Abstract
BACKGROUND: Patients with schizophrenia (SCZ) frequently present with comorbid gastrointestinal diseases. However, the cross-disorder genetic correlations and shared mechanisms remain largely unknown. This study aims to elucidate the shared genetic architecture between SCZ and five types of gastrointestinal diseases: inflammatory bowel disease, Crohn's disease, ulcerative colitis, constipation, and irritable bowel syndrome. Furthermore, we seek to identify shared genetic risk loci, pinpoint potentially implicated tissues, and conduct in-depth analyses of the genetic mechanisms. METHODS: Using summary statistics from large-scale genome-wide association studies (GWAS), we conducted an in-depth analysis of the genetic correlations between schizophrenia (SCZ) and gastrointestinal diseases via linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) methods. Significant genetic correlations were observed between SCZ and gastrointestinal diseases. To further investigate the shared genetic basis, we performed cross-trait pleiotropy analyses to identify common pleiotropic loci and genes. Additionally, to uncover potential links between these complex traits, we conducted comprehensive functional annotation and tissue-specific enrichment analyses. Heritability enrichment analysis was employed to assess the contributions of key tissues. Finally, immune colocalization approaches were utilized to explore immune-mediated relationships between SCZ and gastrointestinal diseases. RESULTS: Our research highlighted shared genetic mechanisms between SCZ and five gastrointestinal diseases. A total of 2,367 novel SNPs were identified at a genome-wide significance level (P < 5 × 10⁻⁸), and annotation revealed 96 pleiotropic genome-wide risk loci, among which 32 passed causal colocalization analysis. Shared loci were identified at regions 1q32.1, 2q33.1, 3p21.31, 10q21.2, 16p11.2, and 18q21.2. Further gene-level analyses identified pleiotropic genes including C1orf106, SLC26A6, FES, BSN, C3orf62 and CELSR3. Pathway analyses revealed critical roles of FOXP3 target genes, lymphocyte activation, T cell activation, and PDZ domain-related pathways in these diseases. Finally, phenotype-level immune colocalization analysis uncovered immunological mediators including PD-L1, CD3, T cells, and CD28 that bridge SCZ and gastrointestinal diseases. CONCLUSION: Our findings support a shared genetic architecture between SCZ and gastrointestinal diseases and shed light on the potential mechanism that might involve in.These findings hold important implications for coordinated interventions targeting SCZ and its comorbid conditions.