604 to be a potential causal variant of the association. Two of the three SNPs (rs6856616 (p=0.00024) and rs11195128 (p=5.32×10(-5))) showed consistent patterns of association in the International IBD Genetics Consortium dataset. Together, the novel and replicated loci accounted for 5.31% of the total genetic variance for CD risk in Koreans.

Conclusions: Our study provides new biological insight to CD and supports the complementary value of genetic studies in different populations.

Keywords: Crohn's Disease; Genetic Polymorphisms; IBD – Genetics; Inflammatory Bowel Disease; Linkage Disequilibrium.