Translational Department, Max Planck Institute for Psychiatry, Kraepelinstrasse 2+10, 80804, Munich, Germany.
Institute of Statistics, Faculty of Mathematics, Informatics and Statistics, Ludwig-Maximilians-University Munich, Munich, Germany.
Clin Epigenetics. 2022 Apr 27;14(1):55. doi: 10.1186/s13148-022-01274-y.
Panic disorder (PD) is characterized by recurrent panic attacks and higher affection of women as compared to men. The lifetime prevalence of PD is about 2-3% in the general population leading to tremendous distress and disability. Etiologically, genetic and environmental factors, such as stress, contribute to the onset and relapse of PD. In the present study, we investigated epigenome-wide DNA methylation (DNAm) in respond to a cumulative, stress-weighted life events score (wLE) in patients with PD and its boundary to major depressive disorder (MDD), frequently co-occurring with symptoms of PD.
DNAm was assessed by the Illumina HumanMethylation450 BeadChip. In a meta-analytic approach, epigenome-wide DNAm changes in association with wLE were first analyzed in two PD cohorts (with a total sample size of 183 PD patients and 85 healthy controls) and lastly in 102 patients with MDD to identify possible overlapping and opposing effects of wLE on DNAm. Additionally, analysis of differentially methylated regions (DMRs) was conducted to identify regional clusters of association.
Two CpG-sites presented with p-values below 1 × 10 in PD: cg09738429 (p = 6.40 × 10, located in an intergenic shore region in next proximity of PYROXD1) and cg03341655 (p = 8.14 × 10, located in the exonic region of GFOD2). The association of DNAm at cg03341655 and wLE could be replicated in the independent MDD case sample indicating a diagnosis independent effect. Genes mapping to the top hits were significantly upregulated in brain and top hits have been implicated in the metabolic system. Additionally, two significant DMRs were identified for PD only on chromosome 10 and 18, including CpG-sites which have been reported to be associated with anxiety and other psychiatric phenotypes.
This first DNAm analysis in PD reveals first evidence of small but significant DNAm changes in PD in association with cumulative stress-weighted life events. Most of the top associated CpG-sites are located in genes implicated in metabolic processes supporting the hypothesis that environmental stress contributes to health damaging changes by affecting a broad spectrum of systems in the body.
惊恐障碍（PD）的特征是反复发作的惊恐发作，女性比男性更容易受到影响。PD 的终身患病率约为普通人群的 2-3%，导致巨大的痛苦和残疾。从病因学上讲，遗传和环境因素，如压力，会导致 PD 的发作和复发。在本研究中，我们调查了在 PD 患者中，对累积的、加权生活事件评分（wLE）的全基因组 DNA 甲基化（DNAm）反应，以及其与经常与 PD 症状共病的重度抑郁症（MDD）的边界。
通过 Illumina HumanMethylation450 BeadChip 评估 DNAm。在一项荟萃分析方法中，首先分析了两个 PD 队列中与 wLE 相关的全基因组 DNAm 变化（总样本量为 183 例 PD 患者和 85 例健康对照），最后在 102 例 MDD 患者中进行了分析，以确定 wLE 对 DNAm 的可能重叠和相反影响。此外，还进行了差异甲基化区域（DMR）分析，以识别关联的区域聚类。
在 PD 中，有两个 CpG 位点的 p 值低于 1×10：cg09738429（p=6.40×10，位于 PYROXD1 下一个临近的基因间岸区）和 cg03341655（p=8.14×10，位于 GFOD2 的外显子区）。cg03341655 处的 DNAm 与 wLE 的关联可在独立的 MDD 病例样本中复制，表明存在诊断独立的效应。映射到前几个命中的基因在大脑中显著上调，前几个命中基因已被证明与代谢系统有关。此外，仅在 10 号和 18 号染色体上确定了两个 PD 特有的显著 DMR，包括已报道与焦虑和其他精神表型相关的 CpG 位点。
这是 PD 中首次进行的 DNAm 分析，首次发现 PD 中与累积的加权生活事件相关的小但显著的 DNAm 变化的证据。大多数前关联的 CpG 位点位于代谢过程中涉及的基因中，支持环境应激通过影响身体中广泛的系统导致健康损害变化的假说。
