Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases.
Aree Witoelar,Iris E. Jansen,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 Brice,Nicholas W. Wood,Peter Heutink,John Hardy,Andrew B. Singleton,Anders M. Dale,Thomas Gasser,Ole A. Andreassen,Manu Sharma +26 more
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TLDR
The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes, which may have implications for future therapeutic trials involving anti-inflammatory agents.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 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 SE TD1A 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.read more
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Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications
TL;DR: A systematic review of the cellular mediators, i.e., microglia, astroglia and endothelial cells, and the genetic and transcriptional control of inflammation in PD and the immunomodulatory role of dopamine and reactive oxygen species is provided.
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Anti-Tumor Necrosis Factor Therapy and Incidence of Parkinson Disease Among Patients With Inflammatory Bowel Disease.
Inga Peter,Marla Dubinsky,Susan B. Bressman,Andrew Park,Changyue Lu,Naijun Chen,Anthony Wang +6 more
TL;DR: A higher incidence of PD was observed among patients with IBD than among individuals without IBD, and early exposure to antiinflammatory anti-TNF therapy was associated with substantially reduced PD incidence, suggesting a role of systemic inflammation in the pathogenesis of both diseases.
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Parkinson disease and the immune system - associations, mechanisms and therapeutics.
Eng-King Tan,Eng-King Tan,Yin Xia Chao,Yin Xia Chao,Andrew B. West,Ling Ling Chan,Ling Ling Chan,Werner Poewe,Joseph Jankovic +8 more
TL;DR: An overview of the clinical and preclinical evidence that immune system dysfunction is involved in Parkinson disease is provided, and how increasing knowledge of the underlying mechanisms is driving development of immune-based therapeutic approaches is discussed.
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Inflammation and immune dysfunction in Parkinson disease
Malú G. Tansey,Rebecca L. Wallings,Madelyn C. Houser,Mary K. Herrick,Cody E. Keating,Valerie Joers +5 more
TL;DR: Parkinson disease (PD) is a progressive neurodegenerative disease that affects peripheral organs as well as the central nervous system and involves a fundamental role of neuroinflammation in its pathophysiology as mentioned in this paper .
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Inflammatory bowel disease increases the risk of Parkinson’s disease: a Danish nationwide cohort study 1977–2014
TL;DR: This nationwide, unselected, cohort study shows a significant association between IBD and later occurrence of PD, which is consistent with recent basic scientific findings of a potential role of GI inflammation in development of parkinsonian disorders.
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