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Journal Articles npj Parkinson's Disease Year : 2019

Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability

Regina H Reynolds (1) , Juan Botía (1) , Mike A Nalls (2) , Alastair J Noyce , Aude Nicolas , Mark R Cookson , Sara Bandres-Ciga , J Raphael Gibbs , Dena G Hernandez , Andrew B Singleton , Xylena Reed , Hampton Leonard , Cornelis Blauwendraat , Faraz Faghri , Jose Bras , Rita Guerreiro , Arianna Tucci , Demis A Kia , Henry Houlden , Helene Plun-Favreau , Kin Y Mok , Nicholas W Wood , Ruth Lovering , Lea R’bibo , Mie Rizig , Viorica Chelban , Daniah Trabzuni , Manuela Tan , Huw R Morris , Ben Middlehurst , John Quinn , Kimberley Billingsley , Peter Holmans , Kerri J Kinghorn , Patrick Lewis , Valentina Escott-Price , Nigel Williams , Thomas Foltynie , Alexis Brice (3) , Fabrice Danjou (3) , Suzanne Lesage (3) , Jean-Christophe Corvol (3) , Maria Martinez , Anamika Giri , Claudia Schulte , Kathrin Brockmann , Javier Simón-Sánchez , Peter Heutink , Thomas Gasser , Patrizia Rizzu , Manu Sharma , Joshua M Shulman , Laurie Robak , Steven Lubbe , Niccolo E Mencacci , Steven Finkbeiner , Codrin Lungu , Sonja W Scholz , Ziv Gan-Or , Guy A Rouleau , Lynne Krohan , Jacobus J van Hilten , Johan Marinus , Astrid D Adarmes-Gómez , Inmaculada Bernal-Bernal , Marta Bonilla-Toribio , Dolores Buiza-Rueda , Fátima Carrillo , Mario Carrión-Claro , Pablo Mir , Pilar Gómez-Garre , Silvia Jesús , Miguel A Labrador-Espinosa , Daniel Macias , Laura Vargas-González , Carlota Méndez-Del-Barrio , Teresa Periñán-Tocino , Cristina Tejera-Parrado , Monica Diez-Fairen , Miquel Aguilar , Ignacio Alvarez , María Teresa Boungiorno , Maria Carcel , Pau Pastor , Juan Pablo Tartari , Victoria Alvarez , Manuel Menéndez González , Marta Blazquez , Ciara Garcia , Esther Suarez-Sanmartin , Francisco Javier Barrero , Elisabet Mondragon Rezola , Jesús Alberto Bergareche Yarza , Ana Gorostidi Pagola , Adolfo López de Munain Arregui , Javier Ruiz-Martínez , Debora Cerdan , Jacinto Duarte , Jordi Clarimón , Oriol Dols-Icardo , Jon Infante , Juan Marín , Jaime Kulisevsky , Javier Pagonabarraga , Isabel Gonzalez-Aramburu , Antonio Sanchez Rodriguez , María Sierra , Raquel Duran , Clara Ruz , Francisco Vives , Francisco Escamilla-Sevilla , Adolfo Mínguez , Ana Cámara , Yaroslau Compta , Mario Ezquerra , Maria Jose Marti , Manel Fernández , Esteban Muñoz , Rubén Fernández-Santiago , Eduard Tolosa , Francesc Valldeoriola , Pedro García-Ruiz , Maria Jose Gomez Heredia , Francisco Perez Errazquin , Janet Hoenicka , Adriano Jimenez-Escrig , Juan Carlos Martínez-Castrillo , Jose Luis Lopez-Sendon , Irene Martínez Torres , Cesar Tabernero , Lydia Vela , Alexander Zimprich , Lasse Pihlstrom , Sulev Koks , Pille Taba , Kari Majamaa , Ari Siitonen , Njideka U Okubadejo , Oluwadamilola O Ojo , Toni Pitcher , Tim Anderson , Steven Bentley , Javed Fowdar , George Mellick , John Dalrymple-Alford , Anjali K Henders , Irfahan Kassam , Grant Montgomery , Julia Sidorenko , Futao Zhang , Angli Xue , Costanza L Vallerga , Leanne Wallace , Naomi R Wray , Jian Yang , Peter M Visscher , Jacob Gratten , Peter A Silburn , Glenda Halliday , Ian Hickie , John Kwok , Simon Lewis , Martin Kennedy , John Pearson , John Hardy (1) , Sarah A Gagliano Taliun (4) , Mina Ryten (1)
