A genome-wide genetic pleiotropy approach identified shared loci between multiple system atrophy and inflammatory bowel disease

Alexey A Shadrin, Sören Mucha, David Ellinghaus, Mary B Makarious, Cornelis Blauwendraat, Ashwin A Sreelatha, Antonio Heras-Garvin, Jinhui Ding, Monia Hammer, Alexandra Foubert-Samier, Wassilios G Meissner, Olivier Rascol, Anne Pavy-Le Traon, Oleksandr Frei, Kevin S O’Connell, Shahram Bahrami, Stefan Schreiber, Wolfgang Lieb, Martina Müller-Nurasyid, Andreas Arnold, Georg Homuth, Carsten O. Schmidt, Markus M. Nöthen, Per Hoffmann, Christian Gieger, J Raphael Gibbs, Andre Franke, John Hardy, Gregor Wenning, Nadia Stefanova, Thomas Gasser, Andrew Singleton, Henry Houlden, Sonja W Scholz, Ole A. Andreassen, Manu Sharma,
. 2019-08-31; :
DOI: 10.1101/751354

We aimed to identify shared genetic background between multiple system atrophy (MSA) and autoimmune diseases by using the conjFDR approach. Our study showed significant genetic overlap between MSA and inflammatory bowel disease and identified DENND1B, C7, and RSP04 loci, which are linked to significant changes in methylation or expression levels of adjacent genes. We obtained evidence of enriched heritability involving immune/digestive categories. Finally, an MSA mouse model showed dysregulation of the C7 gene in the degenerating midbrain compared to wildtype mice. The results identify novel molecular mechanisms and implicate immune and gut dysfunction in MSA pathophysiology.

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