Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
Eur Neuropsychopharmacol. 2019 Oct;29(10):1161-1167. doi: 10.1016/j.euroneuro.2019.07.131. Epub 2019 Jul 26.
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.
惊恐障碍（PD）常与重度抑郁障碍（MDD）共病，这与治疗反应和康复率受损有关。5-羟色胺能系统的改变可能在 PD 和 MDD 的发病机制中起关键作用，并可能构成这两种疾病的共同生物学主干。表观遗传模式，如 5-羟色胺转运体基因（SLC6A4）的高甲基化，与包括 MDD 在内的各种精神障碍有关，但迄今为止，尚未报告与 PD 有关。在本研究中，采用病例对照设计对 PD 患者的两个独立样本进行了 SLC6A4 启动子甲基化研究（样本 1：N=120；样本 2：N=118），同时考虑到两种疾病的高共病性，考虑到共病 MDD 的影响。通过基于荧光素酶的报告基因检测来研究改变的 SLC6A4 启动子甲基化的功能相关性。与健康对照组相比，PD 患者的 SLC6A4 启动子超甲基化是由共病 MDD 驱动的（p=9×10），而无共病 MDD 的患者未观察到改变的甲基化水平。这不仅与健康对照组相比是如此，而且在 PD 患者伴或不伴共病 MDD 之间的直接比较中也是如此（p=0.009）。功能分析显示，研究区域的高甲基化导致报告基因活性降低。本研究结果表明，SLC6A4 启动子的功能相关超甲基化可能是 MDD 的一个特异的表观遗传标志物，但不是 PD 本身的标志物，因此可能构成一个基于个体表观遗传谱的选择性生物标志物，用于进行基于不同的个体化的诊断。
