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

Mike Nalls (1) , Cornelis Blauwendraat (1) , Costanza Vallerga (2) , Karl Heilbron (3) , Sara Bandres-Ciga (4, 5) , Diana Chang , Manuela Tan (6) , Demis Kia (7) , Alastair Noyce (8, 6) , Angli Xue , Jose Bras , Emily Young , Rainer von Coelln (9) , Javier Simón-Sánchez (10, 11) , Claudia Schulte (10, 11) , Manu Sharma (12) , Lynne Krohn (13, 14) , Lasse Pihlstrøm (15) , Ari Siitonen (16, 17) , Hirotaka Iwaki (4, 18) , Hampton Leonard , Faraz Faghri , J Raphael Gibbs , Dena Hernandez , Sonja Scholz , Juan Botia , Maria Martinez (19) , Jean-Christophe Corvol (20) , Suzanne Lesage (20) , Joseph Jankovic , Lisa Shulman , Margaret Sutherland , Pentti Tienari , Kari Majamaa , Mathias Toft , Ole Andreassen , Tushar Bangale , Alexis Brice (20) , 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
Karl Heilbron
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Diana Chang
  • Function : Author
Angli Xue
  • Function : Author
Jose Bras
  • Function : Author
Emily Young
  • Function : Author
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
Joseph Jankovic
  • Function : Author
Lisa Shulman
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Margaret Sutherland
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Pentti Tienari
  • Function : Author
Kari Majamaa
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Mathias Toft
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Ole Andreassen
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Tushar Bangale
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Jian Yang
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Ziv Gan-Or
  • Function : Author
Thomas Gasser
  • Function : Author
Peter Heutink
  • Function : Author
Joshua Shulman
  • Function : Author
Nicholas Wood
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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
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Astrid Adarmes-Gómez
  • Function : Author
Miquel Aguilar
  • Function : Author
Akbota Aitkulova
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Vadim Akhmetzhanov
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Roy Alcalay
  • Function : Author
Ignacio Alvarez
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Victoria Alvarez
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Sara Bandres-Ciga
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Francisco Javier Barrero
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Inmaculada Bernal-Bernal
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Kimberley Billingsley
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Cornelis Blauwendraat
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Marta Blazquez
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Marta Bonilla-Toribio
  • Function : Author
Juan Botía
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María Teresa Boungiorno
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Jose Bras
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Alexis Brice
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Kathrin Brockmann
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Vivien Bubb
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Dolores Buiza-Rueda
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Ana Cámara
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Fátima Carrillo
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Mario Carrión-Claro
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Debora Cerdan
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Viorica Chelban
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Jordi Clarimón
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Carl Clarke
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Yaroslau Compta
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Mark Cookson
  • Function : Author
Jean-Christophe Corvol
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David Craig
  • Function : Author
Fabrice Danjou
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Monica Diez-Fairen
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Oriol Dols-Icardo
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Jacinto Duarte
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Raquel Duran
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Francisco Escamilla-Sevilla
  • Function : Author
Valentina Escott-Price
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Mario Ezquerra
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Faraz Faghri
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Cici Feliz
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Manel Fernández
  • Function : Author
Rubén Fernández-Santiago
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Steven Finkbeiner
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Thomas Foltynie
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Ziv Gan-Or
  • Function : Author
Ciara Garcia
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Pedro García-Ruiz
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Thomas Gasser
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J Raphael Gibbs
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Maria Jose Gomez Heredia
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Pilar Gómez-Garre
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Manuel Menéndez González
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Isabel Gonzalez-Aramburu
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Sebastian Guelfi
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Rita Guerreiro
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John Hardy
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Sharon Hassin-Baer
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Dena Hernandez
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Peter Heutink
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Janet Hoenicka
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Peter Holmans
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Henry Houlden
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Jon Infante
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Hirotaka Iwaki
  • Function : Author
Silvia Jesús
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Adriano Jimenez-Escrig
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Gulnaz Kaishybayeva
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Rauan Kaiyrzhanov
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Altynay Karimova
  • Function : Author
Demis Kia
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Kerri Kinghorn
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Sulev Koks
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Lynne Krohn
  • Function : Author
Jaime Kulisevsky
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Miguel Labrador-Espinosa
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Hampton Leonard
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Suzanne Lesage
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Patrick Lewis
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Jose Luis Lopez-Sendon
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Ruth Lovering
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Steven Lubbe
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Codrin Lungu
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Daniel Macias
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Kari Majamaa
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Claudia Manzoni
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Juan Marín
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Johan Marinus
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Maria Jose Marti
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Maria Martinez
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Irene Martínez Torres
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Marina Mata
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Niccolo Mencacci
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Carlota Méndez-Del-Barrio
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Ben Middlehurst
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Adolfo Mínguez
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Pablo Mir
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Kin Mok
