Abstract Background Genome-wide association studies (GWASs) have identified 320 loci associated with inflammatory bowel disease (IBD). About 15% of these loci include genes that lie in pathways targeted by drugs currently approved to treat IBD. Thus, identifying new loci can not only provide further insights into causal biology but also reveal novel therapeutic targets. Methods We performed a multi-ancestry GWAS meta-analysis of 67 cohorts, from European, East Asian and South Asian populations. The final dataset included 125,992 IBD patients (59,734 with CD; 57,565 with UC) and more than 1.2 million population controls (Fig 1). Genotype imputation was undertaken using the TOPMed diverse population panel and association tests were performed using REGENIE. The results were meta-analysed using a fixed effects meta-analysis via Metal. To prioritise effector genes and generate therapeutic hypotheses, we integrated our results with bulk and single cell transcriptome data from relevant tissues and cell types. Through colocalization analyses we identified those signals driving the expression of nearby genes (cis-eQTL), suggesting that aberrant expression of these genes underpins the association. Results We identified 290 new independent disease susceptibility association signals. Out of these, 125 new signals are located >1Mb from any previously reported loci. Six new loci contain genes implicated in monogenic syndromes that include colitis GUCY2C, G6PC3, NFKBIA, PIK3CD, PIK3R1, ZBTB24. Up to 40% of all disease susceptibility association signals colocalize with a cis-eQTL. For instance, a new variant associated with increased risk of UC (P=8x10-14) decreases the expression of the transmembrane mitochondrial protein TSPO in T cells, B cells, macrophages, and transverse colon. Pro-inflammatory macrophages show consistent TSPO downregulation. Loss of TSPO in mice causes exacerbated DSS-induced colitis. Ongoing clinical trials are evaluating whether targeting this gene could ameliorate the immune response in multiple sclerosis patients. We also identified a new CD susceptibility variant (P=3x10-16) associated with increased expression of WNK1 in monocytes and macrophages. Whereas loss of WNK1 in mice show increased expression of IL-1B in response to NLRP3 inflammasome activation; it also stimulates autophagy through the upregulation of the PI3KC3 complex. Impaired autophagy has shown to be key in promoting CD susceptibility. Conclusion Integrating molecular data from multiple cell types and conditions not only expands our ability to determine novel candidate causal genes, it also provides additional evidence of the utility of genetics as an instrument to guide the development of new therapeutic drugs or the repurposing of existing molecules.