Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

Jimmy Z Liu, Suzanne van Sommeren, Hailiang Huang, Siew C Ng, Rudi Alberts, Atsushi Takahashi, Stephan Ripke, James C Lee, Luke Jostins, Tejas Shah, Shifteh Abedian, Jae Hee Cheon, Judy Cho, Naser E Dayani, Lude Franke, Yuta Fuyuno, Ailsa Hart, Ramesh C Juyal, Garima Juyal, Won Ho Kim, Andrew P Morris, Hossein Poustchi, William G Newman, Vandana Midha, Timothy R Orchard, Homayon Vahedi, Ajit Sood, Joseph Y Sung, Reza Malekzadeh, Harm-Jan Westra, Keiko Yamazaki, Suk-Kyun Yang, Jeffrey C Barrett, Behrooz Z Alizadeh, Miles Parkes, Thelma Bk, Mark J Daly, Michiaki Kubo, Carl A Anderson, and Rinse K Weersma. 2015. “Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.” Nat Genet, 47, 9, Pp. 979-986. Abstract

Ulcerative colitis and Crohn’s disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.

Differential effect of genetic burden on disease phenotypes in Crohn’s disease and ulcerative colitis: analysis of a North American cohort

Ashwin N Ananthakrishnan, Hailiang Huang, Deanna D Nguyen, Jenny Sauk, Vijay Yajnik, and Ramnik J Xavier. 2014. “Differential effect of genetic burden on disease phenotypes in Crohn’s disease and ulcerative colitis: analysis of a North American cohort.” Am J Gastroenterol, 109, 3, Pp. 395-400. Abstract

OBJECTIVES: Crohn’s disease (CD) and ulcerative colitis (UC) are chronic immunologically mediated diseases with a progressive relapsing remitting course. There is considerable heterogeneity in disease course and accurate prediction of natural history has been challenging. The phenotypic implication of increasing genetic predisposition to CD or UC is unknown. METHODS: The data source for our study was a prospective cohort of CD and UC patients recruited from a tertiary referral center. All patients underwent genotyping on the Illumina Immunochip. A genetic risk score (GRS) incorporating strength of association (log odds ratio) and allele dose for each of the 163 inflammatory bowel disease (IBD) risk loci was calculated and phenotypic associations examined across GRS quartiles.
RESULTS: Our study cohort included 1,105 patients (697 CD, 408 UC). Increasing genetic burden was associated with earlier age of diagnosis of CD (Ptrend=0.008). Patients in the highest GRS quartile were likely to develop disease 5 years earlier than those in the lowest quartile. Increasing genetic burden was also associated with ileal involvement in CD (Ptrend <0.0001). The effect of genetic burden was independent of the NOD2 locus and was stronger among those with no NOD2 variants, and in never smokers. UC patients with an involved first-degree relative had a higher genetic burden, but GRS was not associated with disease phenotype in UC.
CONCLUSIONS: Increasing genetic burden is associated with early age of diagnosis in CD, but not UC. The expanded panel of IBD risk loci explains only a fraction of variance of disease phenotype, suggesting limited clinical utility of genetics in predicting natural history.