Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases.

TitleGenome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases.
Publication TypeJournal Article
Year of Publication2017
AuthorsWitoelar, A, Jansen, IE, Wang, Y, Desikan, RS, J Gibbs, R, Blauwendraat, C, Thompson, WK, Hernandez, DG, Djurovic, S, Schork, AJ, Bettella, F, Ellinghaus, D, Franke, A, Lie, BA, McEvoy, LK, Karlsen, TH, Lesage, S, Morris, HR, Brice, A, Wood, NW, Heutink, P, Hardy, J, Singleton, AB, Dale, AM, Gasser, T, Andreassen, OA, Sharma, M
Corporate Authors
JournalJAMA Neurol
Date Published2017 Jul 01
KeywordsArthritis, Rheumatoid, Autoimmune Diseases, Celiac Disease, Colitis, Ulcerative, Crohn Disease, Diabetes Mellitus, Type 1, Genetic Loci, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Multiple Sclerosis, Parkinson Disease, Psoriasis, Risk Factors

Importance: Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes.

Objectives: To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach.

Design, Setting, and Participants: Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017.

Main Outcomes and Measures: The primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases.

Results: Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes.

Conclusions and Relevance: The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.

Alternate JournalJAMA Neurol
Citation Key10.1001/jamaneurol.2017.0469
PubMed ID28586827
PubMed Central IDPMC5710535
Grant ListR01 GM104400 / GM / NIGMS NIH HHS / United States