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

Mike Nalls; Cornelis Blauwendraat; Costanza Vallerga; Karl Heilbron; Sara Bandres-Ciga; Diana Chang; Manuela Tan; Demis Kia; Alastair 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 Hernandez; Sonja Scholz; Juan Botia; Maria Martinez; Jean-Christophe Corvol; Suzanne Lesage; Joseph Jankovic; Lisa Shulman; Margaret Sutherland; Pentti Tienari; Kari Majamaa; Mathias Toft; Ole Andreassen; Tushar Bangale; Alexis Brice; Jian Yang; Ziv Gan-Or; Thomas Gasser; Peter Heutink; Joshua Shulman; Nicholas Wood; David Hinds; John Hardy; Huw Morris; Jacob Gratten; Peter Visscher; Robert Graham; Andrew Singleton; Astrid Adarmes-Gómez; Miquel Aguilar; Akbota Aitkulova; Vadim Akhmetzhanov; Roy 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 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 Cookson; Jean-Christophe Corvol; David 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 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 Kia; Kerri Kinghorn; Sulev Koks; Lynne Krohn; Jaime Kulisevsky; Miguel Labrador-Espinosa; Hampton 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 Mencacci; Carlota Méndez-Del-Barrio; Ben Middlehurst; Adolfo Mínguez; Pablo Mir; Kin Mok; Huw Morris; Esteban Muñoz; Mike Nalls; Derek Narendra; Alastair Noyce; Oluwadamilola Ojo; Njideka 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 Rouleau; Javier Ruiz-Martínez; Clara Ruz; Mina Ryten; Dinara Sadykova; Sonja Scholz; Sebastian Schreglmann; Claudia Schulte; Manu Sharma; Chingiz Shashkin; Joshua Shulman; María Sierra; Ari Siitonen; Javier Simón-Sánchez; Andrew Singleton; Esther Suarez-Sanmartin; Pille Taba; Cesar Tabernero; Manuela Tan; Juan Pablo Tartari; Cristina Tejera-Parrado; Mathias Toft; Eduard Tolosa; Daniah Trabzuni; Francesc Valldeoriola; Jacobus van Hilten; Kendall van Keuren-Jensen; Laura Vargas-González; Lydia Vela; Francisco Vives; Nigel Williams; Nicholas Wood; Nazira Zharkinbekova; Zharkyn Zharmukhanov; Elena Zholdybayeva; Alexander Zimprich; Pauli Ylikotila; Lisa Shulman; Rainer von Coelln; Stephen Reich; Joseph Savitt; Michelle Agee; Babak Alipanahi; Adam Auton; Robert Bell; Katarzyna Bryc; Sarah Elson; Pierre Fontanillas; Nicholas Furlotte; Karen Huber; Barry Hicks; Ethan Jewett; Yunxuan Jiang; Aaron Kleinman; Keng-Han Lin; Nadia Litterman; Jennifer Mccreight; Matthew Mcintyre; Kimberly Mcmanus; Joanna Mountain; Elizabeth Noblin; Carrie A.M. Northover; Steven Pitts; G. David Poznik; J. Fah Sathirapongsasuti; Janie Shelton; Suyash Shringarpure; Chao Tian; Joyce Tung; Vladimir Vacic; Xin Wang; Catherine Wilson; Tim Anderson; Steven Bentley; John Dalrymple-Alford; Javed Fowdar; Jacob Gratten; Glenda Halliday; Anjali Henders; Ian Hickie; Irfahan Kassam; Martin Kennedy; John Kwok; Simon Lewis; George Mellick; Grant Montgomery; John Pearson; Toni Pitcher; Julia Sidorenko; Peter Silburn; Costanza Vallerga; Peter Visscher; Leanne Wallace; Naomi Wray; Angli Xue; Jian Yang; Futao Zhang

doi:10.1016/S1474-4422(19)30320-5

Journal Articles The Lancet Neurology Year : 2019

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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Mike Nalls

Function : Author

National Institutes of Health [Bethesda, MD, USA]

Cornelis Blauwendraat

Function : Author

National Institutes of Health [Bethesda, MD, USA]

Costanza Vallerga

Function : Author

The University of Queensland

Karl Heilbron

Function : Author

23andMe Inc.