Regina H Reynolds
Alastair J Noyce
  • Function : Author
Aude Nicolas
  • Function : Author
Mark R Cookson
  • Function : Author
Sara Bandres-Ciga
  • Function : Author
J Raphael Gibbs
  • Function : Author
Dena G Hernandez
  • Function : Author
Andrew B Singleton
  • Function : Author
Xylena Reed
  • Function : Author
Hampton Leonard
  • Function : Author
Cornelis Blauwendraat
  • Function : Author
Faraz Faghri
  • Function : Author
Jose Bras
  • Function : Author
Rita Guerreiro
  • Function : Author
Arianna Tucci
  • Function : Author
Demis A Kia
  • Function : Author
Henry Houlden
  • Function : Author
Helene Plun-Favreau
  • Function : Author
Kin Y Mok
  • Function : Author
Nicholas W Wood
  • Function : Author
Ruth Lovering
  • Function : Author
Lea R’bibo
  • Function : Author
Mie Rizig
  • Function : Author
Viorica Chelban
  • Function : Author
Daniah Trabzuni
  • Function : Author
Manuela Tan
  • Function : Author
Huw R Morris
  • Function : Author
Ben Middlehurst
  • Function : Author
John Quinn
  • Function : Author
Kimberley Billingsley
  • Function : Author
Peter Holmans
  • Function : Author
Kerri J Kinghorn
  • Function : Author
Patrick Lewis
  • Function : Author
Valentina Escott-Price
  • Function : Author
Nigel Williams
  • Function : Author
Thomas Foltynie
  • Function : Author
Maria Martinez
  • Function : Author
Anamika Giri
  • Function : Author
Claudia Schulte
  • Function : Author
Kathrin Brockmann
  • Function : Author
Javier Simón-Sánchez
  • Function : Author
Peter Heutink
  • Function : Author
Thomas Gasser
  • Function : Author
Patrizia Rizzu
  • Function : Author
Manu Sharma
  • Function : Author
Joshua M Shulman
  • Function : Author
Laurie Robak
  • Function : Author
Steven Lubbe
  • Function : Author
Niccolo E Mencacci
  • Function : Author
Steven Finkbeiner
  • Function : Author
Codrin Lungu
  • Function : Author
Sonja W Scholz
  • Function : Author
Ziv Gan-Or
  • Function : Author
Guy A Rouleau
  • Function : Author
Lynne Krohan
  • Function : Author
Jacobus J van Hilten
  • Function : Author
Johan Marinus
  • Function : Author
Astrid D Adarmes-Gómez
  • Function : Author
Inmaculada Bernal-Bernal
  • Function : Author
Marta Bonilla-Toribio
  • Function : Author
Dolores Buiza-Rueda
  • Function : Author
Fátima Carrillo
  • Function : Author
Mario Carrión-Claro
  • Function : Author
Pablo Mir
  • Function : Author
Pilar Gómez-Garre
  • Function : Author
Silvia Jesús
  • Function : Author
Miguel A Labrador-Espinosa
  • Function : Author
Daniel Macias
  • Function : Author
Laura Vargas-González
  • Function : Author
Carlota Méndez-Del-Barrio
  • Function : Author
Teresa Periñán-Tocino
  • Function : Author
Cristina Tejera-Parrado
  • Function : Author
Monica Diez-Fairen
  • Function : Author
Miquel Aguilar
  • Function : Author
Ignacio Alvarez
  • Function : Author
María Teresa Boungiorno
  • Function : Author
Maria Carcel
  • Function : Author
Pau Pastor
  • Function : Author
Juan Pablo Tartari
  • Function : Author
Victoria Alvarez
  • Function : Author
Manuel Menéndez González
  • Function : Author
Marta Blazquez
  • Function : Author
Ciara Garcia
  • Function : Author
Esther Suarez-Sanmartin
  • Function : Author
Francisco Javier Barrero
  • Function : Author
