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OP016. Transethnic association study of IBD identifies 14 new disease loci and demonstrates pervasive sharing of genetic risk factors and phenotypic features between Europeans and non-Europeans

R.K. Weersma1, International IBD Genetics Consortium2, 1University Medical Center Groningen, Gastroenterology and Hepatology, Groningen, Netherlands, 2, Netherlands

Background

Previous studies in inflammatory bowel disease (IBD) patients of European descent identified 163 genetic susceptibility loci. Although the incidence of IBD is rising across Asia as well as in developing countries, there is little knowledge on the genetic background and phenotypic presentation in IBD patients of non-European descent.

Methods

A new cohort of 9,359 individuals of East Asian (Japan, South Korea, Hong Kong-China and UK individuals from South Asia), Indian and Indo-European (Iran) descent were genotyped using the Immunochip, a custom genotyping array with, among other content, dense coverage of immune related genes. Stringent quality control was performed. A linear mixed model (MMM) was used for case–control association tests. These data were combined with a cohort of 79,584 individuals of European descent (Jostins et al. Nature 2012) to perform a trans-ethnic meta-analysis, as implemented in Mantra, allowing heterogeneity in effect sizes to be correlated to geographical distance between populations. For each known IBD locus, we investigated whether differences in the variance explained in Europeans vs non-Europeans were due to differences in effect size or allele frequency. Phenotype data were collected including the Montreal classification.

Results

We identified 14 novel IBD loci at genome wide significant levels (p < 5×10−8) harbouring genes previously reported for other immune-mediated disease (including CD28, TNFRSF1A, CTLA4, IRF4, PRKCQ, UBASH3A, NFKBIZ, and CD44) and genes not reported for immune-mediated disease (e.g. ZEB2, ZNF366, TSPAN32, CD27, and CCL20). The majority of genetic risk factors, including these 14 novel loci, were common to both European and non-European IBD. However, the amount of phenotypic variance explained by these loci between populations was clearly heterogeneous, driven by a combination of differences in effect size and allele frequency. Phenotype data was available for 3,986 non-European and 47,799 European patients. There was a male predominance for Crohn's disease (69% vs 45%), more ileocolonic disease (54% vs. 39%) and lower colectomy rates in UC (4% vs 18%) in non-European than European populations.

Conclusion

In this largest study to date of genetic risk factors underlying non-European IBD, we identified 14 novel IBD loci increasing the total number of IBD loci to 177. There is pervasive sharing of genetic risk factors between different ethnicities; Despite shared genetics, the relative contributions for individual genes to the variance explained differ between ethnicities. Overall the clinical characteristics are remarkably similar between different ethnicities. The presented similarities and dissimilarities between populations add to the heterogeneity of IBD.