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

Florian Uellendahl-Werth; Carlo Maj; Oleg Borisov; Simonas Juzėnas; 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

doi:10.1038/s42003-022-03031-6

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 ; Juzėnas, 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 ; Ellinghaus, David
DOI	10.1038/s42003-022-03031-6
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Is Part of	Communications biology.. Berlin : Nature Portfolio. 2022, vol. 5, iss. 1, art. no. 80, p. [1-15].. eISSN 2399-3642
Keywords [eng]	schizophrenia ; inflammatory bowel disease ; transcriptome-wide association
Abstract [eng]	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.
Published	Berlin : Nature Portfolio
Type	Journal article
Language	English
Publication date	2022
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„Cross-tissue transcriptome-wide association studies identify susceptibility genes shared between schizophrenia and inflammatory bowel disease“