Genome-wide pleiotropy between Parkinson disease and autoimmune diseases

Aree Witoelar, Iris E. Jansen, for the International Parkinson's Disease Genomics Consortium (IPDGC), United Kingdom Brain Expression Consortium (UKBEC) Investigators, North American Brain Expression Consortium (NABEC), Yunpeng Wang, Rahul S. Desikan, J. Raphael Gibbs, Cornelis Blauwendraat, Wesley K. Thompson, Dena G. Hernandez, Srdjan Djurovic, Andrew J. Schork, Francesco Bettella, David Ellinghaus, Andre Franke, Benedicte A. Lie, Linda K. McEvoy, Tom H. Karlsen, Suzanne Lesage, Huw R. Morris, Alexis BriceNicholas W. Wood, Peter Heutink, John Hardy, Andrew B. Singleton, Anders M. Dale, Thomas Gasser, Ole A. Andreassen, Manu Sharma*, Karin D. Van Dijk, Albert Hofman, Bart Post, Fernando Rivadeneira, Fernando Rivadeneira, Andre G. Uitterlinden

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

216 Citations (Scopus)

Abstract

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 outcomewas 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 inmethylation 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.

Original languageEnglish
Pages (from-to)780-792
Number of pages13
JournalJAMA Neurology
Volume74
Issue number7
DOIs
Publication statusPublished - Jul 2017

Bibliographical note

Funding Information:
This work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (SysINFLAME grant 01ZX1306A). This project received infrastructure support from the Deutsche Forschungsgemeinschaft (DFG) Excellence Cluster 306 "Inflammation at Interfaces." Dr Jansen receives funding from Prinses Beatrix Fonds. Dr Franke receives an endowment professorship by the Foundation for Experimental Medicine (Zurich, Switzerland). Dr Andreassen and his team are supported by The Research Council of Norway (213837, 225989, 223273, and 475 237250/EU Joint Programme-Neurodegenerative Disease Research [EU-JPND]), the South East Norway Health Authority (2013-123), the Norwegian Health Association, and the K. G. Jebsen Foundation. Dr Sharma receives funding from The Michael J Fox Foundation for Parkinson's Research and the EU-JPND program (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease [COURAGE-PD]).

Publisher Copyright:
© 2017 American Medical Association. All rights reserved.

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