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JAMA Neurol. 2017 Jul 1;74(7):780-792. doi: 10.1001/jamaneurol.2017.0469.

Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases.

Author information

1
Norwegian Centre for Mental Disorders Research (NORMENT), K. G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo2Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
2
Department of Clinical Genetics, Vrije Universiteit (VU) University Medical Center, Amsterdam, the Netherlands4German Center for Neurodegenerative Diseases (DZNE), Tübingen.
3
Norwegian Centre for Mental Disorders Research (NORMENT), K. G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo5Multimodal Imaging Laboratory, University of California at San Diego, La Jolla.
4
Multimodal Imaging Laboratory, University of California at San Diego, La Jolla6Department of Radiology and Biomedical Imaging, University of California, San Francisco.
5
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland.
6
German Center for Neurodegenerative Diseases (DZNE), Tübingen.
7
Department of Psychiatry, University of California at San Diego, La Jolla9Department of Psychiatry, University of Copenhagen, Copenhagen, Denmark.
8
Norwegian Centre for Mental Disorders Research (NORMENT), K. G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo10Department of Medical Genetics, University of Oslo, Oslo, Norway11Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
9
Multimodal Imaging Laboratory, University of California at San Diego, La Jolla12Sciences Graduate Program, University of California at San Diego, La Jolla13Department of Neurosciences, University of California at San Diego, La Jolla.
10
Norwegian Centre for Mental Disorders Research (NORMENT), K. G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo.
11
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
12
Department of Medical Genetics, University of Oslo, Oslo, Norway11Department of Medical Genetics, Oslo University Hospital, Oslo, Norway15K. G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo, Norway16Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway17Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
13
Multimodal Imaging Laboratory, University of California at San Diego, La Jolla15K. G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo, Norway.
14
K. G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo, Norway16Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway18Division of Gastroenterology, Institute of Medicine, University of Bergen, Bergen, Norway19Norwegian Primary Sclerosing Cholangitis (PSC) Research Center, Department of Transplantation Medicine, Oslo.
15
Sorbonne Universités, Université Pierre-et-Marie Curie (UPMC) Paris 06, UM 1127, Institut du Cerveau et de la Moelle Epinière (ICM), Paris, France21Institut National de la Santé et de la Récherche Médicale (INSERM), Unité 1127, Institut du Cerveau et de la Moelle Epinière (ICM), Paris, France22Centre National de la Recherche Scientifique (CNRS) UMR 7225, Institut du Cerveau et de la Moelle Epinière (ICM), Paris, France23Institut du Cerveau et de la Moelle Epinière (ICM), Paris, France24Assistance Publique-Hôpitaux de Paris, Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, Paris, France.
16
Department of Clinical Neuroscience, National Hospital for Neurology and Neurosurgery (NHNN), University College London, London, England.
17
Department of Molecular Neurosciences, Institute of Neurology, University College London, London, England.
18
Department of Clinical Genetics, Vrije Universiteit (VU) University Medical Center, Amsterdam, the Netherlands4German Center for Neurodegenerative Diseases (DZNE), Tübingen27Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
19
Rita Lila Weston Institute, University College London, London, England.
20
Multimodal Imaging Laboratory, University of California at San Diego, La Jolla8Department of Psychiatry, University of California at San Diego, La Jolla13Department of Neurosciences, University of California at San Diego, La Jolla29Department of Radiology, University of California at San Diego, La Jolla.
21
German Center for Neurodegenerative Diseases (DZNE), Tübingen27Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
22
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany30Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany.

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 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.

PMID:
28586827
PMCID:
PMC5710535
DOI:
10.1001/jamaneurol.2017.0469
[Indexed for MEDLINE]
Free PMC Article

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