Genetic and epigenetic associations of MAOA and NR3C1 with depression and childhood adversities
Genetic and epigenetic associations of MAOA and NR3C1 with depression and childhood adversities
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DOI：
10.1017/s1461145713000102
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发表时间：
2013-08-01
影响因子：
4.8
通讯作者：
Lavebratt, Catharina
中科院分区：
文献类型：
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作者：
Melas, Philippe A.;Wei, Yabin;Lavebratt, Catharina
单胺氧化酶A （MAOA）具有多态性上游可变数串联重复序列（u-VNTR）。u-VNTR的MAOA-L等位基因在体外导致基因表达水平下降，并已被发现增加童年逆境男性行为障碍的风险。早期生活逆境与糖皮质激素受体（NR3C1）的高甲基化有关。在这项研究中，我们首先对抑郁症患者（n=392）和对照组（n=1276）进行了MAOA u-VNTR的遗传关联分析。接下来，使用抑郁亚组和对照亚组的唾液样本进行MAOA和NR3C1的DNA甲基化分析。童年逆境的成年MAOA- l女性患抑郁症的风险更高（p=0.006），与对照组相比，抑郁症女性的总体MAOA甲基化水平降低（平均抑郁症为42%，平均对照组为44%；p=0.04）。一种特殊的童年逆境[父母早逝（EPD）]与NGFI-A结合位点附近NR3C1的高甲基化有关（平均EPD为19%，平均非EPD为14%；p=0.005）。回归分析表明，这种关联可能是由maaa - l等位基因介导的(调整后R-2=0.24，方差分析：F=23.48, p
Monoamine oxidase A (MAOA) harbours a polymorphic upstream variable-number tandem repeat (u-VNTR). The MAOA-L allele of the u-VNTR leads to decreased gene expression levels in vitro and has been found to increase the risk of conduct disorder in males with childhood adversities. Early-life adversities have been associated with hypermethylation of the glucocorticoid receptor (NR3C1). In this study, we first performed a genetic association analysis of the MAOA u-VNTR using individuals with depression (n=392) and controls (n=1276). Next, DNA methylation analyses of MAOA and NR3C1 were performed using saliva samples of depressed and control subgroups. Adult MAOA-L females with childhood adversities were found to have a higher risk of developing depression (p=0.006) and overall MAOA methylation levels were decreased in depressed females compared to controls (mean depressed, 42% vs. mean controls, 44%; p=0.04). One specific childhood adversity [early parental death (EPD)] was associated with hypermethylation of NR3C1 close to an NGFI-A binding site (mean EPD, 19% vs. mean non-EPD, 14%; p=0.005). Regression analysis indicated that this association may be mediated by the MAOA-L allele (adjusted R-2=0.24, ANOVA: F=23.48, p