Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability
Reynolds RH., Botía J., Nalls MA., 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 J-C., Martinez M., Giri A., Schulte C., Brockmann K., Simón-Sánchez 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-Gómez AD., Bernal-Bernal I., Bonilla-Toribio M., Buiza-Rueda D., Carrillo F., Carrión-Claro M., Mir P., Gómez-Garre P., Jesús S., Labrador-Espinosa MA., Macias D., Vargas-González L., Méndez-del-Barrio C., Periñán-Tocino T., Tejera-Parrado C., Diez-Fairen M., Aguilar M., Alvarez I., Boungiorno MT., Carcel M., Pastor P., Tartari JP., Alvarez V., González MM., Blazquez M., Garcia C., Suarez-Sanmartin E., Barrero FJ., Rezola EM., Yarza JAB., Pagola AG., de Munain Arregui AL., Ruiz-Martínez J., Cerdan D., Duarte J., Clarimón J., Dols-Icardo O., Infante J., Marín J., Kulisevsky J., Pagonabarraga J., Gonzalez-Aramburu I., Rodriguez AS., Sierra M., Duran R., Ruz C., Vives F., Escamilla-Sevilla F., Mínguez A., Cámara A., Compta Y., Ezquerra M., Marti MJ., Fernández M., Muñoz E., Fernández-Santiago R., Tolosa E., Valldeoriola F., García-Ruiz P., Heredia MJG., Errazquin FP., Hoenicka J., Jimenez-Escrig A., Martínez-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 F., Xue A., 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., Hardy J., Gagliano Taliun SA., Ryten M.
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.