Summary Inflammatory bowel diseases (IBD), including Crohn’s disease (CD), are genetically linked to host pathways that implicate an underlying role for aberrant immune responses to intestinal microbiota. However, patterns of gut microbiome dysbiosis in IBD patients are inconsistent among published studies. Using samples from multiple gastrointestinal locations collected prior to treatment in new-onset cases, we studied the microbiome in the largest pediatric CD cohort to date. An axis defined by an increased abundance in bacteria which include Enterobacteriaceae, Pasteurellacaea, Veillonellaceae, and Fusobacteriaceae, and decreased abundance in Erysipelotrichales, Bacteroidales, and Clostridiales, correlates strongly with disease status. Microbiome comparison between CD patients with and without antibiotic exposure indicates that antibiotic use amplifies the microbial dysbiosis associated with CD. Comparing the microbial signatures between the ileum, rectum, and fecal samples indicates that at this early stage of disease, assessing the rectal mucosa-associated microbiome offers unique potential for convenient and early diagnosis of CD.

The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study.

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

K nowledge of clinically relevant targets of individual treatments is important for improving management of patients with inflammatory bowel diseases (IBD). The Selecting Therapeutic Targets in IBD (STRIDE) program was initiated by the International Organization for the Study of IBD (IOIBD) in 2013 using an evidencebased expert consensus process. It subsequently led to a *Authors share co-first authorship.

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...

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.

These modifications are termed the Paris Classification. By adhering to the Montreal framework, we have not jeopardized or altered the ability to use this classification for adult onset disease or by adult gastroenterologists.