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.