Multi-population genome-wide association meta-analysis of acute and chronic pancreatitis

Acute (AP) and chronic (CP) pancreatitis are major causes of gastrointestinal morbidity. However, the genetic architectures of AP and CP remain incompletely defined, as does the degree to which the two conditions share a common genetic basis. Here we report a multi-population GWAS meta-analysis of both AP and CP across five biobanks, comprising 23,292 individuals with and 1,748,420 individuals without AP across five populations and 9,866 individuals with and 1,627,720 individuals without CP across three populations. We identified 16 and 14 genome-wide significant loci for AP and CP, respectively. Combining nearest-gene assignment, fine-mapping, MAGMA, and colocalization with pancreatic eǪTLs, we prioritized 7 genes for AP and 5 genes for CP using two or more approaches, including three previously unreported candidates: TM4SF4 and TCIM for AP, and FFAR4 for CP. We demonstrated that AP and CP are strongly correlated at the genome-wide level ( r _g =0.89); however, we identified 44 regions with significantly lower correlations, including a region on chromosome 18 containing BCL2 with a negative local correlation. Plasma proteome-wide Mendelian randomization (MR) found 15 proteins whose genetically predicted plasma levels were associated with AP and 6 associated with CP, including ABO, whose measured levels likely proxy non-O blood type. Consistent with this, we found that non-O blood type was modestly but significantly associated with both AP and CP in an analysis of electronic health records from over 650,000 individuals. Finally, drug-target MR identified 38 and 45 target genes whose genetically predicted expression levels were associated with genetic liability for AP and CP, respectively. Among these, DRD2 and BCHE (for AP and CP, respectively) were also supported by colocalization analysis. Overall, these results expand the known genetic architecture of pancreatitis and identify tractable therapeutic targets.