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bioRxiv · 10.1101/2024.11.18.623684

Decreased SNCA Expression in Whole-Blood RNA Analysis of Parkinson's Disease Adjusting for Lymphocytes

Xu, K.·Violich, I.·Hutchins, E.·Alsop, E.·Nalls, M. A.·Blauwendraat, C.·Gibbs, J. R.·Cookson, M. R.·Moore, A.·Van Keuren-Jensen, K.·Craig, D. W.
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Abstract

Blood-based RNA transcriptomics offers a promising avenue for identifying biomarkers of Parkinsons Disease (PD) progression and may provide mechanistic insights into the systemic biological processes underlying its pathogenesis beyond the well-defined neurodegenerative features. Previous studies have indicated an age-dependent increase in neutrophil-enriched gene expression, alongside a reduction in lymphocyte counts, in individuals with PD. These immune cell changes can obscure disease-relevant transcriptomic signals. In this study, we performed differential expression (DE) analysis of whole-blood RNA sequencing data from PD cohorts, incorporating a correction for immune cell-enriched gene expression, particularly neutrophil-related pathways, to improve the resolution of PD-associated molecular changes. Using 1,254 Parkinsons Progression Markers Initiative (PPMI) samples with complete blood count (CBC) data, we developed a predictive model to estimate neutrophil percentages in a 6,987 PPMI and Parkinsons Disease Biomarkers Program (PDBP) samples. We mitigated the confounding effects of immune cell-enriched gene expression by integrating predicted neutrophil percentages as a covariate in DE analysis. This approach revealed a consistent and significant downregulation of SNCA across all PD cohorts, a finding previously obscured by immune cell signatures. Lowered SNCA expression was found in individuals with known predisposition genes (e.g., SNCA, GBA, LRRK2) and in non-genetic PD cohorts lacking known pathogenic mutations, suggesting it may represent a key transcriptomic hallmark of the disease.

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Xu, K., Violich, I., Hutchins, E., Alsop, E., Nalls, M. A., Blauwendraat, C., Gibbs, J. R., Cookson, M. R., Moore, A., Van Keuren-Jensen, K., Craig, D. W.. 2024-11-19. Decreased SNCA Expression in Whole-Blood RNA Analysis of Parkinson's Disease Adjusting for Lymphocytes. https://doi.org/10.1101/2024.11.18.623684

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