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Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases
Open accessAbstract
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.
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“Multiple common genetic variants between PD patients and other inflammatory diseases have been identified.249,250”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [249]
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“Genomewide association studies have alluded to a significant genetic overlap between Parkinson's disease and autoimmune diseases.97”
From The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options (2021) · cites this paper as [97]
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Sorted by citations
Role of neuroinflammation in neurodegeneration development
Zhang, W., Xiao, D., Mao, Q., & Xia, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01486-5 · Cited by 1,668
“Multiple common genetic variants between PD patients and other inflammatory diseases have been identified.(249,250) In addition, GWAS have identified several immune-related gene variants in PD,(251) including leucine rich repeat kinase 2 (LRRK2), glucosylceramidase (GBA), parkin RBR E3 ubiquitin protein ligase (PRKN)…”
BackgroundInflammation and immune dysfunction in Parkinson disease
Tansey, M. G., Wallings, R. L., Houser, M. C., Herrick, M. K., Keating, C. E., & Joers, V. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-022-00684-6 · Cited by 1,382
Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications
Pajares, M., I. Rojo, A., Manda, G., Boscá, L., & Cuadrado, A. (2020) · Cells · doi:10.3390/cells9071687 · Cited by 779
Parkinson disease and the immune system - Associations, mechanisms and therapeutics
Tan, E.-K., Chao, Y.-X., West, A., Chan, L.-L., Poewe, W., & Jankovic, J. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-0344-4 · Cited by 457
Ülgen, E., Özışık, O., & Sezerman, O. U. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00858 · Cited by 471
Metadata
- Authors
- Witoelar, A., Jansen, I. E., Wang, Y., Desikan, R. S., Gibbs, J. R., Blauwendraat, C., Thompson, W. K., Hernandez, D. G., Djurovic, S., Schork, A. J., Bettella, F., Ellinghaus, D., Franke, A., Lie, B. A., McEvoy, L. K., Karlsen, T. H., Lesage, S., Morris, H. R., Brice, A., Wood, N. W., Heutink, P., Hardy, J., Singleton, A. B., Dale, A. M., Gasser, T., Andreassen, O. A., Sharma, M., & for the International Parkinson’s Disease Genomics Consortium (IPDGC), N. A. B. E. C. (.
- Affiliations
- Oslo University Hospital (NO)
- German Center for Neurodegenerative Diseases (DE)
- University of Oslo (NO)
- University of California, San Francisco (US)
- National Institutes of Health (US)
- University of Copenhagen (DK)
- University of California San Diego (US)
- Christian-Albrechts-Universität zu Kiel (DE)
- Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany
- Centre National de la Recherche Scientifique (FR)
- National Hospital for Neurology and Neurosurgery (GB)
- UCL Queen Square Institute of Neurology (GB)
- University College London (GB)
- Hertie Institute for Clinical Brain Research (DE)
- Corresponding author
- Sharma, Manu
- ORCID
- Witoelar, Aree
- Jansen, Iris E.
- Wang, Yunpeng
- Desikan, Rahul S.
- Gibbs, J. Raphael
- Blauwendraat, Cornelis
- Thompson, Wesley K.
- Hernandez, Dena G.
- Djurovic, Srdjan
- Schork, Andrew J.
- Bettella, Francesco
- Ellinghaus, David
- Lie, Benedicte A.
- McEvoy, Linda K.
- Karlsen, Tom H.
- Lesage, Suzanne
- Morris, Huw R.
- Brice, Alexis
- Wood, Nicholas W.
- Heutink, Peter
- Hardy, John
- Singleton, Andrew B.
- Dale, Anders M.
- Gasser, Thomas
- Andreassen, Ole A.
- Sharma, Manu
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2017-07-01
- Volume
- 74
- Issue
- 7
- Pages
- 780
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC5710535
- OpenAlex
- W2622719965
- Semantic Scholar
- 77f8aa61d1d32875fc37fcce3fe356cd20cd596e
- Cited by
- 352
- References
- 84
- Citations by year
- 2026: 14 · 2025: 39 · 2024: 60 · 2023: 41 · 2022: 39 · 2021: 62 · 2020: 34 · 2019: 30 · 2018: 24 · 2017: 7
- FWCI
- 18.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Neurology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- HAL (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Site cant be reached (submittedVersion)
- DZNE Pub (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Biogen
- Washington University in St. Louis
- Johns Hopkins University
- University of Rochester
- Wellcome Trust
- Sandwell and West Birmingham Hospitals NHS Trust
- University Hospitals Birmingham NHS Foundation Trust
- Université de Lille
- Parkinson's UK (G-0907, J-0901, J-1402, K-1501)
- Imperial College London
- University College London
- University of Oxford
- Newcastle University
- Cardiff University
- University of Aberdeen
- Institut National de la Santé et de la Recherche Médicale
- Universiteit Leiden
- Universiteit van Amsterdam
- Radboud Universiteit
- Vrije Universiteit Amsterdam
- Eberhard Karls Universität Tübingen
- Centre National de la Recherche Scientifique
- Leids Universitair Medisch Centrum
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- Université Pierre et Marie Curie
- National Institutes of Health
- Genentech
- Medical Research Council
- Erasmus Universitair Medisch Centrum Rotterdam
- Helmholtz Zentrum München
- National Human Genome Research Institute
- National Institute of General Medical Sciences (R01GM104400)
- National Institute of Neurological Disorders and Stroke
- NIH Clinical Center
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Keywords
- Parkinson's disease, autoimmune disease, pleiotropy, type 1 diabetes, Crohn's disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, multiple sclerosis, LRRK2, HLA, MAPT, SETD1A, protein-protein interaction network, DNA methylation, gene expression, anti-inflammatory therapy
- MeSH terms
- Arthritis, Rheumatoid, Autoimmune Diseases, Celiac Disease, Colitis, Ulcerative, Crohn Disease, Diabetes Mellitus, Type 1, Humans, Multiple Sclerosis, Parkinson Disease, Psoriasis, Risk Factors, Genetic Predisposition to Disease, Genome-Wide Association Study, Genetic Loci, Genetic Pleiotropy
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