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 the first human single-nuclei transcriptomic atlas for substantia nigra (SN), generated by sequencing ~ 17,000 nuclei from matched cortical and SN samples. We show that 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 also identified a distinct cell-type association between PD risk and oligodendrocyte-specific expression implicating metabolic and gene expression regulation networks. Beyond PD, we find SN DaNs and GABAergic neurons to be associated with different neuropsychiatric disorders, particularly schizophrenia (SCZ) and bipolar disorder (BP). We identified distinct cortex/SN associations with SCZ genetic risk for both excitatory (synaptic functioning) and dopaminergic neurons (mitochondrial functioning and synaptic signalling). Conditional analyses shows that independent sets of loci associate distinct neuropsychiatric disorders with the same neuronal types. This atlas guides our aetiological understanding by associating SN cell-type expression profiles with specific disease risk. Overall design: Single nuclei were extracted and isolated from 3mm2 blocks that were manually dissected from the substantia nigra and cortex of 5 control (4 males & 1Female)de-identified post-mortem human donors, totaling to 12 matched samples, including 2 SN replicates and sequenced using the 10X chromium system (V2)