| Title: |
Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability |
| Authors: |
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 JC; 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; Reynolds, Regina |
| Publisher Information: |
Springer Science and Business Media LLC |
| Publication Year: |
2021 |
| Collection: |
University of Canterbury, Christchurch: UC Research Repository |
| Subject Terms: |
Fields of Research::32 - Biomedical and clinical sciences::3209 - Neurosciences::320905 - Neurology and neuromuscular diseases; Fields of Research::52 - Psychology::5202 - Biological psychology::520203 - Cognitive neuroscience; Fields of Research::32 - Biomedical and clinical sciences::3208 - Medical physiology::320801 - Cell physiology; Fields of Research::52 - Psychology::5201 - Applied and developmental psychology::520106 - Psychology of ageing; Fields of Research::31 - Biological sciences::3105 - Genetics::310511 - Neurogenetics; Fields of Research::32 - Biomedical and clinical sciences::3202 - Clinical sciences::320213 - Medical genetics (excl. cancer genetics) |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://hdl.handle.net/10092/102170 |
| DOI: |
10.1038/s41531-019-0076-6 |
| Availability: |
https://hdl.handle.net/10092/102170; https://doi.org/10.1038/s41531-019-0076-6 |
| Rights: |
© The Author(s) 2019. Open Access 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/. ; http://hdl.handle.net/10092/17651 |
| Accession Number: |
edsbas.32827544 |
| Database: |
BASE |