Genome-wide Association and Mendelian Randomization Analyses Identify Novel Genetic and Metabolic Determinants of Acute Pancreatitis

Background and Aims : Acute pancreatitis (AP) is a complex trait that may be caused by some cardiometabolic risk factors. The genetic architecture of AP is not fully understood. Here, we aimed at identifying novel genetic and metabolic determinants of AP by combining genome-wide association study (GWAS) and Mendelian randomization (MR).Methods: We performed two new GWAS in the Estonian Biobank (2451 cases and 192521 controls) and the UK Biobank (2359 cases and 405762 controls) and combined these results with FinnGen (3022 cases and 195144 controls) in a genome-wide association meta-analysis totalling 7832 cases and 793427 controls. We then performed a series of inverse variance-weighted MR analyses using 123 metabolites derived from a GWAS of >24,000 Europeans as study exposures. From there, we performed sensitivity analyses using MR-PRESSO and contamination mixture tests to account for horizontal pleiotropy and assess the validity of our instruments, respectively.Results: Our GWAS meta-analysis identified genome-wide significant variants (p<5e-8) at two known AP loci (ABCG8 and SPINK1) as well as at one new locus (TRPV6). Out of the 123 metabolites tested, only the amino-acid glycine (beta [95% CI] = -0.11 [-0.16 – -0.06]; pIVW = 6.21e-06) was significant and negatively associated with AP. No association between triglycerides and AP were found.Conclusions: We identified a genetic variant at the TRPV6 locus as a novel susceptibility locus for AP and as well as a potentially causal negative association between circulating glycine levels and AP. The biological mechanisms underlying these new findings will need to be further investigated. Background and Aims : Acute pancreatitis (AP) is a complex trait that may be caused by some cardiometabolic risk factors. The genetic architecture of AP is not fully understood. Here, we aimed at identifying novel genetic and metabolic determinants of AP by combining genome-wide association study (GWAS) and Mendelian randomization (MR). Methods: We performed two new GWAS in the Estonian Biobank (2451 cases and 192521 controls) and the UK Biobank (2359 cases and 405762 controls) and combined these results with FinnGen (3022 cases and 195144 controls) in a genome-wide association meta-analysis totalling 7832 cases and 793427 controls. We then performed a series of inverse variance-weighted MR analyses using 123 metabolites derived from a GWAS of >24,000 Europeans as study exposures. From there, we performed sensitivity analyses using MR-PRESSO and contamination mixture tests to account for horizontal pleiotropy and assess the validity of our instruments, respectively. Results: Our GWAS meta-analysis identified genome-wide significant variants (p<5e-8) at two known AP loci (ABCG8 and SPINK1) as well as at one new locus (TRPV6). Out of the 123 metabolites tested, only the amino-acid glycine (beta [95% CI] = -0.11 [-0.16 – -0.06]; pIVW = 6.21e-06) was significant and negatively associated with AP. No association between triglycerides and AP were found. Conclusions: We identified a genetic variant at the TRPV6 locus as a novel susceptibility locus for AP and as well as a potentially causal negative association between circulating glycine levels and AP. The biological mechanisms underlying these new findings will need to be further investigated.