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R.H.R. was supported through the award of a Leonard Wolfson Doctoral Training Fellowship in Neurodegeneration. M.A.N. was supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda, MD, USA. J.H. and M.R. were supported by the UK Medical Research Council (MRC), with J.H. supported by a grant (MR/N026004/) and M.R. through the award of a Tenure-track Clinician Scientist Fellowship (MR/N008324/1). J.H. was also supported by the UK Dementia Research Institute. Full consortia acknowledgements are available in the supplemental materials (Text S2).

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

Publicated to:Npj Parkinsons Dis. 5 6- - 2019-04-17 5(), DOI: 10.1038/s41531-019-0076-6

Authors: Reynolds, Regina H; 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 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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