한국인 염증성 장질환 감수성 유전자 발굴

Abstract

Inflammatory bowel disease (IBD), represented by Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease of the gastrointestinal tract. CD is characterized by transmural granulomatous inflammation which affects any part of the gastrointestinal tract, whereas UC is characterized by mucosal inflammation limited to colon. IBD is thought to develop due to dysregulated mucosal immune responses to gut flora in genetically susceptible individuals. Recent meta-analysis of genome-wide association studies (GWASs) of IBD performed in populations of European origin identified over 240 susceptibility loci, improving our understanding of IBD genetics. However, identified common variants account for only a fraction of IBD heritability. Moreover, despite of observed differences in clinical characteristics of IBD among different ethnicities, there have been limited studies in non-European populations. To identify additional IBD susceptibility loci in Asians, we performed a GWAS using 1,726 IBD cases and 378 healthy controls genotyped using the Infinium Asian Screening Array-24 v1.0 (Illumina), and combined our previous GWAS dataset consisted of 1,469 IBD cases and 4,041 healthy controls using an inverse-variance fixed-effects meta-analysis in Korean population. We selected 10 novel candidate loci applying a threshold of Pmeta < 1 × 10-6, and performed replication study using an additional 1,088 IBD cases and 845 controls. The meta-analysis of two GWAS datasets in Koreans identified 1 novel locus for ulcerative colitis at rs76227733 on 10q24 (Pcombined = 6.56 × 10-9) and 2 novel loci for CD at rs2240751 on 19p13 (Pcombined = 3.03 × 10-8) and rs6936629 in on 6q22 (Pcombined = 3.63 × 10-8). Additionally, we examined 245 previously established loci in Europeans in our meta-analysis data. A total of 33 established loci were replicated in Korean population. To gain insight into the potential functional roles of the identified loci, we performed RNA-sequencing using whole blood tissues of 101 Korean CD patients, and then built the eQTL database (http://asan.crohneqtl.com/). In the eQTL analysis, we identified 135,164 cis-eQTLs and 3,816 eGenes with the false discovery rate < 0.05. Integrated analysis of the extended GWAS and eQTL data revealed two target genes at two previously reported loci for IBD including TNFSF15 at 9q32 and GPR35 at 2q37. The IBD risk alleles from the two loci were associated with lower expression of TNFSF15 or GPR35 than protective alleles. To compare biological pathways associated with CD or UC between Asians and Europeans, we performed pathway analysis using meta-analysis of two GWAS datasets in Koreans and summary statistics of GWAS in Europeans. In the case of CD, MHC and antigenic stimulus-related pathways were significant in Korean, whereas cytokine and transcription factor-related pathways were significant in European. In the case of UC, MHC and antigen binding-related pathways identified in the Korean population were also significant in the European population. We also estimated phenotypic variance of CD or UC based on the polygenic risk score (PRS). Variance explained by PRS derived from Korean data explained up to 14% of variance of CD, whereas those derived from European data explained 10%. For UC, variance explained by PRSEUR of 12% was better than those explained by PRSKOR of 7%. We identified 3 novel susceptibility loci for IBD and replicated 33 previously reported loci, indicating distinct as well as common pathways associated with IBD in Europeans and Asians. The current study increased the number of IBD susceptibility loci in Koreans to 54. Our pathway analysis showed major differences in biological pathways associated with CD between East Asians and Europeans. In addition, PRS analysis showed that PRS of CD based on European data is less predictive in Koreans. These findings are consistent with our previous report that the effects for CD were more population-specific than for UC, emphasizing on diversity in genetic research.