Abstract Parkinson’s disease (PD) is a progressive neurodegenerative disorder. However, cell type-dependent transcriptional regulatory programs responsible for PD pathogenesis remain elusive. Here, we establish transcriptomic and epigenomic landscapes of the substantia nigra (SN) by profiling 87,733 nuclei obtained from healthy controls and PD patients. Our multi-omic data integration provides functional annotation of 128,724 cis -regulatory elements ( c REs) and uncovers cell-type specific dysregulated c REs with a strong transcriptional influence on genes implicated in PD. The establishment of high-resolution three-dimensional chromatin contact maps identifies 656 target genes of dysregulated c REs and genetic risk loci, including both novel candidates and known PD risk genes. Notably, these new PD candidate genes exhibit modular gene expression patterns with unique molecular signatures in distinct cell types. Thus, our single-cell transcriptome and epigenome uncover cell type-specific disrupted transcriptional regulations in PD. Teaser Single-cell transcriptome and epigenome uncover cell type-specific disrupted transcriptional regulations in Parkinson’s disease.

Characterization of altered molecular mechanisms in Parkinson’s disease through cell type-resolved multi-omics analyses