Epigenetic regulation of SYNGAP1 in alcohol use disorder in whole blood and saliva

Epigenetic regulation is significantly altered in individuals with alcohol use disorder (AUD), representing a promising avenue for understanding its pathomechanisms and developing new therapies. In an earlier epigenome-wide study of CD3+ T cells, we identified <i>SYNGAP1</i>-a critical regulator of synaptic plasticity that influences neuronal communication and network remodeling-as epigenetically dysregulated, with significantly lower DNA methylation (DNAm) in patients than controls. After three weeks of inpatient withdrawal, <i>SYNGAP1</i> DNAm increased to control levels. In the present study, we aimed to validate these differential <i>SYNGAP1</i> DNAm levels in an independent cohort of 64 AUD patients and 83 healthy controls in peripheral blood and saliva, to assess its potential as a biomarker. Using a linear mixed-effects model including AUD status and covariates, no significant differences were observed. <i>Post hoc</i> analyses revealed an unexpected pattern: In blood, <i>SYNGAP1</i> DNAm was higher in patients before treatment than controls, with no difference after withdrawal; in saliva, no differences or therapy effects were detected. Overall, these results did not confirm our previous findings, suggesting limited value of <i>SYNGAP1</i> DNAm as a biomarker for AUD. While blood methylation showed some association, the effect direction contradicted earlier results, and saliva showed no signal. Further research is needed to clarify <i>SYNGAP1</i> epigenetic regulation in AUD and its potential relevance for biomarkers or therapy.