The hidden genetic and microbial networks connecting neuropsychiatric and digestive disorders

The gut-brain axis is a key interface between neuropsychiatric and digestive disorders, however, the underlying shared genetic mechanisms and microbial mediators remain poorly understood. Utilizing genome-wide association study (GWAS) data from 18 neuropsychiatric and 24 digestive disorders, along with microbial quantitative trait loci (mbQTL) data encompassing 211 taxa (<i>N</i> = 18,340), we conducted a comprehensive analysis integrating linkage disequilibrium score regression, MAGMA gene-based pleiotropy mapping, and Mendelian randomization. We identified 12 significant genetic correlations between gut-brain disorder pairs, including attention-deficit/hyperactivity disorder (ADHD) and fatty liver disease. In total, 5339 pleiotropic genes were discovered, with MSH5 appearing in 28 disorder pairs. Pathway enrichment analysis implicated immune regulation and synaptic signaling as core biological processes. Novel causal relationships were also uncovered, such as ADHD increasing the risk of irritable bowel syndrome. Co-localization analysis validated three causal associations. Microbiota-focused analyses further demonstrated a protective role of <i>Actinobacteria</i> against stroke, resolving previous inconsistencies in the literature. Collectively, these findings highlight the dual role of the gut microbiota-as both modulator and contributor-and provide critical genetic insights that may guide the development of targeted interventions across the gut-brain axis.