Genome-wide association identifies multiple ulcerative colitis susceptibility loci

Abstract

Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.

Figure 1

(a) Cos-7 cells were transfected with pCMV-ORMDL3-GFP. After 24h, cells were fixed using 4% paraformaldehyde and subjected to immunostaining using anti-PDI antibodies as an ER marker. Fluorescence signals were acquired with a confocal microscope. Displayed images represent a single confocal section. (b) HEK293T cells were co-transfected with a firefly luciferase reporter p5xUPRE-GL3, renilla luciferase as transfection control and pCMV-3XHA or pCMV-ORMDL3-3XHA. After 24h, cells were left untreated or treated using 5μg/ml of tunicamycin or 10μM of thapsigargin for 6h. ORMDL3-3XHA was detected using an anti-HA antibody. Luciferase activities were measured to detect UPRE transcription activation. (c). HEK293T cells were co-transfected with plasmids encoding shRNA scramble or directed against ORMDL3, firefly luciferase reporter p5xUPRE-GL3 and renilla luciferase as transfection control. After 48h, cells were left untreated or treated using 5μg/ml of tunicamycin or 10μM of thasigargin. ORMDL3 expression was determined by quantitative RT-PCR (left). Luciferase activities were measured to detect UPRE transcription activation (right)