Multilevel genome-wide analysis reveals shared genetic architecture between acute pancreatitis and body fat distribution.

BACKGROUND Acute pancreatitis (AP) is a heterogeneous inflammatory disease, and its risk and severity may be shaped more by body fat distribution than by overall obesity. However, the shared genetic basis between AP and depot-specific fat accumulation remains unclear. METHODS We meta-analyzed AP genome-wide association study (GWAS) summary statistics from FinnGen, the Million Veteran Program, and the UK Biobank, including 18,045 cases and 1,285,319 controls. Four magnetic resonance imaging (MRI)-derived fat distribution traits, namely intrapancreatic fat deposition (IPFD), liver fat (LF), visceral adipose tissue (VAT), and abdominal subcutaneous adipose tissue (ASAT), were examined. We estimated genetic correlations using linkage disequilibrium score regression (LDSC) and high definition likelihood (HDL); identified pleiotropic loci using cross-phenotype association analysis (CPASSOC) and functional mapping and annotation (FUMA); tested colocalization; and assessed gene-level, pathway, and cell-type signals using multi-marker analysis of genomic annotation (MAGMA), Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG), and web-based cell-type-specific enrichment analysis (WebCSEA). Two-sample and multivariable Mendelian randomization (MR) analyses were conducted to evaluate causal associations. RESULTS The AP meta-analysis identified nine loci of genome-wide significance, including four previously unreported regions. AP showed positive genetic correlations with all four fat traits, particularly with VAT and ASAT. CPASSOC identified 50 pleiotropic risk loci across 26 independent regions, with recurrent signals at 2p21, 5q32, 7q34, and 16q23.1. MAGMA prioritized 63 unique pleiotropic genes, including ABCG5/ABCG8, SPINK1, PRSS1, CTRB1, TM4SF4, and ZFYVE21. Enrichment analyses highlighted digestion; lipid metabolism; xenobiotic processing; inflammation; and pancreatic, intestinal, and hepatic cell contexts. MR supported independent effects of IPFD and VAT on AP risk. CONCLUSION This multilevel genome-wide analysis provides evidence of the shared genetic architecture between AP and depot-specific fat distribution and highlights the pancreas-intestine-liver regulatory axis as a relevant biological context.