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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
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, Volume 18, No. 12, Year 2019
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Description
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). © 2019 Elsevier Ltd
Authors & Co-Authors
Nalls, Mike A.
United States, Bethesda
National Institutes of Health Nih
United States, Glen Echo
Data Tecnica International
Blauwendraat, Cornelis
United States, Bethesda
National Institutes of Health Nih
Bandres-Ciga, Sara
United States, Bethesda
National Institutes of Health Nih
Tan, Manuela M.X.
United Kingdom, London
Ucl Queen Square Institute of Neurology
United Kingdom, London
University College London
Kia, Demis A.
United Kingdom, London
Ucl Queen Square Institute of Neurology
United Kingdom, London
University College London
Noyce, Alastair John
United Kingdom, London
Ucl Queen Square Institute of Neurology
United Kingdom, London
Queen Mary University of London
Brás, José Miguel
United Kingdom, London
Ucl Queen Square Institute of Neurology
United States, Grand Rapids
Van Andel Research Institute
Simón-Sánchez, Javier
Germany, Tubingen
Eberhard Karls Universität Tübingen
Germany, Bonn
Deutsches Zentrum Für Neurodegenerative Erkrankungen
Schulte, Claudia M.S.
Germany, Tubingen
Eberhard Karls Universität Tübingen
Germany, Bonn
Deutsches Zentrum Für Neurodegenerative Erkrankungen
Sharma, Manu
Germany, Tubingen
Eberhard Karls Universität Tübingen
Krohn, Lynne
Canada, Montreal
Université Mcgill
Pihlstrom, Lasse
Norway, Oslo
Oslo Universitetssykehus
Iwaki, Hirotaka
United States, Bethesda
National Institutes of Health Nih
United States, Glen Echo
Data Tecnica International
United States, New York
The Michael J. Fox Foundation for Parkinson‘s Research
Leonard, Hampton L.
United States, Bethesda
National Institutes of Health Nih
United States, Glen Echo
Data Tecnica International
Faghri, Faraz
United States, Bethesda
National Institutes of Health Nih
United States, Urbana
University of Illinois Urbana-champaign
Gibbs, J. Raphael
United States, Bethesda
National Institutes of Health Nih
Hernandez, Dena G.
United States, Bethesda
National Institutes of Health Nih
Scholz, Sonja W.
United States, Bethesda
National Institutes of Health Nih
United States, Baltimore
Johns Hopkins University
Botia, Juan A.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Spain, Murcia
Universidad de Murcia
Martinez, Maria M.
France, Paris
Inserm
France, Toulouse
Université Toulouse Iii - Paul Sabatier
Corvol, Jean Christophe
France, Paris
Institut du Cerveau et de la Moelle Épinière
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Lesage, Suzanne
France, Paris
Institut du Cerveau et de la Moelle Épinière
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Jankovic, Joseph J.
United States, Houston
Baylor College of Medicine
Toft, Mathias
Norway, Oslo
Oslo Universitetssykehus
Norway, Oslo
Universitetet I Oslo
Andreassen, Ole Andreas
Norway, Oslo
Oslo Universitetssykehus
Norway, Oslo
Universitetet I Oslo
Brice, Alexis
France, Paris
Institut du Cerveau et de la Moelle Épinière
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
YANG, Jian
Australia, Brisbane
The University of Queensland
Gan-Or, Ziv
Canada, Montreal
Université Mcgill
Gasser, Thomas
Germany, Tubingen
Eberhard Karls Universität Tübingen
Germany, Bonn
Deutsches Zentrum Für Neurodegenerative Erkrankungen
Heutink, Peter
Germany, Tubingen
Eberhard Karls Universität Tübingen
Germany, Bonn
Deutsches Zentrum Für Neurodegenerative Erkrankungen
Shulman, Joshua M.
United States, Houston
Baylor College of Medicine
United States, Houston
Texas Children's Hospital
Wood, Nick William
United Kingdom, London
Ucl Queen Square Institute of Neurology
United Kingdom, London
University College London
Hinds, David A.
United States, Mountain View
23andme Inc.
Hardy, John A.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Morris, Huw R.
