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Presentation Number: 375

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AuthorBlock: Laura Fachal1, on behalf of the International IBD Genetics Consortium1
1Human Genetics, Wellcome Sanger Institute, Hinxton, Saffron Walden, United Kingdom;

Abstract Body
Background: Genome wide association studies (GWASs) have identified 241 regions of the genome associated with inflammatory bowel disease (IBD). However, the mapping of additional disease loci and fine-mapping causal variants is still limited by sample size, so larger GWASs can provide further insights into causal IBD biology. Methods: We performed a GWAS meta-analysis of 34 genotyped cohorts, totalling 56,101 IBD patients (N= 31,663 with Crohn’s disease (CD) and 22,444 with Ulcerative Colitis (UC)) and 43,038 population controls of European ancestry. Genotype imputation was undertaken using the TOPMed diverse population panel and linear mixed model association tests were performed using REGENIE, with summary statistics meta-analysed using METAL. Results: We identified 81 novel genome-wide significant (p<5x10-8) IBD loci, ten of them driven by variants with low minor allele frequency (MAF <0.01) (Figure 1). Five of the associated regions contain genes implicated in monogenic autosomal recessive syndromes that include colitis: DOCK8, G6PC3, HPS4, NCF1, RAG1, and RAG2. Many risk loci causally alter the expression of nearby genes, suggesting that aberrant expression of these genes underpins the IBD association, including TNFRSF8, PLCG1-AS1, ITPKC and CSF1. Fine-mapping analyses identified likely causal missense variants at two loci, both associated with CD risk. DOK2 (rs34215892 NP_003965:p.P274L; OR = 1.23 p = 4.0x10-10) is a cytoplasmic signalling protein that is highly expressed in macrophages and T cells in the terminal ileum. Loss of Dok-2 in mice causes severe DSS-induced colitis with reduced IL-17A and IL-22 expression, and DOK2 is differentially methylated in colonic tissue of IBD patients compared to controls. SHARPIN (rs34173062 NP_112236:p.S17F; OR = 1.20 p = 4.3x10-16) forms part of an oligodimer called the linear ubiquitin chain assembly complex that modulates activation of the NF-κB signalling pathway. Loss-of-function mutations in other proteins in the complex are associated with both combined immunodeficiency and systemic autoinflammation, with the former thought to be attributable to lower NF-κB activity in B cells and fibroblasts and the latter to increased NF-κB activity in monocytes. Discussion: We performed the largest GWAS meta-analysis of IBD to date, which enabled us to identify low-frequency variants with larger effects on IBD susceptibility than the more common variants typically identified via GWAS. The biological overlap between Mendelian and more complex forms of IBD is demonstrated by the identification of common non-coding variants associated with complex forms of IBD that dysregulate the function of the Mendelian gene. At the meeting we will present results of our fine-mapping and pathway analyses, with a view to identifying candidate drug targets for IBD. Acknowledgement: Wellcome Trust (WT206194); NIDDK (U24 DK062429)