Preliminary findings of DNA hypermethylation of MDGA1 in idiopathic restless legs syndrome.

Background: Both genetic and environmental factors contribute to the development of restless legs syndrome (RLS). Epigenetic mechanisms might play a vital role in RLS but remain underexplored. MDGA1, involved in synaptic inhibition, has been identified by genome-wide association studies as a potential risk gene for RLS. However, its role and underlying mechanisms in RLS are largely unknown.

Objective: To investigate the relationship between DNA methylation levels in the promotor region of MDGA1 and RLS susceptibility and phenotypes.

Methods: Two independent RLS cohorts (including three large RLS families) and healthy controls (HCs) were recruited. Clinical characteristics were recorded, and DNA methylation levels of CpG islands in the MDGA1 gene from peripheral blood mononuclear cells were measured. Associations between MDGA1 methylation (MDGA1m) and RLS phenotypes (age, sex, and family history) were also analyzed.

Results: A total of 62 idiopathic RLS (iRLS) patients (29 from Cohort 1 and 33 from Cohort 2) and 45 healthy controls (24 from Cohort 1 and 21 from Cohort 2) were included. MDGA1 methylation levels were significantly higher in iRLS patients compared to HCs. Among RLS families, both RLS patients and non-RLS family members showed hypermethylation compared to HCs. Moreover, a positive family history of RLS was associated with an increased risk of MDGA1 hypermethylation.

Conclusion: Our study identified hypermethylation of the MDGA1 gene in the peripheral blood of RLS cases, which may be linked to family history.