United Kingdom, London
University College London
Gratten, Jacob
Australia, Brisbane
The University of Queensland
Visscher, Peter M.
Australia, Brisbane
The University of Queensland
Singleton, Andrew B.
United States, Bethesda
National Institutes of Health Nih
Adarmes-GɃmez, Astrid D.
Unknown Affiliation
Aguilar, Miquel Chávez
Unknown Affiliation
Alcalay, Roy N.
Unknown Affiliation
Alvarez, Ignacio
Unknown Affiliation
Álvarez, Victoria M.P.
Unknown Affiliation
Barrero, Francisco Javier
Unknown Affiliation
Bergareche Yarza, Jesús Alberto
Unknown Affiliation
Bernal-Bernal, Inmaculada
Unknown Affiliation
Billingsley, Kimberley J.
Unknown Affiliation
Blázquez Estrada, Marta
Unknown Affiliation
Bonilla-Toribio, Marta
Unknown Affiliation
Boungiorno, María Teresa
Unknown Affiliation
Brockmann, Kathrin
Unknown Affiliation
Bubb, Vivien Jill
Unknown Affiliation
Buiza-Rueda, Dolores
Unknown Affiliation
Cámara, Ana
Unknown Affiliation
Carrillo, Fátima
Unknown Affiliation
Carrion-Claro, Mario
Unknown Affiliation
Cerdán, Débora María
Unknown Affiliation
Chelban, Viorica
Unknown Affiliation
Clarimón, Jordi
Unknown Affiliation
Clarke, Carl E.
Unknown Affiliation
Compta, Yaroslau
Unknown Affiliation
Cookson, Mark Robert
Unknown Affiliation
Craig, David Wesley
Unknown Affiliation
Danjou, Fabrice
Unknown Affiliation
Diez-Fairen, Monica
Unknown Affiliation
Dols-Icardo, Oriol
Unknown Affiliation
Duarte, Jacinto
Unknown Affiliation
Duran, R. L.
Unknown Affiliation
Escamilla, Francisco
Unknown Affiliation
Escott-Price, Valentina
Unknown Affiliation
Ezquerra, Mario
Unknown Affiliation
Feliz, Cici E.
Unknown Affiliation
Fernández-Martínez, Manuel Jesús
Unknown Affiliation
Fernández-Santiago, Rubén
Unknown Affiliation
Finkbeiner, Steven M.
Unknown Affiliation
Foltynie, Thomas
Unknown Affiliation
Garcia, Ciara
Unknown Affiliation
García-Ruiz, Pedro J.
Unknown Affiliation
Gómez-Garre, Pilar
Unknown Affiliation
Menendez-Gonzalez, Manuel
Unknown Affiliation
González-Aramburu, Isabel
Unknown Affiliation
Guelfi, Sebastian
Unknown Affiliation
Guerreiro, Rita João
Unknown Affiliation
Hassin-Baer, Sharon
Unknown Affiliation
Holmans, Peter A.
Unknown Affiliation
Houlden, Henry H.
Unknown Affiliation
Infante-Ceberio, Jon
Unknown Affiliation
Jesús, Silvia
Unknown Affiliation
Kaiyrzhanov, Rauan
Unknown Affiliation
Kinghorn, Kerri J.
Unknown Affiliation
Kõks, Sulev V.
Unknown Affiliation
Labrador-Espinosa, Miguel A.
Unknown Affiliation
Lewis, Patrick A.
Unknown Affiliation
Lovering, Ruth C.
Unknown Affiliation
Lubbe, Steven J.
Unknown Affiliation
Lungu, Codrin I.
Unknown Affiliation
Macías, Daniel
Unknown Affiliation
Manzoni, Claudia
Unknown Affiliation
Marinus, Johan
Unknown Affiliation
Martí, María José
Unknown Affiliation
Mencacci, Niccolò Emanuele
Unknown Affiliation
Méndez-Del-Barrio, Carlota
Unknown Affiliation
Middlehurst, Ben
Unknown Affiliation
Mir, Pablo
Unknown Affiliation
Mok, Kin Y.
Unknown Affiliation
Narendra, Derek P.
