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A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders

Agarwal, Devika, Sandor, Cynthia, Volpato, Viola, Caffrey, Tara M., Monzon-Sandoval, Jimena, Bowden, Rory, Alegre-Abarrategui, Javier, Wade-Martins, Richard and Webber, Caleb 2020. A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders. Nature Communications 11 (1) , 4183. 10.1038/s41467-020-17876-0

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Abstract

We describe a human single-nuclei transcriptomic atlas for the substantia nigra (SN), generated by sequencing approximately 17,000 nuclei from matched cortical and SN samples. We show that the common genetic risk for Parkinson’s disease (PD) is associated with dopaminergic neuron (DaN)-specific gene expression, including mitochondrial functioning, protein folding and ubiquitination pathways. We identify a distinct cell type association between PD risk and oligodendrocyte-specific gene expression. Unlike Alzheimer’s disease (AD), we find no association between PD risk and microglia or astrocytes, suggesting that neuroinflammation plays a less causal role in PD than AD. Beyond PD, we find associations between SN DaNs and GABAergic neuron gene expression and multiple neuropsychiatric disorders. Conditional analysis reveals that distinct neuropsychiatric disorders associate with distinct sets of neuron-specific genes but converge onto shared loci within oligodendrocytes and oligodendrocyte precursors. This atlas guides our aetiological understanding by associating SN cell type expression profiles with specific disease risk.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Nature Research
ISSN: 2041-1723
Funders: MRC
Date of First Compliant Deposit: 2 September 2020
Date of Acceptance: 21 July 2020
Last Modified: 14 Sep 2020 13:03
URI: http://orca-mwe.cf.ac.uk/id/eprint/134633

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