DNA methylation of HPA-axis genes and the onset of major depressive disorder in adolescent girls: a prospective analysis
DNA methylation of HPA-axis genes and the onset of major depressive disorder in adolescent girls: a prospective analysis
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DOI：
10.1038/s41398-019-0582-7
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发表时间：
2019-10-03
影响因子：
6.8
通讯作者：
Gotlib, Ian H.
中科院分区：
文献类型：
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作者：
Humphreys, Kathryn L.;Moore, Sarah R.;Gotlib, Ian H.
患有重度抑郁症 (MDD) 以及罹患 MDD 的风险较高的人的压力反应系统会受到干扰。我们检查了 HPA 轴基因内 CpG 位点的 DNA 甲基化 (DNAm) 水平是否可以预测 MDD 的发病。对 77 名女孩进行了纵向随访，其中大约一半 (n = 37) 有患 MDD 的家族风险。唾液样本是在青春期（M 年龄 = 13.06 岁 [SD = 1.52]）采集的，当时参与者当前或过去没有 MDD 诊断。大约每 18 个月进行一次诊断访谈，直到首次出现 MDD 或成年早期（最后一次随访的 M 年龄 = 19.23 岁 [SD = 2.69]）。我们使用 Illumina EPIC 芯片对唾液样本中的 DNAm 进行定量，并检查了 6 个关键 HPA 轴基因（NR3C1、NR3C2、CRH、CRHR1、CRHR2、FKBP5）内的 CpG 位点以及用于标记捕获顺式遗传变异性的 SNP 的 59 个基因型。 NR3C1、CRH、CRHR1 和 CRHR2 中 CpG 位点内的 DNAm 水平与青春期和成年早期患 MDD 的风险相关。为了排除发现结果仅仅是由于遗传变异的影响的可能性，我们重新分析了控制这些候选基因内顺式遗传变异的数据。重要的是，这些 CpG 位点的甲基化水平继续显着预测 MDD 的发病，这表明表观基因组的变异（独立于近端遗传变异）可以前瞻性地预测 MDD 的发病。这些发现表明，HPA 轴在甲基化组水平上的变化可以预测 MDD 的发展。
The stress response system is disrupted in individuals with major depressive disorder (MDD) as well as in those at elevated risk for developing MDD. We examined whether DNA methylation (DNAm) levels of CpG sites within HPA-axis genes predict the onset of MDD. Seventy-seven girls, approximately half (n = 37) of whom were at familial risk for MDD, were followed longitudinally. Saliva samples were taken in adolescence (M age = 13.06 years [SD = 1.52]) when participants had no current or past MDD diagnosis. Diagnostic interviews were administered approximately every 18 months until the first onset of MDD or early adulthood (M age of last follow-up = 19.23 years [SD = 2.69]). We quantified DNAm in saliva samples using the Illumina EPIC chip and examined CpG sites within six key HPA-axis genes (NR3C1, NR3C2, CRH, CRHR1, CRHR2, FKBP5) alongside 59 genotypes for tagging SNPs capturing cis genetic variability. DNAm levels within CpG sites in NR3C1, CRH, CRHR1, and CRHR2 were associated with risk for MDD across adolescence and young adulthood. To rule out the possibility that findings were merely due to the contribution of genetic variability, we re-analyzed the data controlling for cis genetic variation within these candidate genes. Importantly, methylation levels in these CpG sites continued to significantly predict the onset of MDD, suggesting that variation in the epigenome, independent of proximal genetic variants, prospectively predicts the onset of MDD. These findings suggest that variation in the HPA axis at the level of the methylome may predict the development of MDD.