Unknown Affiliation
Ojo, Oluwadamilola Omolara
Unknown Affiliation
Okubadejo, Njideka U.
Unknown Affiliation
Pagola, Ana Gorostidi
Unknown Affiliation
Pástor, Pau
Unknown Affiliation
Periñan, Maria Teresa
Unknown Affiliation
Plun-Favreau, Hélène
Unknown Affiliation
Quinn, John P.
Unknown Affiliation
Reed, Xylena
Unknown Affiliation
Rezola, Elisabet Mondragón
Unknown Affiliation
Rizig, Mie A.
Unknown Affiliation
Rizzu, Patrizia
Unknown Affiliation
Robak, Laurie A.
Unknown Affiliation
Rouleau, Guy Armand
Unknown Affiliation
Ruíz-Martínez, Javier
Unknown Affiliation
Ryten, Mina
Unknown Affiliation
Sadykova, Dinara Z.
Unknown Affiliation
Schreglmann, Sebastian R.
Unknown Affiliation
Shashkin, Chingiz
Unknown Affiliation
Suarez-Sanmartin, Esther
Unknown Affiliation
Taba, Pille
Unknown Affiliation
Tan, Manuela M.X.
Unknown Affiliation
Tartari, Juan Pablo
Unknown Affiliation
Tejera-Parrado, Cristina
Unknown Affiliation
Tolosa, Eduardo S.
Unknown Affiliation
Trabzuni, Daniah
Unknown Affiliation
van Hilten, Jacobus Johannes Bob
Unknown Affiliation
Van Keuren-Jensen, Kendall R.
Unknown Affiliation
Vargas-González, Laura
Unknown Affiliation
Vives, F.
Unknown Affiliation
Williams, Nigel M.
Unknown Affiliation
Zharkinbekova, N. A.
Unknown Affiliation
Zimprich, Alexander
Unknown Affiliation
Reich, Stephen G.
Unknown Affiliation
Auton, Adam
Unknown Affiliation
Bell, Robert K.
Unknown Affiliation
Bryc, Katarzyna
Unknown Affiliation
Elson, Sarah L.
Unknown Affiliation
Fontanillas, Pierre
Unknown Affiliation
Furlotte, Nicholas A.
Unknown Affiliation
Huber, Karen E.
Unknown Affiliation
Jewett, Ethan M.
Unknown Affiliation
Kleinman, Aaron
Unknown Affiliation
Litterman, Nadia K.
Unknown Affiliation
McIntyre, Matthew H.
Unknown Affiliation
Mountain, Joanna L.
Unknown Affiliation
Noblin, Elizabeth S.
Unknown Affiliation
Northover, Carrie A.M.
Unknown Affiliation
Pitts, Steven J.
Unknown Affiliation
Poznik, G. David
Unknown Affiliation
Sathirapongsasuti, Jarupon Fah
Unknown Affiliation
Shelton, Janie F.
Unknown Affiliation
Shringarpure, Suyash S.
Unknown Affiliation
Tian, Chao
Unknown Affiliation
Tung, Joyce Y.
Unknown Affiliation
Vacic, Vladimir
Unknown Affiliation
Wilson, Catherine H.
Unknown Affiliation
Dalrymple-Alford, J. C.
Unknown Affiliation
Halliday, Glenda Margaret
Unknown Affiliation
Henders, Anjali K.
Unknown Affiliation
Hickie, I. Bernard
Unknown Affiliation
Kennedy, Martin A.
Unknown Affiliation
Kwok, John B.J.
Unknown Affiliation
Mellick, George D.
Unknown Affiliation
Montgomery, Grant W.
Unknown Affiliation
Pitcher, Toni L.
Unknown Affiliation
Silburn, Peter A.S.
Unknown Affiliation
Wray, Naomi R.
Unknown Affiliation
Zhang, Futao
Unknown Affiliation
Statistics
Citations: 918
Authors: 174
Affiliations: 29
Identifiers
Doi:
10.1016/S1474-4422(19)30320-5
ISSN:
14744422
Research Areas
Genetics And Genomics
Study Design
Cross Sectional Study
Cohort Study
Study Approach
Quantitative
Systematic review