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Huw Morris
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Esteban Muñoz
  • Function : Author
Mike Nalls
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Derek Narendra
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Alastair Noyce
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Oluwadamilola Ojo
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Njideka Okubadejo
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Ana Gorostidi Pagola
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Pau Pastor
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Francisco Perez Errazquin
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Teresa Periñán-Tocino
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Lasse Pihlstrom
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Helene Plun-Favreau
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John Quinn
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Lea R'Bibo
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Xylena Reed
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Elisabet Mondragon Rezola
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Mie Rizig
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Patrizia Rizzu
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Laurie Robak
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Antonio Sanchez Rodriguez
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Guy Rouleau
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Javier Ruiz-Martínez
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Clara Ruz
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Mina Ryten
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Dinara Sadykova
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Sonja Scholz
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Sebastian Schreglmann
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Claudia Schulte
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Manu Sharma
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Chingiz Shashkin
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Joshua Shulman
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María Sierra
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Ari Siitonen
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Javier Simón-Sánchez
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Andrew Singleton
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Esther Suarez-Sanmartin
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Pille Taba
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Cesar Tabernero
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Manuela Tan
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Juan Pablo Tartari
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Cristina Tejera-Parrado
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Mathias Toft
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Eduard Tolosa
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Daniah Trabzuni
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Francesc Valldeoriola
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Jacobus van Hilten
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Kendall van Keuren-Jensen
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Laura Vargas-González
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Lydia Vela
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Francisco Vives
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Nigel Williams
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Nicholas Wood
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Nazira Zharkinbekova
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Zharkyn Zharmukhanov
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Elena Zholdybayeva
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Alexander Zimprich
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Pauli Ylikotila
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Lisa Shulman
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Rainer von Coelln
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Stephen Reich
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Joseph Savitt
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Michelle Agee
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Babak Alipanahi
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Adam Auton
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Robert Bell
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Katarzyna Bryc
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Sarah Elson
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Pierre Fontanillas
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Nicholas Furlotte
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Karen Huber
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Barry Hicks
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Ethan Jewett
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Yunxuan Jiang
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Aaron Kleinman
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Keng-Han Lin
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Nadia Litterman
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Jennifer Mccreight
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Matthew Mcintyre
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Kimberly Mcmanus
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Joanna Mountain
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Elizabeth Noblin
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Carrie A.M. Northover
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Steven Pitts
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G. David Poznik
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J. Fah Sathirapongsasuti
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Janie Shelton
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Suyash Shringarpure
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Chao Tian
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Joyce Tung
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Vladimir Vacic
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Xin Wang
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Catherine Wilson
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Tim Anderson
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Steven Bentley
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John Dalrymple-Alford
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Javed Fowdar
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Jacob Gratten
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Glenda Halliday
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Anjali Henders
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Ian Hickie
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Irfahan Kassam
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Martin Kennedy
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John Kwok
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Simon Lewis
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George Mellick
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Grant Montgomery
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John Pearson
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Toni Pitcher
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Julia Sidorenko
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Peter Silburn
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Costanza Vallerga
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Peter Visscher
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Leanne Wallace
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Naomi Wray
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Angli Xue
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Jian Yang
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Futao Zhang
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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. 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

Dates and versions

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

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Cite

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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