Cross-tissue transcriptome-wide association studies identify susceptibility genes shared between schizophrenia and inflammatory bowel disease.


Florian Uellendahl-Werth, Carlo Maj, Oleg Borisov, Simonas Juzenas, Eike Matthias Wacker, Isabella Friis Jørgensen, Tim Alexander Steiert, Saptarshi Bej, Peter Krawitz, Per Hoffmann, Christoph Schramm, Olaf Wolkenhauer, Karina Banasik, Søren Brunak, Stefan Schreiber, Tom Hemming Karlsen, Franziska Degenhardt, Markus Nöthen, Andre Franke, Trine Folseraas, David Ellinghaus

Year of publication



Commun Biol







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Genetic correlations and an increased incidence of psychiatric disorders in inflammatory-bowel disease have been reported, but shared molecular mechanisms are unknown. We performed cross-tissue and multiple-gene conditioned transcriptome-wide association studies for 23 tissues of the gut-brain-axis using genome-wide association studies data sets (total 180,592 patients) for Crohn’s disease, ulcerative colitis, primary sclerosing cholangitis, schizophrenia, bipolar disorder, major depressive disorder and attention-deficit/hyperactivity disorder. We identified NR5A2, SATB2, and PPP3CA (encoding a target for calcineurin inhibitors in refractory ulcerative colitis) as shared susceptibility genes with transcriptome-wide significance both for Crohn’s disease, ulcerative colitis and schizophrenia, largely explaining fine-mapped association signals at nearby genome-wide association study 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 gut-brain-axis. PPP3CA together with three further suggestive loci can be linked to calcineurin-related signaling pathways such as NFAT activation or Wnt.