Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Borderline Personal Disord Emot Dysregul. 2015 Apr 15;2:8. doi: 10.1186/s40479-015-0029-6. eCollection 2015.
Research has demonstrated an association between exposure to early life stress and an increased risk of psychiatric disorders in later life, in particular depression. However, the mechanism through which early life stress contributes to disease development remains unclear. Previous studies have reported an association between early life stress and altered methylation of the serotonin transporter gene (SLC6A4), a key candidate gene for several psychiatric disorders. These differences in methylation are influenced by sex and genetic variation in the SLC6A4-linked polymorphic region (5-HTTLPR). Furthermore, one study indicated that stress during pregnancy may induce methylation changes in SLC6A4 in the newborn. The present study is the first to investigate whether early life stress during pregnancy impacts on SLC6A4 methylation in newborns, taking into account the influence of genetic variation and sex.
Cord blood was obtained from newborns with high (n = 45) or low (n = 45) early life stress, defined as maternal stress during pregnancy. The effect on methylation of early life stress, 5-HTTLPR genotype, and sex was assessed at four cytosin-phosphate-guanine dinucleotide (CpG) sites in the promoter associated CpG island north shore (CpG 1 to 4). The epigenetic analyses focused on these CpG sites, since research has shown that CpG island shore methylation has functional consequences.
Significant sex-specific methylation was observed, with females displaying higher methylation levels than males (p < 0.001). Importantly, this effect was influenced by neither early life stress nor genotype.
The present data suggest that sex-specific methylation of SLC6A4 is present at birth, and is independent of early life stress and 5-HTTLPR genotype. This may contribute to the sex-specific prevalence of depression.
研究表明，早期生活应激与晚年精神障碍（尤其是抑郁症）风险增加之间存在关联。然而，早期生活应激导致疾病发展的机制尚不清楚。先前的研究报告称，早期生活应激与 5-羟色胺转运体基因（SLC6A4）的甲基化改变有关，SLC6A4 是几种精神障碍的关键候选基因。这种甲基化的差异受性别和 SLC6A4 相关多态性区域（5-HTTLPR）的遗传变异的影响。此外，有一项研究表明，怀孕期间的应激可能会导致 SLC6A4 在新生儿中的甲基化改变。本研究首次调查了怀孕期间的早期生活应激是否会影响新生儿的 SLC6A4 甲基化，同时考虑了遗传变异和性别的影响。
从早期生活应激水平较高（n=45）或较低（n=45）的新生儿脐带血中提取，定义为母亲怀孕期间的应激。采用四碱基胞嘧啶-磷酸-鸟嘌呤二核苷酸（CpG）位点在启动子相关 CpG 岛北岸（CpG1 到 4）评估早期生活应激、5-HTTLPR 基因型和性别对甲基化的影响。该表观遗传分析集中在这些 CpG 位点，因为研究表明 CpG 岛岸甲基化具有功能后果。
观察到明显的性别特异性甲基化，女性的甲基化水平高于男性（p<0.001）。重要的是，这种效应既不受早期生活应激也不受基因型影响。
本研究数据表明，SLC6A4 的性别特异性甲基化在出生时就存在，且独立于早期生活应激和 5-HTTLPR 基因型。这可能导致抑郁症的性别特异性患病率。
