Comparative Peripheral Blood Transcriptomic Profiles in Parkinson’s Disease and Restless Legs Syndrome: An Exploratory Between-Cohort Analysis

Restless legs syndrome (RLS) and RLS-like symptoms are frequently reported in Parkinson’s disease (PD), but whether this clinical overlap reflects shared biology or convergent symptom expression remains uncertain. We performed an exploratory comparative analysis of peripheral blood mononuclear cell RNA-seq data from 17 drug-free patients with RLS and 60 patients with PD, most of whom were receiving dopaminergic treatment. Because the two cohorts were derived from independent datasets and no healthy control group was included, all findings were interpreted as relative PD-versus-RLS differences rather than disease-specific alterations. Differential expression and pathway analyses identified broad transcriptomic separation between the two groups. Genes with relatively higher expression in PD than RLS included transcripts related to dopamine metabolism, tetrahydrobiopterin biology, iron transport, oxidative stress, and inflammatory signaling, whereas genes with relatively higher expression in RLS than PD involved iron/ferroptosis-related biology, GPCR-mediated signaling, synaptic modulation, and circadian-related pathways. These results suggest that peripheral blood transcriptomics may help generate hypotheses on the biological heterogeneity underlying RLS-like symptoms in PD. However, because of treatment imbalance, cohort differences, batch-group confounding, absence of healthy controls, and the use of PBMCs as a peripheral tissue, the findings should be considered hypothesis-generating and require independent validation.