Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability
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Botia, Juan
Nalls, Mike A
Hardy, John
Taliun, Sarah A Gagliano
Ryten, Mina
Noyce, Alastair J
Nicolas, Aude
Cookson, Mark R
Bandres-Ciga, Sara
Gibbs, J Raphael
Hernandez, Dena G
Singleton, Andrew B
Reed, Xylena
Leonard, Hampton
Blauwendraat, Cornelis
Faghri, Faraz
Bras, Jose
Guerreiro, Rita
Tucci, Arianna
Kia, Demis A
Houlden, Henry
Plun-Favreau, Helene
Mok, Kin Y
Wood, Nicholas W
Lovering, Ruth
R'Bibo, Lea
Rizig, Mie
Chelban, Viorica
Trabzuni, Daniah
Tan, Manuela
Morris, Huw R
Middlehurst, Ben
Quinn, John
Billingsley, Kimberley
Holmans, Peter
Kinghorn, Kerri J
Lewis, Patrick
Escott-Price, Valentina
Williams, Nigel
Foltynie, Thomas
Brice, Alexis
Danjou, Fabrice
Lesage, Suzanne
Corvol, Jean-Christophe
Martinez, Maria
Giri, Anamika
Schulte, Claudia
Brockmann, Kathrin
Simon-Sanchez, Javier
Heutink, Peter
Gasser, Thomas
Rizzu, Patrizia
Sharma, Manu
Shulman, Joshua M
Robak, Laurie
Lubbe, Steven
Mencacci, Niccolo E
Finkbeiner, Steven
Lungu, Codrin
Scholz, Sonja W
Gan-Or, Ziv
Rouleau, Guy A
Krohan, Lynne
van Hilten, Jacobus J
Marinus, Johan
Adarmes-Gomez, Astrid D
Bernal-Bernal, Inmaculada
Bonilla-Toribio, Marta
Buiza-Rueda, Dolores
Carrillo, Fatima
Carrion-Claro, Mario
Mir, Pablo
Gomez-Garre, Pilar
Jesus, Silvia
Labrador-Espinosa, Miguel A
Macias, Daniel
Vargas-Gonzalez, Laura
Mendez-del-Barrio, Carlota
Perinan-Tocino, Teresa
Tejera-Parrado, Cristina
Diez-Fairen, Monica
Aguilar, Miquel
Alvarez, Ignacio
Teresa Boungiorno, Mara
Carcel, Maria
Pastor, Pau
Pablo Tartari, Juan
Alvarez, Victoria
Menendez Gonzalez, Manuel
Blazquez, Marta
Garcia, Ciara
Suarez-Sanmartin, Esther
Javier Barrero, Francisco
Mondragon Rezola, Elisabet
Bergareche Yarza, Jesus Alberto
Gorostidi Pagola, Ana
de Munain Arregui, Adolfo Lopez
Ruiz-Martinez, Javier
Cerdan, Debora
Duarte, Jacinto
Clarimon, Jordi
Dols-Icardo, Oriol
Infante, Jon
Marin, Juan
Kulisevsky, Jaime
Pagonabarraga, Javier
Gonzalez-Aramburu, Isabel
Sanchez Rodriguez, Antonio
Sierra, Mara
Duran, Raquel
Ruz, Clara
Vives, Francisco
Escamilla-Sevilla, Francisco
Minguez, Adolfo
Camara, Ana
Compta, Yaroslau
Ezquerra, Mario
Jose Marti, Maria
Fernandez, Manel
Munoz, Esteban
Fernandez-Santiago, Ruben
Tolosa, Eduard
Valldeoriola, Francesc
Garcia-Ruiz, Pedro
Gomez Heredia, Maria Jose
Perez Errazquin, Francisco
Hoenicka, Janet
Jimenez-Escrig, Adriano
Carlos Martinez-Castrillo, Juan
Luis Lopez-Sendon, Jose
Martinez Torres, Irene
Tabernero, Cesar
Vela, Lydia
Zimprich, Alexander
Pihlstrom, Lasse
Koks, Sulev
Taba, Pille
Majamaa, Kari
Siitonen, Ari
Okubadejo, Njideka U
Ojo, Oluwadamilola O
Pitcher, Toni
Anderson, Tim
Bentley, Steven
Fowdar, Javed
Mellick, George
Dalrymple-Alford, John
Henders, Anjali K
Kassam, Irfahan
Montgomery, Grant
Sidorenko, Julia
Zhang, Futao
Xue, Angli
Vallerga, Costanza L
Wallace, Leanne
Wray, Naomi R
Yang, Jian
Visscher, Peter M
Gratten, Jacob
Silburn, Peter A
Halliday, Glenda
Hickie, Ian
Kwok, John
Lewis, Simon
Kennedy, Martin
Pearson, John
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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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npj Parkinson's Disease
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5
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1
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© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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Biomedical and clinical sciences
Science & Technology
Life Sciences & Biomedicine
Neurosciences
Neurosciences & Neurology
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Reynoldset al., Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability, npj Parkinson's Disease DISEASE, 2019, 5 (1)