Sara Bandres-Ciga

Function : Author

National Institute on Aging [Bethesda, USA]

ibs.GRANADA Instituto de Investigación Biosanitaria [Granada, Spain]

Diana Chang

Function : Author

Manuela Tan

Function : Author

UCL Queen Square Institute of Neurology

Demis Kia

Function : Author

UCL Institute of Neurology, Queen Square [London]

Alastair Noyce

Function : Author

Queen Mary University of London

UCL Queen Square Institute of Neurology

Angli Xue

Function : Author

Jose Bras

Function : Author

Emily Young

Function : Author

Rainer von Coelln

Function : Author

University of Maryland School of Medicine

Javier Simón-Sánchez

Function : Author

Deutsches Zentrum für Neurodegenerative Erkrankungen [Ulm]

Hertie Institute for Clinical Brain Research [Tubingen]

Claudia Schulte

Function : Author

Deutsches Zentrum für Neurodegenerative Erkrankungen [Ulm]

Hertie Institute for Clinical Brain Research [Tubingen]

Manu Sharma

Function : Author

Eberhard Karls Universität Tübingen = University of Tübingen

Lynne Krohn

Function : Author

McGill University = Université McGill [Montréal, Canada]

Montreal Neurological Institute and Hospital

Lasse Pihlstrøm

Function : Author

Oslo University Hospital [Oslo]

Ari Siitonen

Function : Author

University of Oulu

Oulu University Hospital [Oulu]

Hirotaka Iwaki

Function : Author

National Institute on Aging [Bethesda, USA]

The Michael J Fox Foundation for Parkinson's Research

Hampton Leonard

Function : Author

Faraz Faghri

Function : Author

J Raphael Gibbs

Function : Author

Dena Hernandez

Function : Author

Sonja Scholz

Function : Author

Juan Botia

Function : Author

Maria Martinez

Function : Author

Université Toulouse III - Paul Sabatier

Jean-Christophe Corvol

Function : Author

Institut du Cerveau = Paris Brain Institute

Suzanne Lesage

Function : Author

Institut du Cerveau = Paris Brain Institute

Joseph Jankovic

Function : Author

Lisa Shulman

Function : Author

Margaret Sutherland

Function : Author

Pentti Tienari

Function : Author

Kari Majamaa

Function : Author

Mathias Toft

Function : Author

Ole Andreassen

Function : Author

Tushar Bangale

Function : Author

Alexis Brice

Function : Author
PersonId : 1104774
ORCID : 0000-0002-0941-3990
IdRef : 050512935

