Methylation of the serotonin reuptake transporter gene and non-motor symptoms in dystonia patients

Abstract

Background: Dystonia is a rare movement disorder, in which patients suffer from involuntary twisting movements or abnormal posturing. Next to these motor symptoms, patients have a high prevalence of psychiatric comorbidity, suggesting a role for serotonin in its pathophysiology. This study investigates the percentage of DNA methylation of the gene encoding for the serotonin reuptake transporter (SLC6A4) in dystonia patients and the associations between methylation levels and presence and severity of psychiatric symptoms.

Methods: Patients with cervical dystonia (n = 49), myoclonus dystonia (n = 41) and dopa-responsive dystonia (DRD) (n = 27) and a group of healthy controls (n = 56) were included. Psychiatric comorbidity was evaluated with validated questionnaires. Methylation levels of 20 CpG sites situated 69 to 213 base pairs upstream of the start codon of SLC6A4 were investigated. Methylation in dystonia patients was compared to healthy controls, correcting for age, and correlated with psychiatric comorbidity.

Results: Bootstrapped quantile regression analysis showed that being a dystonia patient compared to a healthy control significantly explains the methylation level at two CpG sites (CpG 24: pseudo-R² = 0.05, p = 0.04, CpG 32: pseudo-R² = 0.14, p = 0.03). Subgroup analysis revealed that being a DRD patient significantly explained a part of the variance of methylation levels at two CpG sites (CpG 21: pseudo-R² = 0.03, p = 0.00, CpG 24: pseudo-R² = 0.06, p = 0.03). Regression analysis showed that methylation level at CpG 38 significantly explained a small proportion of the variance of severity score for anxiety (R² = 0.07, p = 0.04) and having a diagnosis of depression (Nagelkerke R²: 0.11, p = 0.00). Genotype of the 5-HTTLPR polymorphism had no additional effect on these associations.

Conclusions: This study showed an association between percentage of methylation at several specific sites of the promoter region of SLCA64 and (dopa-responsive) dystonia patients compared to healthy controls. Furthermore, methylation levels were associated with severity of anxiety and presence of a depressive disorder in the dystonia group. This study suggests alterations in the serotonergic metabolism in dystonia patients, and its relation with the non-motor symptoms.

Keywords: Dystonia; Epigenetics; Methylation; Non-motor symptoms; Psychiatry; SLC6A4; Serotonin reuptake transporter.