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<p>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 <i>SNCA</i> downregulation in all PD cohorts, a signal previously obscured by immune cell-related effects. Lowered <i>SNCA</i> expression was observed in individuals with known PD-linked gene mutations (e.g., <i>SNCA</i>, <i>GBA1</i>, <i>LRRK2</i>) and those without known pathogenic variants. These findings suggest that decreased <i>SNCA</i> expression in whole blood may be a defining transcriptomic feature of PD.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月14日

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  • Kayla Y. Xu,
  • Ivo Violich,
  • Elizabeth Hutchins,
  • Eric Alsop,
  • Mike A. Nalls,
  • Anni Moore,
  • Cornelis Blauwendraat,
  • J. Raphael Gibbs,
  • Mark R. Cookson,
  • Kendall Van Keuren-Jensen,
  • David W. Craig

摘要

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.