A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1

We performed a genome-wide association study of 19,779 nonsynonymous SNPs in 735 individuals with Crohn disease and 368 controls. A total of 7,159 of these SNPs were informative. We followed up on all 72 SNPs with P <= 0.01 with an allele- based disease association test in 380 independent Crohn disease trios, 498 Crohn disease singleton cases and 1,032 controls. Disease association of rs2241880 in the autophagy- related 16- like 1 gene ( ATG16L1) was replicated in these samples ( P 4.0 X 10(-8)) and confirmed in a UK case-control sample ( P =0.0004). By haplotype and regression analysis, we found that marker rs2241880, a coding SNP ( T300A), carries virtually all the disease risk exerted by the ATG16L1 locus. The ATG16L1 gene encodes a protein in the autophagosome pathway that processes intracellular bacteria. We found a statistically significant interaction with respect to Crohn disease risk between rs2241880 and the established CARD15 susceptibility variants ( P =0.039). Together with the lack of association between rs2241880 and ulcerative colitis ( P > 0.4), these data suggest that the underlying biological process may be specific to Crohn disease.