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Introduction
Schizophrenia (SCZ) is one of the most severe psychiatric disorders affecting approximately 1% general population globally and is listed as the top disability disease in mental disorders across the global burden of disease study (Ferrari et al., 2022; Jauhar, Johnstone, & McKenna, 2022). A growing body of epidemiological evidence shows the widespread comorbidity among SCZ patients, especially for inflammatory bowel disease (IBD), (e.g. Bernstein et al., discovered the risk of SCZ in IBD patients was 1.64 folds higher than non-IBD patients (Bernstein et al., 2019), and in Sung's study (Sung et al., 2022), there was a 3.28 times greater risk of IBD among SCZ patients than non-SCZ patients), highlighting a crucial role of the brain–gut axis (BGA) (Gracie, Hamlin, & Ford, 2019). SCZ patients were found to have a disruption of the intestinal epithelial barrier and reflection of inflammatory cytokines (Gao et al., 2022; Murphy et al., 2022; Szabo et al., 2022). Therefore, clinicians have to face a critical issue of how to safely and effectively treat individuals with both SCZ and IBD.
A recent study has reported strong positive genetic correlations between SCZ and ulcerative colitis (UC) as well as Crohn's disease (CD), indicating that the underlying biological mechanism of the BGA is partially attributed to shared genetic architecture (Tylee et al., 2022). Both SCZ and IBD are highly heritable and heterogeneous diseases, with twin studies estimating family heritability of 79% for SCZ, and 67–75% for IBD (Gordon, Trier Moller, Andersen, & Harbord, 2015; Hilker et al., 2018). Genome-wide association studies (GWASs) of SCZ and IBD have reported several susceptibility loci related to immune-related signals (Jostins et al., 2012; Liu et al., 2015; Trubetskoy et al., 2022). Moreover, through a cross-tissue transcriptome-wide association study, Uellendahl-Werth et al. have identified several shared susceptibility genes between SCZ and IBD, including NR5A2, SATB2, and PPP3CA (Uellendahl-Werth et al., 2022). These findings reflect genetic overlap existed between SCZ and IBD, but the magnitude of shared genetic components and the causality relationship between them remains unclear.
By leveraging the hitherto largest GWAS summary statistics of SCZ and IBD, we conducted a comprehensive genetic pleiotropic analysis to uncover shared loci, genes, or biological processes underpinning the observed co-morbidity between SCZ and IBD. First, we performed Linkage disequilibrium...