Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Abstract

Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources).

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Affiliated Institutions

• University of Tübingen DE
• Université Toulouse III - Paul Sabatier FR
• Mater Research AU
• Assistance Publique – Hôpitaux de Paris FR
• Helsinki University Hospital FI
• Sorbonne Université FR
• University College London GB
• Texas Children's Hospital US
• National Institute on Aging US
• National Institute of Neurological Disorders and Stroke US
• Hertie Institute for Clinical Brain Research DE
• Michael J. Fox Foundation US
• University of Oslo
• Baylor College of Medicine US
• German Center for Neurodegenerative Diseases DE
• Sorbonne Paris Cité FR
• National Institutes of Health US
• University Medical Center US
• Centre National de la Recherche Scientifique FR
• Oslo University Hospital
• Montreal Neurological Institute and Hospital CA
• University of Illinois Urbana-Champaign US
• The University of Queensland AU
• University of Maryland, Baltimore US
• Oulu University Hospital FI
• Van Andel Institute US
• Inserm FR
• Neurological Research Institute US
• National Hospital for Neurology and Neurosurgery GB
• 23andMe (United States) US
• Data Tecnica International (United States) US
• Queen Mary University of London GB
• University of Oulu FI
• Universidad de Murcia ES
• University of Helsinki FI
• McGill University CA
• Johns Hopkins University US
• Institut du Cerveau FR

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