Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson\u2019s disease heritability

Regina H Reynolds ,Sarah A Gagliano Taliun,Juan A Botía ,Mike A Nalls,John Hardy,Mina Ryten

doi:10.1038/s41531-019-0076-6

Abstract

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.

Highlights

Late-onset sporadic forms of neurodegenerative diseases are devastating conditions imposing an increasing burden on healthcare systems worldwide
For all stratified-linkage disequilibrium (LD) score regression (LDSC) analyses, we report coefficient p-values, which test whether the regression coefficient of an annotation category positively contributes to trait heritability, conditional
One of the most striking features of Parkinson’s disease (PD) is the specificity of its neuropathology and clinical symptoms, which has implicated αsynuclein biology in dopaminergic neurons of the substantia nigra pars compacta as a key component of the disease.[1,2]

Summary

INTRODUCTION

Late-onset sporadic forms of neurodegenerative diseases are devastating conditions imposing an increasing burden on healthcare systems worldwide. Related pathways and, by implication, neurons in both sporadic and Mendelian forms of PD Despite this neuronal focus, there is growing evidence to suggest the involvement of other cell types in PD pathogenesis. The increasing power of GWASs (with the most recently published PD GWAS including 37.7K cases, 18.6K ‘proxy-cases’ and 1.4M controls, resulting in 90 associated loci14) coupled with the increased availability of cell-specific gene expression data provides a new opportunity to address the potential cellular specificity of disease heritability, as was elegantly demonstrated for schizophrenia in a study by Skene et al.[15] Brain regions contain a mixture of cell types, such as neurons, microglia and astrocytes, which may exhibit their own specific regulatory features that could be masked when averaging features across cell types. A comparison of eQTLs specific to each brain region revealed no

RESULTS

DISCUSSION

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