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

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 microgl...

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Autores: Reynolds, RH, Botia, J, Nalls, MA, Hardy, J, Taliun, SAG, Ryten, M, Noyce, AJ, Nicolas, A, Cookson, MR, Bandres-Ciga, S, Gibbs, JR, Hernandez, DG, Singleton, AB, Reed, X, Leonard, H, Blauwendraat, C, Faghri, F, Bras, J, Guerreiro, R, Tucci, A, Kia, DA, Houlden, H, Plun-Favreau, H, Mok, KY, Wood, NW, Lovering, R, R'Bibo, L, Rizig, M, Chelban, V, Trabzuni, D, Tan, M, Morris, HR, Middlehurst, B, Quinn, J, Billingsley, K, Holmans, P, Kinghorn, KJ, Lewis, P, Escott-Price, V, Williams, N, Foltynie, T, Brice, A, Danjou, F, Lesage, S, Corvol, JC, Martinez, M, Giri, A, Schulte, C, Brockmann, K, Simon-Sanchez, J, Heutink, P, Gasser, T, Rizzu, P, Sharma, M, Shulman, JM, Robak, L, Lubbe, S, Mencacci, NE, Finkbeiner, S, Lungu, C, Scholz, SW, Gan-Or, Z, Rouleau, GA, Krohan, L, van Hilten, JJ, Marinus, J, Adarmes-Gomez, AD, Bernal-Bernal, I, Bonilla-Toribio, M, Buiza-Rueda, D, Carrillo, F, Carrion-Claro, M, Mir, P, Gomez-Garre, P, Jesus, S, Labrador-Espinosa, MA, Macias, D, Vargas-Gonzalez, L, Mendez-del-Barrio, C, Perinan-Tocino, T, Tejera-Parrado, C, Diez-Fairen, M, Aguilar, M, Alvarez, I, Boungiorno, MT, Carcel, M, Pastor, P, Tartari, JP, Alvarez, V, Gonzalez, MM, Blazquez, M, Garcia, C, Suarez-Sanmartin, E, Barrero, FJ, Rezola, EM, Yarza, JAB, Pagola, AG, Arregui, ALD, Ruiz-Martinez, J, Cerdan, D, Duarte, J, Clarimon, J, Dols-Icardo, O, Infante, J, Marin, J, Kulisevsky, J, Pagonabarraga, J, Gonzalez-Aramburu, I, Rodriguez, AS, Sierra, M, Duran, R, Ruz, C, Vives, F, Escamilla-Sevilla, F, Minguez, A, Camara, A, Compta, Y, Ezquerra, M, Marti, MJ, Fernandez, M, Munoz, E, Fernandez-Santiago, R, Tolosa, E, Valldeoriola, F, Garcia-Ruiz, P, Heredia, MJG, Errazquin, FP, Hoenicka, J, Jimenez-Escrig, A, Martinez-Castrillo, JC, Lopez-Sendon, JL, Torres, IM, Tabernero, C, Vela, L, Zimprich, A, Pihlstrom, L, Koks, S, Taba, P, Majamaa, K, Siitonen, A, Okubadejo, NU, Ojo, OO, Pitcher, T, Anderson, T, Bentley, S, Fowdar, J, Mellick, G, Dalrymple-Alford, J, Henders, AK, Kassam, I, Montgomery, G, Sidorenko, J, Zhang, FT, Xue, AL, Vallerga, CL, Wallace, L, Wray, NR, Yang, J, Visscher, PM, Gratten, J, Silburn, PA, Halliday, G, Hickie, I, Kwok, J, Lewis, S, Kennedy, M, Pearson, J
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p2332
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2332
http://ddd.uab.cat/record/223586
Access Level:acceso abierto
Descripción
Sumario: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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