Elisabet Mondragon Rezola
  • Function : Author
Ana Gorostidi Pagola
  • Function : Author
Javier Ruiz-Martínez
  • Function : Author
Debora Cerdan
  • Function : Author
Jacinto Duarte
  • Function : Author
Jordi Clarimón
  • Function : Author
Oriol Dols-Icardo
  • Function : Author
Jon Infante
  • Function : Author
Juan Marín
  • Function : Author
Jaime Kulisevsky
  • Function : Author
Javier Pagonabarraga
  • Function : Author
Isabel Gonzalez-Aramburu
  • Function : Author
Antonio Sanchez Rodriguez
  • Function : Author
María Sierra
  • Function : Author
Raquel Duran
  • Function : Author
Clara Ruz
  • Function : Author
Francisco Vives
  • Function : Author
Francisco Escamilla-Sevilla
  • Function : Author
Adolfo Mínguez
  • Function : Author
Ana Cámara
  • Function : Author
Yaroslau Compta
  • Function : Author
Mario Ezquerra
  • Function : Author
Maria Jose Marti
  • Function : Author
Manel Fernández
  • Function : Author
Esteban Muñoz
  • Function : Author
Rubén Fernández-Santiago
  • Function : Author
Eduard Tolosa
  • Function : Author
Francesc Valldeoriola
  • Function : Author
Pedro García-Ruiz
  • Function : Author
Maria Jose Gomez Heredia
  • Function : Author
Francisco Perez Errazquin
  • Function : Author
Janet Hoenicka
  • Function : Author
Adriano Jimenez-Escrig
  • Function : Author
Jose Luis Lopez-Sendon
  • Function : Author
Irene Martínez Torres
  • Function : Author
Cesar Tabernero
  • Function : Author
Lydia Vela
  • Function : Author
Alexander Zimprich
  • Function : Author
Lasse Pihlstrom
  • Function : Author
Sulev Koks
  • Function : Author
Pille Taba
  • Function : Author
Kari Majamaa
  • Function : Author
Ari Siitonen
  • Function : Author
Njideka U Okubadejo
  • Function : Author
Oluwadamilola O Ojo
  • Function : Author
Toni Pitcher
  • Function : Author
Tim Anderson
  • Function : Author
Steven Bentley
  • Function : Author
Javed Fowdar
  • Function : Author
George Mellick
  • Function : Author
John Dalrymple-Alford
  • Function : Author
Anjali K Henders
  • Function : Author
Irfahan Kassam
  • Function : Author
Grant Montgomery
  • Function : Author
Julia Sidorenko
  • Function : Author
Futao Zhang
  • Function : Author
Angli Xue
  • Function : Author
Costanza L Vallerga
  • Function : Author
Leanne Wallace
  • Function : Author
Naomi R Wray
  • Function : Author
Jian Yang
  • Function : Author
Peter M Visscher
  • Function : Author
Jacob Gratten
  • Function : Author
Peter A Silburn
  • Function : Author
Glenda Halliday
  • Function : Author
Ian Hickie
  • Function : Author
John Kwok
  • Function : Author
Simon Lewis
  • Function : Author
Martin Kennedy
  • Function : Author
John Pearson
  • Function : Author
Mina Ryten
  • Function : Author
  • PersonId : 1348510

Abstract

Abstract Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types.
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Dates and versions

hal-04444412 , version 1 (07-02-2024)

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Regina H Reynolds, Juan Botía, Mike A Nalls, Alastair J Noyce, Aude Nicolas, et al.. Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability. npj Parkinson's Disease, 2019, 5 (1), pp.6. ⟨10.1038/s41531-019-0076-6⟩. ⟨hal-04444412⟩
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