| Title: | Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies |
| Journal: | The Lancet Neurology |
| Published: | 1 Dec 2019 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/31701892/ |
| DOI: | https://doi.org/10.1016/s1474-4422(19)30320-5 |
| URL: | https://discovery.ucl.ac.uk/10085837/1/meta5_acceptedversion.pdf |
| Citations: | 1548 (643 in last 2 years) as of 8 Aug 2024 |
Publication 3631
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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.</p>
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.</p>
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).</p>
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.</p>
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).</p>
7 Keywords
- Databases, Genetic
- Genetic Loci
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Parkinson Disease
- Risk Factors
273 Authors
- Mike A Nalls
- Cornelis Blauwendraat
- Costanza L Vallerga
- Karl Heilbron
- Sara Bandres-Ciga
- Diana Chang
- Manuela Tan
- Demis A Kia
- Alastair J Noyce
- Angli Xue
- Jose Bras
- Emily Young
- Rainer von Coelln
- Javier Simón-Sánchez
- Claudia Schulte
- Manu Sharma
- Lynne Krohn
- Lasse Pihlstrøm
- Ari Siitonen
- Hirotaka Iwaki
- Hampton Leonard
- Faraz Faghri
- J Raphael Gibbs
- Dena G Hernandez
- Sonja W Scholz
- Juan A Botia
- Maria Martinez
- Jean-Christophe Corvol
- Suzanne Lesage
- Joseph Jankovic
- Lisa M Shulman
- Margaret Sutherland
- Pentti Tienari
- Kari Majamaa
- Mathias Toft
- Ole A Andreassen
- Tushar Bangale
- Alexis Brice
- Jian Yang
- Ziv Gan-Or
- Thomas Gasser
- Peter Heutink
- Joshua M Shulman
- Nicholas W Wood
- David A Hinds
- John A Hardy
- Huw R Morris
- Jacob Gratten
- Peter M Visscher
- Robert R Graham
- Andrew B Singleton
- 23andMe Research Team
- System Genomics of Parkinson's Disease Consortium
- International Parkinson's Disease Genomics Consortium
- Astrid D Adarmes-Gómez
- Miquel Aguilar
- Akbota Aitkulova
- Vadim Akhmetzhanov
- Roy N Alcalay
- Ignacio Alvarez
- Victoria Alvarez
- Sara Bandres-Ciga
- Francisco Javier Barrero
- Jesús Alberto Bergareche Yarza
- Inmaculada Bernal-Bernal
- Kimberley Billingsley
- Cornelis Blauwendraat
- Marta Blazquez
- Marta Bonilla-Toribio
- Juan A Botía
- María Teresa Boungiorno
- Jose Bras
- Alexis Brice
- Kathrin Brockmann
- Vivien Bubb
- Dolores Buiza-Rueda
- Ana Cámara
- Fátima Carrillo
- Mario Carrión-Claro
- Debora Cerdan
- Viorica Chelban
- Jordi Clarimón
- Carl Clarke
- Yaroslau Compta
- Mark R Cookson
- Jean-Christophe Corvol
- David W Craig
- Fabrice Danjou
- Monica Diez-Fairen
- Oriol Dols-Icardo
- Jacinto Duarte
- Raquel Duran
- Francisco Escamilla-Sevilla
- Valentina Escott-Price
- Mario Ezquerra
- Faraz Faghri
- Cici Feliz
- Manel Fernández
- Rubén Fernández-Santiago
- Steven Finkbeiner
- Thomas Foltynie
- Ziv Gan-Or
- Ciara Garcia
- Pedro García-Ruiz
- Thomas Gasser
- J Raphael Gibbs
- Maria Jose Gomez Heredia
- Pilar Gómez-Garre
- Manuel Menéndez González
- Isabel Gonzalez-Aramburu
- Sebastian Guelfi
- Rita Guerreiro
- John Hardy
- Sharon Hassin-Baer
- Dena G Hernandez
