TY - JOUR
T1 - Single-Cell RNA-Seq of Mouse Dopaminergic Neurons Informs Candidate Gene Selection for Sporadic Parkinson Disease
AU - Hook, Paul W.
AU - McClymont, Sarah A.
AU - Cannon, Gabrielle H.
AU - Law, William D.
AU - Morton, A. Jennifer
AU - Goff, Loyal A.
AU - McCallion, Andrew S.
N1 - Funding Information:
The authors wish to thank Stephen M. Brown for implementation and optimization of smFISH, Dr. Zhiguang Zheng and Mrs. Wendy Leavens for excellent technical support with the Cplx1 knockout mice and immunohistochemistry, and Drs. Kerstin Reim and Niels Brose for the gift of the founder mice for the Cambridge Cplx1 knockout mice colony. This research was supported in part by US NIH grants R01 NS62972 and MH106522 to A.S.M. and a grant from CHDI Inc. to A.J.M.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
AB - 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.
KW - Complexin 1
KW - Parkinson disease
KW - dopaminergic neurons
KW - gene regulatory networks
KW - genome-wide association studies
KW - mouse
KW - single-cell RNA sequencing
KW - substantia nigra
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U2 - 10.1016/j.ajhg.2018.02.001
DO - 10.1016/j.ajhg.2018.02.001
M3 - Article
C2 - 29499164
AN - SCOPUS:85042498991
VL - 102
SP - 427
EP - 446
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 3
ER -