Blood RNA patterns track essential tremor brain and cognitive differences

Blood RNA sequencing in a study of 75 participants identified modest molecular differences associated with essential tremor, while showing clearer links to variation in cognition, tremor severity and brain structure within the disorder. The research combined peripheral blood transcriptomics, clinical assessments and structural magnetic resonance imaging, offering proof-of-concept that blood expression patterns may reflect some of the biological processes underlying the substantial variation among people with essential tremor. The findings do not establish a diagnostic blood test, and the authors emphasize that larger, longitudinal cohorts are needed for validation.

The study included 38 people with essential tremor and 37 healthy controls. Investigators tested blood-gene expression differences with DESeq2, adjusting for age, sex, RNA-sequencing technical quality and estimated immune-cell composition. After correction for multiple comparisons, four genes were significantly elevated in the essential tremor group: CXCL5, HSPB1, CLEC7A and PRDX6. These case-control effects were sparse, but they remained significant across sensitivity analyses. CLEC7A also showed nominal concordance in an independent dataset of RNA-sequenced cerebellar tissue from people with essential tremor. More broadly, 59.9% of genes nominally associated with essential tremor in blood had effect directions that matched those in the cerebellum, a concordance rate described as exceeding chance expectation. This cross-tissue agreement suggests that some blood signals may correspond to biological changes measurable in brain tissue, although it does not demonstrate that blood expression can be used to diagnose the condition.

The strongest results emerged when researchers examined differences within the essential tremor group rather than simply comparing affected participants with controls. Covariate-adjusted linear models linked expression of 40 genes to scores from the Montreal Cognitive Assessment, including GNLY, ZAP70 and KLRD1. Gene-expression patterns were also associated with regional brain measurements: 253 genes correlated with right pericalcarine cortical thickness and 46 with the volume of the anterior corpus callosum. The analysis did not find significant case-control differences in the study’s primary global neuroimaging measures. The contrast is important because it indicates that peripheral blood expression carried a limited signal for diagnosis but may contain information about the varied cognitive and neuroanatomical profiles found within essential tremor.

Weighted gene co-expression network analysis identified coordinated groups of genes whose activity tracked those clinical and imaging characteristics. A cytotoxic immune module was strongly associated with lower MoCA scores, with a correlation of r = −0.76 and an adjusted p-value of 0.0002. A second module, containing genes related to mitochondrial expression and translation, was associated with right pericalcarine cortical thickness (r = −0.65, adjusted p = 0.01). An erythroid and vascular transport module correlated with anterior corpus callosum volume (r = 0.70, adjusted p = 0.0046). These are associations observed in a relatively small observational cohort, not evidence that changes in those pathways cause cognitive impairment or structural brain differences. The network results nevertheless point toward immune, metabolic and vascular processes that may help explain phenotypic heterogeneity in essential tremor and justify testing whether the same relationships appear in independent and longitudinal samples.

Subject of Research: Blood transcriptome associations with clinical and neuroimaging variation in essential tremor

Article Title: Blood transcriptional variation is associated with clinical and neuroimaging phenotypes in essential tremor

Article References: Welton, T., Teo, T. W. J., Ng, E. Y., Sun, Q., Lee, B., Saffari, E., Chan, L. L., Tan, L. C. S., & Tan, E.-K. (2026). Blood transcriptional variation is associated with clinical and neuroimaging phenotypes in essential tremor. Scientific Reports. https://doi.org/10.1038/s41598-026-76750-z

Image Credits: AI Generated

DOI: 10.1038/s41598-026-76750-z

Keywords: essential tremor, blood transcriptomics, RNA sequencing, brain MRI, cognition, immune pathways, gene networks, cerebellar tissue, biomarkers, Blood, transcriptional, variation