A deep cellular atlas of the human ventral substantia nigra in Parkinson’s identifies a genetic and molecular overlap with Type 2 Diabetes

Parkinson’s disease (PD) is a complex neurodegenerative disorder characterised by selective neuronal loss. We integrate deep full-length single-nuclei sequencing of the human ventral substantia nigra with genome-wide association studies (GWAS) to reveal genetic and cellular drivers of PD. Genetic risk converges onto AGTR1+ dopaminergic neurons and perineuronal (non-myelinating) oligodendrocytes, both reduced in PD, along with oligodendrocyte precursor cells, with risk enriched among disease-disrupted cellular interactions. AGTR1+ neurons represent a metabolically stressed state, not a distinct cell type, marked by renin-angiotensin system (RAS) and MAPK activation, oxidative stress, and mitochondrial dysfunction. This state is associated with type 2 diabetes (T2D) genetic risk. A GWAS of comorbid PD and T2D identifies significant loci in AGTR1 and TCF7L2, providing a mechanistic link between diseases, while AGTR1+ neurons specifically upregulate RAS and T2D drug targets. Comorbid PD/T2D risk is associated with multiple PD rare variant genes that cause non-Lewy body PD, mechanistically stratifying PD.