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

Regina H. Reynolds; Juan Botia; Mike A. Nalls; John Hardy; Sarah A. Gagliano Taliun; Mina Ryten; 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; Fabrice Danjou; Suzanne Lesage; Jean-Christophe Corvol; Maria Martinez; Anamika Giri; Claudia Schulte; Kathrin Brockmann; Javier Simon-Sanchez; 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-Gomez; Inmaculada Bernal-Bernal; Marta Bonilla-Toribio; Dolores Buiza-Rueda; Fatima Carrillo; Mario Carrion-Claro; Pablo Mir; Pilar Gomez-Garre; Silvia Jesus; Miguel A. Labrador-Espinosa; Daniel Macias; Laura Vargas-Gonzalez; Carlota Mendez-del-Barrio; Teresa Perinan-Tocino; Cristina Tejera-Parrado; Monica Diez-Fairen; Miquel Aguilar; Ignacio Alvarez; Mara Teresa Boungiorno; Maria Carcel; Pau Pastor; Juan Pablo Tartari; Victoria Alvarez; Manuel Menendez Gonzalez; Marta Blazquez; Ciara Garcia; Esther Suarez-Sanmartin; Francisco Javier Barrero; Elisabet Mondragon Rezola; Jesus Alberto Bergareche Yarza; Ana Gorostidi Pagola; Adolfo Lopez de Munain Arregui; Javier Ruiz-Martinez; Debora Cerdan; Jacinto Duarte; Jordi Clarimon; Oriol Dols-Icardo; Jon Infante; Juan Marin; Jaime Kulisevsky; Javier Pagonabarraga; Isabel Gonzalez-Aramburu; Antonio Sanchez Rodriguez; Mara Sierra; Raquel Duran; Clara Ruz; Francisco Vives; Francisco Escamilla-Sevilla; Adolfo Minguez; Ana Camara; Yaroslau Compta; Mario Ezquerra; Maria Jose Marti; Manel Fernandez; Esteban Munoz; Ruben Fernandez-Santiago; Eduard Tolosa; Francesc Valldeoriola; Pedro Garcia-Ruiz; Maria Jose Gomez Heredia; Francisco Perez Errazquin; Janet Hoenicka; Adriano Jimenez-Escrig; Juan Carlos Martinez-Castrillo; Jose Luis Lopez-Sendon; Irene Martinez 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; Int Parkinsons Dis Genomics

doi:10.1038/s41531-019-0076-6

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

Journal article

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

Regina H. Reynolds, Juan Botia, Mike A. Nalls, John Hardy, Sarah A. Gagliano Taliun, Mina Ryten, Alastair J. Noyce, Aude Nicolas, Mark R. Cookson, Sara Bandres-Ciga, …

NPJ Parkinson's Disease, Vol.5(1), pp.6-6

17/04/2019

DOI: https://doi.org/10.1038/s41531-019-0076-6

Handle:

https://hdl.handle.net/10523/28165

Abstract

Life Sciences & Biomedicine

Neurosciences

Neurosciences & Neurology

Science & Technology

Parkinson's disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of a-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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Record Identifier: 9926515141001891
Title: Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability
Creators: Regina H. Reynolds
Juan Botia
Mike A. Nalls
John Hardy
Sarah A. Gagliano Taliun
Mina Ryten
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
Fabrice Danjou
Suzanne Lesage
Jean-Christophe Corvol
Maria Martinez
Anamika Giri
Claudia Schulte
Kathrin Brockmann
Javier Simon-Sanchez
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-Gomez
Inmaculada Bernal-Bernal
Marta Bonilla-Toribio
Dolores Buiza-Rueda
Fatima Carrillo
Mario Carrion-Claro
Pablo Mir
Pilar Gomez-Garre
Silvia Jesus
Miguel A. Labrador-Espinosa
Daniel Macias
Laura Vargas-Gonzalez
Carlota Mendez-del-Barrio
Teresa Perinan-Tocino
Cristina Tejera-Parrado
Monica Diez-Fairen
Miquel Aguilar
Ignacio Alvarez
Mara Teresa Boungiorno
Maria Carcel
Pau Pastor
Juan Pablo Tartari
Victoria Alvarez
Manuel Menendez Gonzalez
Marta Blazquez
Ciara Garcia
Esther Suarez-Sanmartin
Francisco Javier Barrero
Elisabet Mondragon Rezola
Jesus Alberto Bergareche Yarza
Ana Gorostidi Pagola
Adolfo Lopez de Munain Arregui
Javier Ruiz-Martinez
Debora Cerdan
Jacinto Duarte
Jordi Clarimon
Oriol Dols-Icardo
Jon Infante
Juan Marin
Jaime Kulisevsky
Javier Pagonabarraga
Isabel Gonzalez-Aramburu
Antonio Sanchez Rodriguez
Mara Sierra
Raquel Duran
Clara Ruz
Francisco Vives
Francisco Escamilla-Sevilla
Adolfo Minguez
Ana Camara
Yaroslau Compta
Mario Ezquerra
Maria Jose Marti
Manel Fernandez
Esteban Munoz
Ruben Fernandez-Santiago
Eduard Tolosa
Francesc Valldeoriola
Pedro Garcia-Ruiz
Maria Jose Gomez Heredia
Francisco Perez Errazquin
Janet Hoenicka
Adriano Jimenez-Escrig
Juan Carlos Martinez-Castrillo
Jose Luis Lopez-Sendon
Irene Martinez 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
Int Parkinsons Dis Genomics
Publication Details: NPJ Parkinson's Disease, Vol.5(1), pp.6-6
Academic Unit: Office of the Dean (UOC); Pathology and Molecular Medicine (UOC); Medicine (UOC)
Publisher: NATURE PORTFOLIO
Grant note: Leonard Wolfson Doctoral Training Fellowship in Neurodegeneration Data Tecnica International National Institute on Aging, NIH, Bethesda, MD, USA; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) UK Dementia Research Institute MR/N008324/1 / Tenure-track Clinician Scientist Fellowship MR/K01417X/1; MR/N026004/1; UKDRI-1009; G0701075; G0901254; MR/N008324/1 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) UK Medical Research Council (MRC); UK Research & Innovation (UKRI); Medical Research Council UK (MRC)
Date published ; e-published: 17/04/2019
Language: English
Resource Type ; Subtype: Journal article