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

Essential tremor (ET) is a clinically heterogeneous movement disorder, but the extent to which peripheral transcriptional variation reflects diagnosis, clinical severity, or neuroanatomical variation is unknown. We investigated whether blood RNA expression is associated with ET and with individual differences in cognitive, motor, and structural brain phenotypes. We integrated peripheral blood RNA sequencing, clinical assessment, and structural brain MRI in 75 participants, including 38 individuals with ET and 37 healthy controls.

Differential expression was tested using DESeq2 with adjustment for age, sex, technical quality, and estimated immune cell composition. Within the ET group, gene-level associations with Montreal Cognitive Assessment (MoCA), Essential Tremor Rating Assessment Scale measures, and regional brain morphometry were tested using covariate-adjusted linear models. Weighted gene co-expression network analysis identified coordinated transcriptional modules, which were related to clinical and imaging phenotypes and interpreted using Gene Ontology enrichment.

Cross-tissue reproducibility was assessed in an independent ET cerebellar RNA-sequencing dataset. Case-control differences were sparse. Four genes were significantly upregulated in ET after false discovery rate correction: CXCL5, HSPB1, CLEC7A, and PRDX6.

These effects were robust across sensitivity models, and CLEC7A showed nominal concordance in independent cerebellar tissue. Among genes nominally associated with ET in blood, 59.9% showed concordant effect directions in cerebellum, exceeding chance expectation. No significant case-control differences were observed in the primary global neuroimaging measures.

In contrast to the limited diagnostic signal, peripheral expression was more strongly associated with within-ET heterogeneity. MoCA scores were associated with 40 genes, including GNLY, ZAP70, and KLRD1. Regional imaging analyses identified 253 genes associated with right pericalcarine cortical thickness and 46 genes associated with anterior corpus callosum volume.

Network analysis reinforced these findings: a cytotoxic immune module was strongly associated with MoCA (r = − 0.76, adjusted p = 0.0002), a mitochondrial gene-expression and translation module was associated with pericalcarine thickness (r = − 0.65, adjusted p = 0.01), and an erythroid and vascular transport module was associated with anterior corpus callosum volume (r = 0.70, adjusted p = 0.0046). Peripheral blood transcriptional differences in ET are modest at the diagnostic level but show structured relationships with cognitive and neuroanatomical heterogeneity. These findings provide proof-of-concept that blood transcriptomics may capture systemic immune, metabolic, and vascular processes relevant to phenotypic variation in ET, while requiring validation in larger longitudinal cohorts.