Allele-specific expression modulates the immunological and cis-regulatory landscape of Parkinson's Disease.

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder with a complex etiology, in which genetic variability in non-coding regions and epigenetic mechanisms play a central role. This study investigated allele-specific expression (ASE) patterns in peripheral blood RNA-Seq data from 487 individuals with idiopathic PD (iPD) and healthy controls from the PPMI initiative, aiming to characterize disease-associated transcriptional imbalances and their relationship with CpG islands. We identified 31,219 significant variants at heterozygous sites, with 4537 variants unique to the iPD group (14.53% of the total) mapping to 921 genes, a number significantly higher than that observed in controls (73 genes). Functional analysis revealed consistent enrichment in immune pathways (HLA-B antigen presentation, FcγR signaling, Th17 differentiation) and processes involving ubiquitination and protein degradation, suggesting an integrated molecular signature of immune dysregulation and proteostatic stress. Chromosomal distribution showed hotspots on chromosomes 1, 2, 6, 12, and 17, with a predominance of transition variants in CpG-rich regions. However, no direct linear correlation was observed between variant characteristics and CpG island metrics (density, GC content), indicating that regulatory effects may operate independently of local methylation. Protein interaction network analysis highlighted sub-networks featuring hub genes such as PINK1, GBA1, LRRK2, and PRKN, connected to autophagy and immune response pathways. These results support the view that ASE captures a broad regulatory signature in iPD, distinct from the DNA methylation context, and reinforces the role of immunogenetic dysregulation as a primary component of the disease's pathophysiology, offering new targets for mechanistic investigation and peripheral biomarkers.