Hypermethylation of the serotonin transporter gene promoter in panic disorder-Epigenetic imprint of comorbid depression?

Panic disorder (PD) is frequently comorbid with major depressive disorder (MDD), which has been associated with impaired treatment response and recovery rates. Alterations in the serotonergic system may play a crucial role in the pathogenesis of PD and MDD and might constitute a shared biological trunk of both disorders. Epigenetic patterns such as hypermethylation of the serotonin transporter gene (SLC6A4) have been associated with various mental disorders including MDD, but, to date, no association with PD has been reported. In the present study, SLC6A4 promoter methylation was investigated in two independent samples of PD patients in a case-control design (sample 1: N = 120; sample 2: N = 118), while - given the reported high comorbidity of both disorders - taking into account the effect of comorbid MDD. The functional relevance of altered SLC6A4 promoter methylation was investigated by means of luciferase-based reporter gene assays. SLC6A4 promoter hypermethylation in PD patients relative to healthy controls was driven by comorbid diagnosis of MDD (p = 9 × 10), whereas no altered methylation levels were observed in patients without comorbid MDD. This held true not only in comparison to healthy controls, but also in direct comparison between PD patients with and without comorbid MDD (p = .009). Functional analyses revealed increased methylation of the investigated region to confer decreased reporter gene activity. The present results suggest functionally relevant SLC6A4 promoter hypermethylation as a possibly specific epigenetic marker of MDD, but not of PD itself, and thus might constitute a selective biomarker informing differential diagnosis based on individual epigenetic profiles.