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...

There are thousands of rare human disorders caused by a single deleterious, protein-coding genetic variant 1. However, patients with the same genetic defect can have different clinical presentation 2–4, and some individuals carrying known disease-causing variants can appear unaffected 5. What explains these differences? Here, we show in a cohort of 6,987 children with heterogeneous severe neurodevelopmental disorders expected to be almost entirely monogenic that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome wide common variant burden by showing that it is over-transmitted from parents to children in an independent sample of 728 trios from the same cohort. Our common variant signal is significantly positively correlated with genetic predisposition to fewer years of schooling, decreased intelligence, and risk of schizophrenia. We found that common variant risk was not significantly different between individuals with and without a known protein-coding diagnostic variant, suggesting that common variant risk is not confined to patients without a monogenic diagnosis. In addition, previously published common variant scores for autism, height, birth weight, and intracranial volume were all correlated with those traits within our cohort, suggesting that phenotypic expression in individuals with monogenic disorders is affected by the same variants as the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in disorders typically considered to be monogenic.

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