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

By Regina H. Reynolds, Juan Botía, Mike A Nalls, International Parkinson’s Disease Genomics Consortium (IPDGC), System Genomics of Parkinson’s Disease (SGPD), John Hardy, Sarah A. Gagliano, Mina Ryten

Posted 16 Oct 2018
bioRxiv DOI: 10.1101/442152 (published DOI: 10.1038/s41531-019-0076-6)

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 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 specifically expressed in astrocytic and microglial 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 to which cell types may have varying vulnerability.

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