Abstract
BACKGROUND: Inflammatory bowel disease (IBD) has been suggested to be associated with neuropsychiatric disorders, but the underlying mechanisms remain poorly understood. METHODS: We employed Cell-Stratified Mendelian Randomisation (csMR) to analyse genetic variants associated with IBD and their effects on neuropsychiatric disorders. We conducted two-sample MR analyses using the partitioned genetic variants and performed SuSiE co-localisation analysis to identify shared causal variants between GWAS traits and the single-cell eQTL data. We also examined the imaging-derived phenotypes (IDPs) to understand the structural changes in the brain. FINDINGS: We identified specific cell types and IDPs associated with the interplay between IBD and neuropsychiatric disorders. Importantly, the oligodendrocytes (ODC)-stratified variants associated with IBD were linked to multiple sclerosis and schizophrenia, astrocytes-stratified variants associated with ulcerative colitis (UC) were connected to obsessive-compulsive disorder and schizophrenia, and inhibitory neurons -stratified variants associated with Crohn's disease (CD) were linked to multiple sclerosis. Moreover, mediation analysis suggested that 31.4% of the association from UC to schizophrenia was mediated by alterations in mean diffusivity in the left tapetum, while structural changes in the right inferior temporal region associated with CD accounted for a 37.5% increased risk of cerebral aneurysm. INTERPRETATION: Our findings may facilitate understanding of the molecular mechanisms involved in diseases modulated by the gut-brain axis and develop novel therapeutic strategies for IBD and neuropsychiatric disorders. FUNDING: CZ was supported by National Key Research and Development Program of China (2023YFC2705700), and operational funds from The First Affiliated Hospital of Nanchang University (500021010). LZ was supported by National Natural Science Foundation of China (82160155).