Institut du Cerveau = Paris Brain Institute

Jian Yang

Function : Author

Ziv Gan-Or

Function : Author

Thomas Gasser

Function : Author

Peter Heutink

Function : Author

Joshua Shulman

Function : Author

Nicholas Wood

Function : Author

David Hinds

Function : Author

John Hardy

Function : Author

Huw Morris

Function : Author

Jacob Gratten

Function : Author

Peter Visscher

Function : Author

Robert Graham

Function : Author

Andrew Singleton

Function : Author

Astrid Adarmes-Gómez

Function : Author

Miquel Aguilar

Function : Author

Akbota Aitkulova

Function : Author

Vadim Akhmetzhanov

Function : Author

Roy Alcalay

Function : Author

Ignacio Alvarez

Function : Author

Victoria Alvarez

Function : Author

Sara Bandres-Ciga

Function : Author

Francisco Javier Barrero

Function : Author

Jesús Alberto Bergareche Yarza

Function : Author

Inmaculada Bernal-Bernal

Function : Author

Kimberley Billingsley

Function : Author

Cornelis Blauwendraat

Function : Author

Marta Blazquez

Function : Author

Marta Bonilla-Toribio

Function : Author

Juan Botía

Function : Author

María Teresa Boungiorno

Function : Author

Jose Bras

Function : Author

Alexis Brice

Function : Author

Kathrin Brockmann

Function : Author

Vivien Bubb

Function : Author

Dolores Buiza-Rueda

Function : Author

Ana Cámara

Function : Author

Fátima Carrillo

Function : Author

Mario Carrión-Claro

Function : Author

Debora Cerdan

Function : Author

Viorica Chelban

Function : Author

Jordi Clarimón

Function : Author

Carl Clarke

Function : Author

Yaroslau Compta

Function : Author

Mark Cookson

Function : Author

Jean-Christophe Corvol

Function : Author

David Craig

Function : Author

Fabrice Danjou

Function : Author

Monica Diez-Fairen

Function : Author

Oriol Dols-Icardo

Function : Author

Jacinto Duarte

Function : Author

Raquel Duran

Function : Author

Francisco Escamilla-Sevilla

Function : Author

Valentina Escott-Price

Function : Author

Mario Ezquerra

Function : Author

Faraz Faghri

Function : Author

Cici Feliz

Function : Author

Manel Fernández

Function : Author

Rubén Fernández-Santiago

Function : Author

Steven Finkbeiner

Function : Author

Thomas Foltynie

Function : Author

Ziv Gan-Or

Function : Author

Ciara Garcia

Function : Author

Pedro García-Ruiz

Function : Author

Thomas Gasser

Function : Author

J Raphael Gibbs

Function : Author

Maria Jose Gomez Heredia

Function : Author

Pilar Gómez-Garre

Function : Author

Manuel Menéndez González

Function : Author

Isabel Gonzalez-Aramburu

Function : Author

Sebastian Guelfi

Function : Author

Rita Guerreiro

Function : Author

John Hardy

Function : Author

Sharon Hassin-Baer

Function : Author

Dena Hernandez

Function : Author

Peter Heutink

Function : Author

Janet Hoenicka

Function : Author

Peter Holmans

Function : Author

Henry Houlden

Function : Author

Jon Infante

Function : Author

Hirotaka Iwaki

Function : Author

Silvia Jesús

Function : Author

Adriano Jimenez-Escrig

Function : Author

Gulnaz Kaishybayeva

Function : Author

Rauan Kaiyrzhanov

Function : Author

Altynay Karimova

Function : Author

Demis Kia

Function : Author

Kerri Kinghorn

Function : Author

Sulev Koks

Function : Author

Lynne Krohn

Function : Author

Jaime Kulisevsky

Function : Author

Miguel Labrador-Espinosa

Function : Author

Hampton Leonard

Function : Author

Suzanne Lesage

Function : Author

Patrick Lewis

Function : Author

Jose Luis Lopez-Sendon

Function : Author

Ruth Lovering

Function : Author

Steven Lubbe

Function : Author

Codrin Lungu

Function : Author

Daniel Macias

Function : Author

Kari Majamaa

Function : Author

Claudia Manzoni

Function : Author

Juan Marín

Function : Author

Johan Marinus

Function : Author

Maria Jose Marti

Function : Author

Maria Martinez

Function : Author

Irene Martínez Torres

Function : Author

Juan Carlos Martínez-Castrillo

Function : Author

Marina Mata

Function : Author

Niccolo Mencacci

Function : Author

Carlota Méndez-Del-Barrio

Function : Author

Ben Middlehurst

Function : Author

Adolfo Mínguez

Function : Author

Pablo Mir

Function : Author

Kin Mok

Function : Author

Huw Morris

Function : Author

Esteban Muñoz

Function : Author

Mike Nalls

Function : Author

Derek Narendra

Function : Author

Alastair Noyce

Function : Author

Oluwadamilola Ojo

Function : Author

Njideka Okubadejo

Function : Author

Ana Gorostidi Pagola

Function : Author

Pau Pastor

Function : Author

Francisco Perez Errazquin

Function : Author

Teresa Periñán-Tocino

Function : Author

Lasse Pihlstrom

Function : Author

Helene Plun-Favreau

Function : Author

John Quinn

