Decreased SNCA expression in whole-blood RNA analysis of Parkinson's disease adjusting for neutrophils

Blood-based RNA transcriptomics offers a promising avenue for identifying biomarkers of Parkinson's disease (PD) progression and mechanisms of pathogenesis. Previous work uncovered an age-related increase of neutrophil-enriched gene expression in PD whole blood, which may obscure disease-relevant transcriptomic signals. To better capture PD-associated molecular differences, we analyzed PD whole-blood RNA sequencing data using a differential expression approach that accounts for neutrophil composition. We built a model to estimate neutrophil percentages in 6897 Parkinson's Progression Markers Initiative and Parkinson's Disease Biomarkers Program samples from gene expression. By incorporating predicted neutrophil percentages as a covariate, we see significant SNCA downregulation in all PD cohorts, a signal previously obscured by immune cell-related effects. Lowered SNCA expression was observed in individuals with known PD-linked gene mutations (e.g., SNCA, GBA1, LRRK2) and those without known pathogenic variants. These findings suggest that decreased SNCA expression in whole blood may be a defining transcriptomic feature of PD.