We present a genome-wide association study of ileal Crohn's disease (CD) and two independent replication studies that identify five novel regions of association to CD. Specifically, in addition to the previously established CARD15 and IL23R associations, we report strong associations with independent replication to variation in the genomic regions encoding the PHOX2B, NCF4 and ATG16L1 genes, as well as a predicted gene on 16q24.1 (FAM92B) and an intergenic region on 10q21.1. We further demonstrate that the ATG16L1 gene is expressed in intestinal epithelial cell lines and that functional knock down of this gene abrogates autophagy of Salmonella typhimurium. Together these findings suggest that autophagy and host cell responses to intra-cellular microbes are involved in the pathogenesis of CD.Crohn's disease (CD) and ulcerative colitis (UC) represent the two common forms of idiopathic inflammatory bowel disease (IBD), each with a prevalence of roughly 100-150 per 100,000 individuals of European ancestry 1 . CD most commonly involves the ileum and colon but can affect any region of the gut. UC always involves the rectum, and inflammation may extend as far as the cecum in a contiguous pattern 2 . Strong familial aggregation, twin studies and established genetic associations attest to the important role of genetics in IBD pathogenesis [3][4][5] . There is also very strong evidence that the enteric microflora plays a central role in the initiation and maintenance of disease. Therefore, like most complex trait diseases, IBD results from a combination of genetic and non-genetic risk factors, where each individual factor may be expected to have a relatively modest effect on diseaserisk.While a combination of genome-wide linkage, candidate gene and targeted association mapping studies have been successful in the identification of CD-associated genetic variants in CARD15 and the IBD5 haplotype, these explain only a small fraction of the heritability of CD [6][7][8] . We therefore embarked upon a genome-wide association (GWA) study of CD in order to find additional genetic risk factors. Phenotypes for both CD and UC vary considerably among individuals, primarily with regard to sites of inflammation, disease behavior, severity and extraintestinal manifestations. Furthermore, CD site and behavior are likely under genetic control based on clustering within affected sibling pairs 9 , as well as specific observations that CARD15 mutations are a greater risk factor for ileal CD and stricturing behavior 10 . Therefore we have exclusively focused on patients with CD involving the ileal region of the small intestine (with or without other sites of involvement) in an attempt to minimize clinical and genetic heterogeneity. Based on an interim analysis approximately halfway through this study, we identified, confirmed and published the discovery of genetic variants in the IL23R gene that significantly influence risk to developing CD and UC 11 . Specifically at that point, 567 nonJewish ileal CD cases had been scanned and analyz...

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