Function : Author

Lea R'Bibo

Function : Author

Xylena Reed

Function : Author

Elisabet Mondragon Rezola

Function : Author

Mie Rizig

Function : Author

Patrizia Rizzu

Function : Author

Laurie Robak

Function : Author

Antonio Sanchez Rodriguez

Function : Author

Guy Rouleau

Function : Author

Javier Ruiz-Martínez

Function : Author

Clara Ruz

Function : Author

Mina Ryten

Function : Author

Dinara Sadykova

Function : Author

Sonja Scholz

Function : Author

Sebastian Schreglmann

Function : Author

Claudia Schulte

Function : Author

Manu Sharma

Function : Author

Chingiz Shashkin

Function : Author

Joshua Shulman

Function : Author

María Sierra

Function : Author

Ari Siitonen

Function : Author

Javier Simón-Sánchez

Function : Author

Andrew Singleton

Function : Author

Esther Suarez-Sanmartin

Function : Author

Pille Taba

Function : Author

Cesar Tabernero

Function : Author

Manuela Tan

Function : Author

Juan Pablo Tartari

Function : Author

Cristina Tejera-Parrado

Function : Author

Mathias Toft

Function : Author

Eduard Tolosa

Function : Author

Daniah Trabzuni

Function : Author

Francesc Valldeoriola

Function : Author

Jacobus van Hilten

Function : Author

Kendall van Keuren-Jensen

Function : Author

Laura Vargas-González

Function : Author

Lydia Vela

Function : Author

Francisco Vives

Function : Author

Nigel Williams

Function : Author

Nicholas Wood

Function : Author

Nazira Zharkinbekova

Function : Author

Zharkyn Zharmukhanov

Function : Author

Elena Zholdybayeva

Function : Author

Alexander Zimprich

Function : Author

Pauli Ylikotila

Function : Author

Lisa Shulman

Function : Author

Rainer von Coelln

Function : Author

Stephen Reich

Function : Author

Joseph Savitt

Function : Author

Michelle Agee

Function : Author

Babak Alipanahi

Function : Author

Adam Auton

Function : Author

Robert Bell

Function : Author

Katarzyna Bryc

Function : Author

Sarah Elson

Function : Author

Pierre Fontanillas

Function : Author

Nicholas Furlotte

Function : Author

Karen Huber

Function : Author

Barry Hicks

Function : Author

Ethan Jewett

Function : Author

Yunxuan Jiang

Function : Author

Aaron Kleinman

Function : Author

Keng-Han Lin

Function : Author

Nadia Litterman

Function : Author

Jennifer Mccreight

Function : Author

Matthew Mcintyre

Function : Author

Kimberly Mcmanus

Function : Author

Joanna Mountain

Function : Author

Elizabeth Noblin

Function : Author

Carrie A.M. Northover

Function : Author

Steven Pitts

Function : Author

G. David Poznik

Function : Author

J. Fah Sathirapongsasuti

Function : Author

Janie Shelton

Function : Author

Suyash Shringarpure

Function : Author

Chao Tian

Function : Author

Joyce Tung

Function : Author

Vladimir Vacic

Function : Author

Xin Wang

Function : Author

Catherine Wilson

Function : Author

Tim Anderson

Function : Author

Steven Bentley

Function : Author

John Dalrymple-Alford

Function : Author

Javed Fowdar

Function : Author

Jacob Gratten

Function : Author

Glenda Halliday

Function : Author

Anjali Henders

Function : Author

Ian Hickie

Function : Author

Irfahan Kassam

Function : Author

Martin Kennedy

Function : Author

John Kwok

Function : Author

Simon Lewis

Function : Author

George Mellick

Function : Author

Grant Montgomery

Function : Author

John Pearson

Function : Author

Toni Pitcher

Function : Author

Julia Sidorenko

Function : Author

Peter Silburn

Function : Author

Costanza Vallerga

Function : Author

Peter Visscher

Function : Author

Leanne Wallace

Function : Author

Naomi Wray

Function : Author

Angli Xue

Function : Author

Jian Yang

Function : Author

Futao Zhang

Function : Author

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

Domains

Human health and pathology

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Submitted on : Friday, May 17, 2024-10:01:24 AM

Last modification on : Thursday, November 7, 2024-2:22:12 PM

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hal-04578692 , version 1 (17-05-2024)

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HAL Id : hal-04578692 , version 1
DOI : 10.1016/S1474-4422(19)30320-5
PUBMED : 31701892
PUBMEDCENTRAL : PMC8422160

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Mike Nalls, Cornelis Blauwendraat, Costanza Vallerga, Karl Heilbron, Sara Bandres-Ciga, et al.. 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, 2019, 18 (12), pp.1091-1102. ⟨10.1016/S1474-4422(19)30320-5⟩. ⟨hal-04578692⟩

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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

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