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 SYNGAP1-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, SYNGAP1 DNAm increased to control levels. In the present study, we aimed to validate these differential SYNGAP1 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. Post hoc analyses revealed an unexpected pattern: In blood, SYNGAP1 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 SYNGAP1 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 SYNGAP1 epigenetic regulation in AUD and its potential relevance for biomarkers or therapy.