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 ?-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. I...

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Autores: Reynolds, Regina H., Botía, Juan, Nalls, A., Hardy, john, Gagliano Taliun, Sarah A., Ryten, Mina, Infante Ceberio, Jon|||0000-0003-4025-4606
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/24106
Acceso en línea:http://hdl.handle.net/10902/24106
Access Level:acceso abierto
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spelling Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritabilityReynolds, Regina H.Botía, JuanNalls, A.Hardy, johnGagliano Taliun, Sarah A.Ryten, MinaInfante Ceberio, Jon|||0000-0003-4025-4606Parkinson?s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of ?-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.Nature Publishing GroupUniversidad de Cantabria20192019-04-17journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articlehttp://hdl.handle.net/10902/24106NPJ Parkinson's disease 5, 6 (2019)reponame:UCrea Repositorio Abierto de la Universidad de Cantabriainstname:Universidad de Cantabria (UC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositorio.unican.es:10902/241062026-06-02T12:39:31Z
dc.title.none.fl_str_mv Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability
title Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability
spellingShingle Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability
Reynolds, Regina H.
title_short Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability
title_full Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability
title_fullStr Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability
title_full_unstemmed Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability
title_sort Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability
dc.creator.none.fl_str_mv Reynolds, Regina H.
Botía, Juan
Nalls, A.
Hardy, john
Gagliano Taliun, Sarah A.
Ryten, Mina
Infante Ceberio, Jon|||0000-0003-4025-4606
author Reynolds, Regina H.
author_facet Reynolds, Regina H.
Botía, Juan
Nalls, A.
Hardy, john
Gagliano Taliun, Sarah A.
Ryten, Mina
Infante Ceberio, Jon|||0000-0003-4025-4606
author_role author
author2 Botía, Juan
Nalls, A.
Hardy, john
Gagliano Taliun, Sarah A.
Ryten, Mina
Infante Ceberio, Jon|||0000-0003-4025-4606
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad de Cantabria
description Parkinson?s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of ?-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.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019-04-17
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10902/24106
url http://hdl.handle.net/10902/24106
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv NPJ Parkinson's disease 5, 6 (2019)
reponame:UCrea Repositorio Abierto de la Universidad de Cantabria
instname:Universidad de Cantabria (UC)
instname_str Universidad de Cantabria (UC)
reponame_str UCrea Repositorio Abierto de la Universidad de Cantabria
collection UCrea Repositorio Abierto de la Universidad de Cantabria
repository.name.fl_str_mv
repository.mail.fl_str_mv
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