A human single-cell atlas of the Substantia nigra reveals novel cell-specific pathways associated with the genetic risk of Parkinson’s disease and neuropsychiatric disorders

We describe a human single-nuclei transcriptomic atlas for the Substantia nigra ( SN) , generated by sequencing ~ 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 patterns with multiple neuropsychiatric disorders. Nevertheless, we find that each neuropsychiatric disorder is associated with a distinct set of genes within that neuron type. This atlas guides our aetiological understanding by associating SN cell type expression profiles with specific disease risk.