- Peter Heutink
- Janet Hoenicka
- Peter Holmans
- Henry Houlden
- Jon Infante
- Hirotaka Iwaki
- Silvia Jesús
- Adriano Jimenez-Escrig
- Gulnaz Kaishybayeva
- Rauan Kaiyrzhanov
- Altynay Karimova
- Demis A Kia
- Kerri J Kinghorn
- Sulev Koks
- Lynne Krohn
- Jaime Kulisevsky
- Miguel A Labrador-Espinosa
- Hampton L Leonard
- Suzanne Lesage
- Patrick Lewis
- Jose Luis Lopez-Sendon
- Ruth Lovering
- Steven Lubbe
- Codrin Lungu
- Daniel Macias
- Kari Majamaa
- Claudia Manzoni
- Juan Marín
- Johan Marinus
- Maria Jose Marti
- Maria Martinez
- Irene Martínez Torres
- Juan Carlos Martínez-Castrillo
- Marina Mata
- Niccolo E Mencacci
- Carlota Méndez-del-Barrio
- Ben Middlehurst
- Adolfo Mínguez
- Pablo Mir
- Kin Y Mok
- Huw R Morris
- Esteban Muñoz
- Mike A Nalls
- Derek Narendra
- Alastair J Noyce
- Oluwadamilola O Ojo
- Njideka U Okubadejo
- Ana Gorostidi Pagola
- Pau Pastor
- Francisco Perez Errazquin
- Teresa Periñán-Tocino
- Lasse Pihlstrom
- Helene Plun-Favreau
- John Quinn
- Lea R'Bibo
- Xylena Reed
- Elisabet Mondragon Rezola
- Mie Rizig
- Patrizia Rizzu
- Laurie Robak
- Antonio Sanchez Rodriguez
- Guy A Rouleau
- Javier Ruiz-Martínez
- Clara Ruz
- Mina Ryten
- Dinara Sadykova
- Sonja W Scholz
- Sebastian Schreglmann
- Claudia Schulte
- Manu Sharma
- Chingiz Shashkin
- Joshua M Shulman
- María Sierra
- Ari Siitonen
- Javier Simón-Sánchez
- Andrew B Singleton
- Esther Suarez-Sanmartin
- Pille Taba
- Cesar Tabernero
- Manuela X Tan
- Juan Pablo Tartari
- Cristina Tejera-Parrado
- Mathias Toft
- Eduard Tolosa
- Daniah Trabzuni
- Francesc Valldeoriola
- Jacobus J van Hilten
- Kendall Van Keuren-Jensen
- Laura Vargas-González
- Lydia Vela
- Francisco Vives
- Nigel Williams
- Nicholas W Wood
- Nazira Zharkinbekova
- Zharkyn Zharmukhanov
- Elena Zholdybayeva
- Alexander Zimprich
- Pauli Ylikotila
- Lisa M. Shulman
- Rainer von Coelln
- Stephen Reich
- Joseph Savitt
- Michelle Agee
- Babak Alipanahi
- Adam Auton
- Robert K. Bell
- Katarzyna Bryc
- Sarah L. Elson
- Pierre Fontanillas
- Nicholas A. Furlotte
- Karen E. Huber
- Barry Hicks
- Ethan M. Jewett
- Yunxuan Jiang
- Aaron Kleinman
- Keng-Han Lin
- Nadia K. Litterman
- Jennifer C. McCreight
- Matthew H. McIntyre
- Kimberly F. McManus
- Joanna L. Mountain
- Elizabeth S. Noblin
- Carrie A.M. Northover
- Steven J. Pitts
- G. David Poznik
- J. Fah Sathirapongsasuti
- Janie F. Shelton
- Suyash Shringarpure
- Chao Tian
- Joyce Tung
- Vladimir Vacic
- Xin Wang
- Catherine H. Wilson
- Tim Anderson
- Steven Bentley
- John Dalrymple-Alford
- Javed Fowdar
- Jacob Gratten
- Glenda Halliday
- Anjali K. Henders
- Ian Hickie
- Irfahan Kassam
- Martin Kennedy
- John Kwok
- Simon Lewis
- George Mellick
- Grant Montgomery
- John Pearson
- Toni Pitcher
- Julia Sidorenko
- Peter A. Silburn
- Costanza L. Vallerga
- Peter M. Visscher
- Leanne Wallace
- Naomi R. Wray
- Angli Xue
- Jian Yang
- Futao Zhang
1 Application
| Application ID | Title |
|---|---|
| 12505 | Dissecting the genetic basis of relationships between early-life and later-life events |
Enabling scientific discoveries that improve human health