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Single-Cell RNA-Seq of Mouse Dopaminergic Neurons Informs Candidate Gene Selection for Sporadic Parkinson Disease.

Accepted version
Peer-reviewed

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Type

Article

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Authors

Hook, Paul W 
McClymont, Sarah A 
Cannon, Gabrielle H 
Law, William D 
Morton, A Jennifer 

Abstract

Genetic variation modulating risk of sporadic Parkinson disease (PD) has been primarily explored through genome-wide association studies (GWASs). However, like many other common genetic diseases, the impacted genes remain largely unknown. Here, we used single-cell RNA-seq to characterize dopaminergic (DA) neuron populations in the mouse brain at embryonic and early postnatal time points. These data facilitated unbiased identification of DA neuron subpopulations through their unique transcriptional profiles, including a postnatal neuroblast population and substantia nigra (SN) DA neurons. We use these population-specific data to develop a scoring system to prioritize candidate genes in all 49 GWAS intervals implicated in PD risk, including genes with known PD associations and many with extensive supporting literature. As proof of principle, we confirm that the nigrostriatal pathway is compromised in Cplx1-null mice. Ultimately, this systematic approach establishes biologically pertinent candidates and testable hypotheses for sporadic PD, informing a new era of PD genetic research.

Description

Keywords

Complexin 1, Parkinson disease, dopaminergic neurons, gene regulatory networks, genome-wide association studies, mouse, single-cell RNA sequencing, substantia nigra, Animals, Cell Separation, Dopaminergic Neurons, Gene Regulatory Networks, Genetic Association Studies, Genetic Loci, Genetic Markers, Genome-Wide Association Study, Mice, Knockout, Parkinson Disease, Sequence Analysis, RNA, Single-Cell Analysis, Substantia Nigra

Journal Title

Am J Hum Genet

Conference Name

Journal ISSN

0002-9297
1537-6605

Volume Title

102

Publisher

Elsevier BV
Sponsorship
CHDI Foundation, Inc (NO REF)