Several new risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further we have combined the data from three studies (a total of 3,230 cases and 4,829 controls) and performed replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 new loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1, and ITLN1. The expanded molecular understanding of the basis of disease offers promise for informed therapeutic development. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe first genome-wide association studies (GWAS) have identified many common variants associated with complex diseases, and have rapidly expanded our knowledge of the genetic architecture of these traits. Progress in Crohn's disease (CD), a common idiopathic inflammatory bowel disease (IBD) with high heritability (λ s ∼ 20-35), has been especially striking, with recent GWAS publications increasing the number of confirmed associated loci from two to more than ten 1 . The results have identified new pathogenic mechanisms of IBD and promise to advance fundamentally our understanding of CD biology. These recent discoveries highlight, for instance, the key importance of autophagy and innate immunity 2-5 as determinants of the dysregulated host-bacterial interactions implicated in disease pathogenesis. Furthermore, genetic associations have been shown to be shared between CD and other auto-inflammatory conditions -for example, IL23R variants 6 are also associated with psoriasis 7 and ankylosing spondylitis 8 , and PTPN2 variants with type 1 diabetes 3,5 . As in other complex diseases, restricted sample sizes have resulted in early CD studies focusing on only the strongest effects, which turn out to explain only a fraction of the heritability of disease.We recently published three separate GWA scans for CD in European-derived populationsthe details of which are shown in Table 1 4,5,9 . Motivated by the need for larger datasets to improve power to detect loci of modest effect, we carried out a genome-wide meta-analysis from our three CD scans. These analyses, together with a replication study in an equivalently sized, independent panel, have enabled us to identify at genome-wide levels of significance 21 novel Crohn's disease susceptibility genes and loci. This brings the total number of independent loci conclusively associated with Crohn's disease to more than 30 and provides unprecedented insight into both CD pathogenesis as well as the general genetic architecture of a multifactorial disease. Results Meta-analysis of three genome-wide association scansThe combined GWAS study samples (Table 1) consisted of 3,230 cases and 4,829 controls, all of European descent. While the individual scans did identify new risk factors, they were only well-powered to discover common alleles with odds-ratios (ORs) a...

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease

Genome-wide association studies (GWAS) and candidate gene studies in ulcerative colitis (UC) have identified 18 susceptibility loci. We conducted a meta-analysis of 6 UC GWAS, comprising 6,687 cases and 19,718 controls, and followed-up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P<5×10-8), increasing the number of UC associated loci to 47. After annotating associated regions using GRAIL, eQTL data and correlations with non-synonymous SNPs, we identified many candidate genes providing potentially important insights into disease pathogenesis, including IL1R2, IL8RA/B, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease (IBD) risk loci is now 99, including a minimum of 28 shared association signals between Crohn’s disease (CD) and UC.