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- Title
Cross-tissue transcriptome-wide association studies identify susceptibility genes shared between schizophrenia and inflammatory bowel disease.
- Authors
Uellendahl-Werth, Florian; Maj, Carlo; Borisov, Oleg; Juzenas, Simonas; Wacker, Eike Matthias; Jørgensen, Isabella Friis; Steiert, Tim Alexander; Bej, Saptarshi; Krawitz, Peter; Hoffmann, Per; Schramm, Christoph; Wolkenhauer, Olaf; Banasik, Karina; Brunak, Søren; Schreiber, Stefan; Karlsen, Tom Hemming; Degenhardt, Franziska; Nöthen, Markus; Franke, Andre; Folseraas, Trine
- Abstract
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. Florian Uellendahl-Werth et al. conduct cross-tissue transcriptome-wide association studies to explore genetic mechanisms shared across immune-related and psychiatric traits. Their results identify several genes (including PPP3CA) that could mediate the interplay between psychiatric and inflammatory disease.
- Publication
Communications Biology, 2022, Vol 5, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-022-03031-6