Dissecting the genetic etiology of intestinal obstruction: mendelian randomization identifies potential therapeutic targets

Intestinal obstruction, a prevalent and serious condition, necessitates deeper understanding of its genetic architecture. This study rigorously employed two-sample Mendelian randomization to dissect the causal influence of gene expression on intestinal obstruction risk, leveraging comprehensive summary-level data from eQTLGen and FinnGen GWAS. To enhance causal inference, Summary-data-based Mendelian Randomization was integrated, utilizing GTEx eQTL data to specifically assess tissue-relevant gene expression. Our multi-pronged analyses provide compelling genetic evidence supporting causal roles for genetically predicted expression of CHRNB2 and MIAT in intestinal obstruction. Specifically, increased genetically proxied CHRNB2 expression was associated with a protective effect, while higher genetically proxied MIAT expression suggested an elevated susceptibility to intestinal obstruction. Colocalization analysis, alongside HEIDI heterogeneity testing within the SMR framework, further bolstered the robustness of these findings by distinguishing causality from linkage disequilibrium. These convergent results offer novel mechanistic insights into intestinal obstruction pathogenesis, positioning CHRNB2 and MIAT as promising therapeutic targets for both prevention and treatment strategies. Future research is crucial to validate these findings across diverse ancestries and to fully elucidate the intricate biological mechanisms underpinning these gene-disease associations.