Integrative Multi‐Omics Analysis Reveals Convergent Epigenome and Transcriptome Changes in Parkinson's Disease

BACKGROUND: The mechanisms that predispose dopaminergic neurons (DAN) to degeneration in Parkinson's disease (PD) are incompletely understood. OBJECTIVE: To perform an integrative multi-omics reanalysis of single-cell transcriptomic and epigenomic data to identify convergent alterations predisposing dopaminergic neurons to degeneration in Parkinson's disease, and to generate new bulk ATAC-seq profiles from peripheral monocytes to assess whether these alterations extend to a systemic, cross-tissue epigenetic signature. METHODS: We reanalyzed single-cell RNA sequencing (scRNA-seq; n = 27 PD, 11 controls) and single-cell ATAC sequencing (scATAC-seq; n = 10 PD, 2 controls) data from induced pluripotent stem cell (iPSC)-derived DANs (Foundational Data Initiative for Parkinson's Disease [FOUNDIN-PD]) to identify convergent transcriptional and epigenetic alterations. We generated new bulk ATAC-seq from peripheral monocytes of parkinsonian disorder patients (n = 10) and controls (n = 4) to assess cross-tissue epigenetic signatures. RESULTS: Convergent downregulation in neurodevelopmental and synaptic pathways was observed across neuronal maturation stages. Network perturbation analysis identified SMARCA4 as a key upstream regulator. Monocyte comparison revealed 44 genes with concordant chromatin accessibility changes, with NFATC2 exhibiting decreased accessibility across all neuronal subtypes and monocytes. CONCLUSION: This exploratory analysis identifies shared transcriptomic-epigenomic alterations at gene, pathway, and network levels in PD neurons and preliminary systemic epigenetic signatures that warrant validation in larger cohorts. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.