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

Paul W. Hook, Sarah A. McClymont, Gabrielle H. Cannon, William D. Law, A. Jennifer Morton, Loyal A. Goff, Andrew S. McCallion

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)427-446
Number of pages20
JournalAmerican journal of human genetics
Volume102
Issue number3
DOIs
StatePublished - Mar 1 2018

Keywords

  • Complexin 1
  • Parkinson disease
  • dopaminergic neurons
  • gene regulatory networks
  • genome-wide association studies
  • mouse
  • single-cell RNA sequencing
  • substantia nigra

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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