Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies
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Résumé
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: ). 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).
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La notice
- Revue
- The Lancet Neurology
- Thématique
- Parkinson's Disease Mechanisms and Treatments
- Domaine
- Medicine
- Établissements canadiens
- McGill UniversityMontreal Neurological Institute and Hospital
- Organismes subventionnaires
- Division of Human Resource ManagementNational Institute on AgingMedical Research CouncilSchool of Public Health, University of California BerkeleyFédération pour la Recherche sur le CerveauNorges ForskningsrådAgence Nationale de la RechercheChung Hua UniversityObstetric Anaesthetists' AssociationBiogenLondon Mathematical SocietyParkinson's UKNovartisPSP AssociationAdrienne Helis Malvin Medical Research FoundationGE HealthcareNorth Carolina GlaxoSmithKline FoundationNational Institutes of HealthRosetrees TrustAssociation France ParkinsonEuropean CommissionSanofiBarts CharityBoehringer IngelheimMichael J. Fox Foundation for Parkinson's ResearchRocheInstitut de FranceFondation Roger de SpoelberchH. Lundbeck A/SBurroughs Wellcome Fund
- Mots-clés
- Genome-wide association studyDiseaseLRRK2Genetic associationSingle-nucleotide polymorphismMendelian randomizationGeneticsBiologyMeta-analysisMendelian inheritanceHeritabilityMissing heritability problemParkinson's diseaseBioinformaticsMedicineGenotypeGeneGenetic variantsInternal medicine
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