Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability
Authors: Reynolds Regina H. , Botía Juan , Nalls Mike A. ,   International Parkinson’s Disease Genomics Consortium (IPDGC), 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 , Simón-Sánchez 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-Gómez Astrid D. , Bernal-Bernal Inmaculada , Bonilla-Toribio Marta , Buiza-Rueda Dolores , Carrillo Fátima , Carrión-Claro Mario , Mir Pablo , Gómez-Garre Pilar , Jesús Silvia , Labrador-Espinosa Miguel A. , Macias Daniel , Vargas-González Laura , Méndez-del-Barrio Carlota , Periñán-Tocino Teresa , Tejera-Parrado Cristina , Diez-Fairen Monica , Aguilar Miquel , Alvarez Ignacio , Boungiorno María Teresa , Carcel Maria , Pastor Pau , Tartari Juan Pablo , Alvarez Victoria , González Manuel Menéndez , Blazquez Marta , Garcia Ciara , Suarez-Sanmartin Esther , Barrero Francisco Javier , Rezola Elisabet Mondragon , Yarza Jesús Alberto Bergareche , Pagola Ana Gorostidi , de Munain Arregui Adolfo López , Ruiz-Martínez Javier , Cerdan Debora , Duarte Jacinto , Clarimón Jordi , Dols-Icardo Oriol , Infante Jon , Marín Juan , Kulisevsky Jaime , Pagonabarraga Javier , Gonzalez-Aramburu Isabel , Rodriguez Antonio Sanchez , Sierra María , Duran Raquel , Ruz Clara , Vives Francisco , Escamilla-Sevilla Francisco , Mínguez Adolfo , Cámara Ana , Compta Yaroslau , Ezquerra Mario , Marti Maria Jose , Fernández Manel , Muñoz Esteban , Fernández-Santiago Rubén , Tolosa Eduard , Valldeoriola Francesc , García-Ruiz Pedro , Heredia Maria Jose Gomez , Errazquin Francisco Perez , Hoenicka Janet , Jimenez-Escrig Adriano , Martínez-Castrillo Juan Carlos , Lopez-Sendon Jose Luis , Torres Irene Martínez , Tabernero Cesar , Vela Lydia , Zimprich Alexander , Pihlstrom Lasse , Koks Sulev , Taba Pille , Majamaa Kari , Siitonen Ari , Okubadejo Njideka U. , Ojo Oluwadamilola O. ,   System Genomics of Parkinson’s Disease (SGPD), 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 , Hardy John , Gagliano Taliun Sarah A. , Ryten Mina 
Published: April 2019

AbstractParkinson’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.