TY - JOUR
T1 - Genome-wide pleiotropy between Parkinson disease and autoimmune diseases
AU - for the International Parkinson's Disease Genomics Consortium (IPDGC), United Kingdom Brain Expression Consortium (UKBEC) Investigators, North American Brain Expression Consortium (NABEC)
AU - Witoelar, Aree
AU - Jansen, Iris E.
AU - Wang, Yunpeng
AU - Desikan, Rahul S.
AU - Gibbs, J. Raphael
AU - Blauwendraat, Cornelis
AU - Thompson, Wesley K.
AU - Hernandez, Dena G.
AU - Djurovic, Srdjan
AU - Schork, Andrew J.
AU - Bettella, Francesco
AU - Ellinghaus, David
AU - Franke, Andre
AU - Lie, Benedicte A.
AU - McEvoy, Linda K.
AU - Karlsen, Tom H.
AU - Lesage, Suzanne
AU - Morris, Huw R.
AU - Brice, Alexis
AU - Wood, Nicholas W.
AU - Heutink, Peter
AU - Hardy, John
AU - Singleton, Andrew B.
AU - Dale, Anders M.
AU - Gasser, Thomas
AU - Andreassen, Ole A.
AU - Sharma, Manu
AU - Nalls, Mike A.
AU - Plagnol, Vincent
AU - Sheerin, Una Marie
AU - Saad, Mohamad
AU - Simon-Sanchez, Javier
AU - Schulte, Claudia
AU - Sveinbjornsdottir, Sigurlaug
AU - Arepalli, Sampath
AU - Barker, Roger
AU - Ben-Shlomo, Yoav
AU - Berendse, Henk W.
AU - Berg, Daniela
AU - Bhatia, Kailash
AU - De Bie, Rob M.A.
AU - Biffi, Alessandro
AU - Bloem, Bas
AU - Bochdanovits, Zoltan
AU - Bonin, Michael
AU - Bras, Jose M.
AU - Brockmann, Kathrin
AU - Brooks, Janet
AU - Burn, David J.
AU - Majounie, Elisa
N1 - Publisher Copyright:
© 2017 American Medical Association. All rights reserved.
PY - 2017/7
Y1 - 2017/7
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85024384526
U2 - 10.1001/jamaneurol.2017.0469
DO - 10.1001/jamaneurol.2017.0469
M3 - Article
C2 - 28586827
AN - SCOPUS:85024384526
SN - 2168-6149
VL - 74
SP - 780
EP - 792
JO - JAMA Neurology
JF - JAMA Neurology
IS - 7
ER -