From gut to pancreas: Shared genetic susceptibility and biological convergence in acute pancreatitis and Crohn's disease.

Wenbin Xu; Aocheng Ji; Lu Han; Hao Xiong; Yiyi Jin; Wen Lin; Yonghui Wu; Yun Wang; Huan Zhong; Longxin Xiong; Chunyan Zeng

doi:10.1371/journal.pone.0353031

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From gut to pancreas: Shared genetic susceptibility and biological convergence in acute pancreatitis and Crohn's disease.

Wenbin Xu·Aocheng Ji·Lu Han·Hao Xiong·Yiyi Jin·Wen Lin·Yonghui Wu·Yun Wang·Huan Zhong·Longxin Xiong·Chunyan Zeng

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Abstract

BACKGROUND: Acute pancreatitis (AP) and Crohn's disease (CD) exhibit overlapping clinical presentations and an unexpectedly high rate of comorbidity. Whether this reflects shared genetic susceptibilities remains unclear. METHODS: We performed a cross-trait genome-wide association analysis leveraging European-ancestry summary statistics for AP (Ncases = 8446; Ncontrols = 437,418) and CD (Ncases = 12,194; Ncontrols = 28,072). Firstly, cross-trait genetic correlation was estimated using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Secondly, to pinpoint specific pleiotropic loci and prioritize candidate genes, we employed PLACO under a rigorous composite null hypothesis, integrated with Bayesian colocalization and SMR/HEIDI analyses. Finally, we dissected the underlying biological context by mapping tissue-specific regulatory enrichment and pathway convergence using FUMA, MAGMA, and Stratified LD Score Regression (S-LDSC). RESULTS: AP and CD showed significant positive genetic correlation (LDSC: rg = 0.178, SE = 0.079, P = 0.025; HDL: rg = 0.294, SE = 0.096, P = 0.0021). Pleiotropy analyses revealed 86 SNPs and 6 independent genome-wide significant pleiotropic loci (lead variants at 5q33.1, 6q22.33, 7q34, 10q24.2, 15q22.33 and 19q13.11, PPLACO < 5 × 10-8). Colocalization showed suggestive evidence of a shared causal signal at 6q22.33 (PP4 = 0.666). Gene-based tests of the AP-CD cross-trait statistics prioritized eight pleiotropic genes-RSPO3, ATG16L1, SMAD3, FADS1, ZPBP2, FADS2, PRKAA1 and IRGM. Gene-set analyses highlighted IL-23/Th17-related and broader inflammatory response pathways. CONCLUSIONS: AP and CD share polygenic susceptibility and converge on immune and inflammatory processes, with prioritized genes pointing to autophagy, lipid metabolism and TGF-β/SMAD-related biology.

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Humans Crohn Disease Genetic Predisposition to Disease Pancreatitis Genome-Wide Association Study Polymorphism, Single Nucleotide Linkage Disequilibrium Pancreas Bayes Theorem Journal Article

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Wenbin Xu, Aocheng Ji, Lu Han, Hao Xiong, Yiyi Jin, Wen Lin, Yonghui Wu, Yun Wang, Huan Zhong, Longxin Xiong, Chunyan Zeng. 2026-09-11. From gut to pancreas: Shared genetic susceptibility and biological convergence in acute pancreatitis and Crohn's disease.. https://doi.org/10.1371/journal.pone.0353031

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