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Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases

Lookup NU author(s): Professor David Burn, Professor Patrick Chinnery, Dr Gavin Hudson

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Abstract

© 2017 American Medical Association. All rights reserved. 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.


Publication metadata

Author(s): Witoelar A, Jansen IE, Wang Y, Desikan RS, Gibbs JR, 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, Nalls MA, Plagnol V, Sheerin U-M, Saad M, Simon-Sanchez J, Schulte C, Sveinbjornsdottir S, Arepalli S, Barker R, Ben-Shlomo Y, Berendse HW, Berg D, Bhatia K, De Bie RMA, Biffi A, Bloem B, Bochdanovits Z, Bonin M, Bras JM, Brockmann K, Brooks J, Burn DJ, Majounie E, Charlesworth G, Lungu C, Chen H, Chinnery PF, Chong S, Clarke CE, Cookson MR, Cooper JM, Corvol JC, Counsell C, Damier P, Dartigues J-F, Deloukas P, Deuschl G, Dexter DT, Van Dijk KD, Dillman A, Durif F, Durr A, Edkins S, Evans JR, Foltynie T, Dong J, Gardner M, Goate A, Gray E, Guerreiro R, Harris C, Van Hilten JJ, Hofman A, Hollenbeck A, Holton J, Hu M, Huang X, Wurster I, Matzler W, Hudson G, Hunt SE, Huttenlocher J, Illig T, Jonsson PV, Lambert J-C, Langford C, Lees A, Lichtner P, Limousin P, Lopez G, Lorenz D, McNeill A, Moorby C, Moore M, Morrison KE, Escott-Price V, Mudanohwo E, O'Sullivan SS, Pearson J, Perlmutter JS, Petursson H, Pollak P, Post B, Potter S, Ravina B, Revesz T, Riess O, Rivadeneira F, Rizzu P, Ryten M, Sawcer S, Schapira A, Scheffer H, Shaw K, Shoulson I, Shulman J, Sidransky E, Smith C, Spencer CCA, Stefansson H, Stockton JD, Strange A, Talbot K, Tanner CM, Tashakkori-Ghanbaria A, Tison F, Trabzuni D, Traynor BJ, Uitterlinden AG, Velseboer D, Vidailhet M, Walker R, Van De Warrenburg B, Wickremaratchi M, Williams N, Williams-Gray CH, Winder-Rhodes S, Stefansson K, Martinez M, Ferrucci L, Johnson R, Longo DL, Nalls MA, O'Brien R, Troncoso J, Van Der Brug M, Zielke HR, Zonderman A, Hardy JA, Weale M

Publication type: Article

Publication status: Published

Journal: JAMA Neurology

Year: 2017

Volume: 74

Issue: 7

Pages: 780-792

Print publication date: 01/07/2017

Online publication date: 05/06/2017

Acceptance date: 08/03/2017

ISSN (print): 2168-6149

ISSN (electronic): 2168-6157

Publisher: American Medical Association

URL: https://doi.org/10.1001/jamaneurol.2017.0469

DOI: 10.1001/jamaneurol.2017.0469

PubMed id: 28586827


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