Genetic association studies have identified 215 risk loci for inflammatory bowel disease 1–8, which have revealed fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals, and meta-analyzed with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new loci, three of which contain integrin genes that encode proteins in pathways identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4, ITGB8) and at previously implicated loci (ITGAL, ICAM1). In all four cases, the expression increasing allele also increases disease risk. We also identified likely causal missense variants in the primary immune deficiency gene PLCG2 and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new common variant associations continue to identify genes relevant to therapeutic target identification and prioritization.

The genetic architectures of common, complex diseases are largely uncharacterized. We modeled the genetic architecture underlying genome-wide association study (GWAS) data for rheumatoid arthritis and developed a new method using polygenic risk-score analyses to infer the total liability-scale variance explained by associated GWAS SNPs. Using this method, we estimated that, together, thousands of SNPs from rheumatoid arthritis GWAS explain an additional 20% of disease risk (excluding known associated loci). We further tested this method on datasets for three additional diseases and obtained comparable estimates for celiac disease (43% excluding the major histocompatibility complex), myocardial infarction and coronary artery disease (48%) and type 2 diabetes (49%). Our results are consistent with simulated genetic models in which hundreds of associated loci harbor common causal variants and a smaller number of loci harbor multiple rare causal variants. These analyses suggest that GWAS will continue to be highly productive for the discovery of additional susceptibility loci for common diseases.

Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation(1-3). We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip(4). We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases

Genetic association studies have identified 215 risk loci for inflammatory bowel disease 1-8, which have revealed fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals, and meta-analyzed with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new loci, three of which contain integrin genes that encode proteins in pathways identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4, ITGB8) and at previously implicated loci (ITGAL, ICAM1). In all four cases, the expression increasing allele also increases disease risk. We also identified likely causal missense variants in the primary immune deficiency gene PLCG2 and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new common variant associations continue to identify genes relevant to therapeutic target identification and prioritization. Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsInflammatory bowel disease (IBD) is a chronic, debilitating, disorder of the gastrointestinal tract that includes two common disease subtypes, Crohn's disease and ulcerative colitis. Disease pathogenesis is poorly understood but is likely driven by a dysregulated immune response to unknown environmental triggers in genetically susceptible individuals. Treatment regimes often use potent immunomodulators to achieve and maintain remission of symptoms. However, patients commonly experience side effects, lose response to treatment, or develop complications of IBD, with many ultimately requiring major abdominal surgery. Previous genome-wide association studies (GWAS) and targeted follow-up using the Immunochip have been very successful at identifying genetic risk loci for IBD, but increased biological understanding has not yet had a significant impact on therapy for these disorders.In order to further expand our understanding of the biology of these disorders we carried out a GWAS of 12,160 IBD cases and 13,145 population controls of European ancestry that had not been included in any genome-wide meta-analysis of IBD to date (Supplementary Table 1, Online Methods). We imputed genotypes using a reference panel comprising whole genome sequences from 4,686 IBD cases9 and 6,285 publically available population controls10,11. Following quality control (Online Methods) we tested 9.7 million sites for association. At the 232 IBD associated SNPs in the latest meta-analysis by the International IBD Genetics Consortium1, 228 had effects in the same direction in our data, 188 showed at least nominal evidence of replication (P<0.05) and none showed significant evidence of heterogeneity of effect by Cochrane's Q test. Among these replicated loci was a genomewide significant association on chromosome 10q25 that was only previously significantly associated with Crohn's disease in individuals of East Asian a...