Actin-Related Protein 2/3 (Arp2/3)-Associated Gene Expression in Repetitive Head Impacts and Chronic Traumatic Encephalopathy: Analysis of Two Human Transcriptomic Datasets

Background: We evaluated actin-related protein 2/3 (Arp2/3)-associated and SOX9/MEGF10 gene-expression modules in repetitive head impacts (RHI) and chronic traumatic encephalopathy (CTE).Methods: Public bulk RNA-sequencing data (GSE193407; 136 brains) and single-nucleus RNA-sequencing data (GSE261807; 28 donors) were analyzed.Sensitivity analyses examined neuronal and astrocytic marker adjustment, cell-type selection, and alternative Arp2/3 module definitions.Results: In bulk tissue, nominal CTE-stage associations with Arp2/3 (P = 0.0151) and SOX9/MEGF10 (P < 0.001) were attenuated after adjustment for neuronal and astrocytic markers (P = 0.2751 and P = 0.6899, respectively).In exploratory single-nucleus analyses, the six-cell-type omnibus comparison was nonsignificant (P = 0.0617), and no individual cell-type association survived false discovery rate correction.The post hoc three-cell-type composite did not establish a CTE-versus-RHI difference (95% CI, -0.532 to 0.539).Single-nucleus analyses were unadjusted for donor-level covariates; cell-type annotations were not independently validated, and donor overlap between datasets could not be excluded.Conclusions: The principal sensitivity analyses did not establish robust CTE-specific expression differences.These predominantly null findings are descriptive and hypothesis-generating.