Cross-tissue transcriptome-wide association studies of 885,176 individuals and seven diseases of the gut-brain axis identify susceptibility genes shared between schizophrenia and inflammatory bowel disease

Abstract Genetic correlations and an increased incidence of psychiatric disorders in inflammatory-bowel disease (IBD) have been reported, but shared molecular mechanisms are unknown. We performed cross-tissue and multiple-gene conditioned transcriptome-wide association studies (TWAS) for 23 tissues of the gut-brain-axis (GBA) using GWAS data sets (total 246,772 patients and 638,454 controls) for Crohn’s disease (CD), ulcerative colitis (UC), primary sclerosing cholangitis (PSC), schizophrenia (SCZ), bipolar disorder (BD), major depressive disorder (MDD) and attention-deficit/hyperactivity disorder (ADHD). We identified NR5A2, SATB2, and PPP3CA (encoding a target for calcineurin inhibitors in refractory UC) as shared susceptibility genes with transcriptome-wide significance both for CD/UC and SCZ, largely explaining fine-mapped association signals at nearby GWAS susceptibility loci. Analysis of bulk and single-cell RNA-sequencing data showed that PPP3CA expression was strongest in neurons and in enteroendocrine and Paneth-like cells of the ileum, colon, and rectum, indicating a possible link to the GBA. Gene-disease associations as part of calcineurin-related signaling pathways such as NFAT activation or Wnt are the most likely shared candidate pathways for IBD and SCZ, where risk is mediated by gene expression.