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Nature Research, npj Parkinson's Disease, 1(5), 2019

DOI: 10.1038/s41531-019-0076-6

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

Journal article published in 2019 by Regina H. Reynolds, Alastair J. Noyce, Andrew B. Singleton, Aude Nicolas, Arianna Tucci, Mike A. Nalls, Xylena Reed, Hampton Leonard, Nicholas W. Wood, Lea R’Bibo, Daniah Trabzuni, Manuela Tan, Demis A. Kia, Henry Houlden, Helene Plun-Favreau and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Data provided by SHERPA/RoMEO

Abstract

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.