Exploring the genetic correlation between inflammatory bowel disease and psychiatric disorders: insights from genome-wide association studies.

Inflammatory bowel disease (IBD) and psychiatric disorders exhibit complex comorbid patterns, with anxiety and depressive disorders being significantly more prevalent in IBD patients compared to the general population. These comorbidities may differ between Crohn's disease (CD) and ulcerative colitis (UC), suggesting heterogeneous but potentially shared genetic mechanisms mediated through the gut-brain axis (GBA). To systematically investigate global and local genetic correlations between IBD and eight psychiatric disorders and to identify shared pathogenic mechanisms underlying these comorbidities. Using publicly available large-scale GWAS summary statistics, including a meta-analysis of 486,601 individuals for IBD and large international consortia datasets for eight psychiatric disorders, we conducted global genetic correlation analysis to quantify overall genetic overlap, local genetic correlation analysis to identify region-specific associations, summary data-based Mendelian randomization (SMR) to evaluate putative causal gene-trait relationships, and multi-trait analysis of GWAS (MTAG) to detect pleiotropic variants. Significant global genetic correlations were observed between IBD and ADHD (rho = 4.79 × 10- 3, p = 3.07 × 10- 5), anxiety disorder (rho = 1.89 × 10- 2, p = 8.02 × 10- 11), ASD (rho = 6.65 × 10- 3, p = 7.24 × 10- 4), OCD (rho = 7.84 × 10- 3, p = 1.32 × 10- 3), and PTSD (rho = 2.19 × 10- 2, p = 1.16 × 10- 19). Local genetic correlation analysis identified 274 significant regions (Bonferroni-corrected), with loci 464 (chr3: 47.6-50.4 Mb) and 960 (chr6: 31.3-31.4 Mb) showing consistent cross-trait associations. MTAG identified 1,125 independent pleiotropic loci, while SMR and MAGMA integration prioritized 21 key pleiotropic genes, including NOD2, IL10, and AURKB. Enrichment analyses highlighted immune-related and neurobiological pathways, including JAK-STAT signaling, FoxO signaling, oxidative stress response, and GABAergic synapse pathways. Our findings provide multi-layered genetic evidence supporting a structured and locus-specific shared genetic architecture between IBD and several psychiatric disorders. The identification of key genes and pathways, particularly NOD2 and immune-synaptic signaling cascades, offers potential molecular targets for understanding and managing comorbid disease within the GBA framework.