Abstract
Background: 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. Methods: 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. Findings: Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation: 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. Funding: 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).
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1091-1102 |
| Number of pages | 12 |
| Journal | The Lancet Neurology |
| Volume | 18 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2019 |
Funding
MAN reports that this work was done under a consulting contract with National Institutes of Health, he also consults for Lysosomal Therapeutics Inc, Neuron23, and Illumina. KH reports other support from 23andMe, during the conduct of the study outside the submitted work. DC reports other support from Genentech outside the submitted work. MT reports grants from Parkinson's UK during the conduct of the study. AJN reports grants from Parkinson's UK and Virginia Kieley benefaction; grants and non-financial support from GE Healthcare; and personal fees from Profile, Bial, and Britannia, outside the submitted work. RvC reports grants from American Brain Foundation and Michael and Eugenia Brin Foundation, during the conduct of the study. LP reports grants from Southeastern Regional Health Authority, Norway, during the conduct of the study. AS reports grants from Sigrid Juselius Foundation, during the conduct of the study. SWS is a scientific advisory council member for the Lewy Body Dementia Association. J-CC reports grants from French Ministry of Health, during the conduct of the study; grants from Sanofi, personal fees from Ever Pharma, Denali, Biogen, Air Liquide, BrainEver, and Theranexus, outside the submitted work. LMS reports grants from National Institutes of Health, outside the submitted work. PT has a patent c9orf72 in the diagnosis and treatment of neurodegenerative disease pending. MT reports grants from Research Council of Norway, Regional Health Authority South-Eastern Norway, and Michael J Fox Foundation, and personal fees from Roche, outside the submitted work. OAA reports grants from Research Council of Norway, and KG Jebsen Stiftelsen during the conduct of the study; and personal fees from Lundbeck, outside the submitted work; OAA also has a patent (PCT/US2014/011014) pending. TB reports other from Genentech, outside the submitted work. AB reports grants from France Parkinson and Fondation pour la Recherche sur le Cerveau, grants from Agence nationale de recherche (ANR) EPIG, grants from ANR joint program in neurodegenerative disease, grants from Roger de Spoelberch Foundation, France Alzheimer, Ecole des neurosciences Paris, Institut de France, CHU de Nimes, European Rare Disease Network, ANR EPIG, and APHP, outside the submitted work. ZG-O reports personal fees from Lysosomal Therapeutics, Idorsia, Inception Sciences, Denali, and Prevail Therapeutics, outside the submitted work. TG reports grants from The Michael J Fox Foundation for Parkinson's Research, personal fees from UCB Pharma, other from Joint Programming for Neurodegenerative Diseases program, funded by the European Commission, personal fees from Novartis, Teva, and MedUpdate, outside the submitted work; and has a patent issued (EP1802749 [A2] KASPP [LRRK2] gene), for the detection and treatment of neurodegenerative disorders issued PH is a consultant for NEURON23. JMS reports grants from Burroughs Wellcome Fund during the conduct of the study, grants from National Institutes of Health, and personal fees from Helis Medical Foundation, outside the submitted work. DAH reports other from 23andMe, outside the submitted work. HRM reports grants from NIHR Biomedical Research Centre, Parkinson's UK, Medical Research Council, and The Cure Parkinson's Trust, during the conduct of the study; grants from PSP Association and CBD Solutions, personal fees from Teva, Boehringer Ingelheim, GlaxoSmithKline, grants from Drake Foundation, personal fees from Biogen, UCB, and Biohaven, outside the submitted work. RRG reports other from Genentech, during the conduct of the study and other from Genentech, outside the submitted work. All other authors declare no competing interests.
ASJC Scopus subject areas
- Clinical Neurology