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. 2022 Dec 11;14(1):170.
doi: 10.1186/s13148-022-01384-7.

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

Elze R Timmers  1   2 , Torsten Plösch  3 , Marenka Smit  4   5 , Ingrid H Hof  6 , Rikst Nynke Verkaik-Schakel  3 , Marina A J Tijssen  4   5 , Tom J de Koning  5   7 , Klary E Niezen-Koning  5   6
Affiliations

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

Elze R Timmers et al. Clin Epigenetics. .

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.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Median percentage of methylation per CpG site per group. Error bars represent interquartile range. Distance between the CpG sites on the x-axis represents the distance of CpG sites in the gene. *Indicates that variance of methylation level at this CpG site is significantly predicted by having dopa-responsive dystonia compared to healthy controls when corrected for age using bootstrapped quantile regression analysis.**Indicates that the variance of methylation at this CpG site is significantly predicted by having dystonia compared to healthy controls, when corrected for age. CD cervical dystonia, M-D myoclonus dystonia, DRD dopa-responsive dystonia
Fig. 2
Fig. 2
Associations between psychiatry and methylation at CpG38 in all dystonia patients
See this image and copyright information in PMC

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