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    Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies (2019)

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    Nalls_Lancet with appendix_Noyce_Identification-of-novel-risk-loci-PD_NZBRI in System Genomics of PD_2019.pdf (3.462Mb)
    Type of Content
    Journal Article
    UC Permalink
    https://hdl.handle.net/10092/102173
    
    Publisher's DOI/URI
    http://doi.org/10.1016/S1474-4422(19)30320-5
    
    Publisher
    Elsevier BV
    ISSN
    1474-4422
    1474-4465
    Language
    eng
    Collections
    • Science: Journal Articles [1099]
    Authors
    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
    show all
    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).

    Citation
    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.
    This citation is automatically generated and may be unreliable. Use as a guide only.
    Keywords
    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
    ANZSRC Fields of Research
    32 - Biomedical and clinical sciences::3209 - Neurosciences::320905 - Neurology and neuromuscular diseases
    32 - Biomedical and clinical sciences::3202 - Clinical sciences::320213 - Medical genetics (excl. cancer genetics)
    31 - Biological sciences::3105 - Genetics::310511 - Neurogenetics
    31 - Biological sciences::3105 - Genetics::310509 - Genomics
    Rights
    All rights reserved unless otherwise stated
    http://hdl.handle.net/10092/17651

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