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

Type of content
Journal Article
Thesis discipline
Degree name
Elsevier BV
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Volume Title
Nalls MA
Blauwendraat C
Vallerga CL
Heilbron K
Bandres-Ciga S
Chang D
Tan M
Kia DA
Noyce AJ
Xue A

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).

Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S, Chang D, Tan M, Kia DA, Noyce AJ, Xue A, Bras J, Young E, von Coelln R, Simón-Sánchez J, Schulte C, Sharma M, Krohn L, Pihlstrøm L, Siitonen A, Iwaki H, Leonard H, Faghri F, Gibbs JR, Hernandez DG, Scholz SW, Botia JA, Martinez M, Corvol JC, Lesage S, Jankovic J, Shulman LM, Sutherland M, Tienari P, Majamaa K, Toft M, Andreassen OA, Bangale T, Brice A, Yang J, Gan-Or Z, Gasser T, Heutink P, Shulman JM, Wood NW, Hinds DA, Hardy JA, Morris HR, Gratten J, Visscher PM, Graham RR, Singleton AB, Adarmes-Gómez AD, Aguilar M, Aitkulova A, Akhmetzhanov V, Alcalay RN, Alvarez I, Alvarez V, Barrero FJ, Bergareche Yarza JA, Bernal-Bernal I, Billingsley K, Blazquez M, Bonilla-Toribio M, Boungiorno MT, Brockmann K, Bubb V, Buiza-Rueda D, Cámara A, Carrillo F, Carrión-Claro M, Cerdan D, Chelban V, Clarimón J, Clarke C, Compta Y, Cookson MR, Craig DW, Danjou F, Diez-Fairen M, Dols-Icardo O, Duarte J, Duran R, Escamilla-Sevilla F, Escott-Price V, Ezquerra M, Feliz C, Fernández M, Fernández-Santiago R, Finkbeiner S, Foltynie T, Garcia C, García-Ruiz P, Gomez Heredia MJ, Gómez-Garre P, González MM, Gonzalez-Aramburu I, Guelfi S, Guerreiro R (2019). Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. The Lancet Neurology. 18(12). 1091-1102.
23andMe Research Team, System Genomics of Parkinson's Disease Consortium, International Parkinson's Disease Genomics Consortium, Humans, Parkinson Disease, Genetic Predisposition to Disease, Risk Factors, Databases, Genetic, Genome-Wide Association Study, Genetic Loci
Ngā upoko tukutuku/Māori subject headings
ANZSRC fields of research
1103 Clinical Sciences
1109 Neurosciences
Fields of Research::32 - Biomedical and clinical sciences::3209 - Neurosciences::320905 - Neurology and neuromuscular diseases
Fields of Research::32 - Biomedical and clinical sciences::3202 - Clinical sciences::320213 - Medical genetics (excl. cancer genetics)
Fields of Research::31 - Biological sciences::3105 - Genetics::310511 - Neurogenetics
Fields of Research::31 - Biological sciences::3105 - Genetics::310509 - Genomics
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