Epigenetic signatures of the FKBP5 Gene as predictor for depressive disorders

重度抑郁症（MDD）影响全世界15%的受试者，造成很高的个人和社会经济负担。因此，早期识别重度抑郁症高危人群是至关重要的。生物和环境因素相互作用调节重度抑郁症的个体风险。我们的研究小组已经证明，FKBP5基因（糖皮质激素受体复合物的共同伴侣）中的风险多态性（rs1360780）与儿童虐待相互作用，使MDD的风险增加了8倍。最近，一种长期存在的DNA低甲基化模式与FKBP5风险多态性有关，这种多态性与儿童虐待有关，发生在内含子7bin 2的特定CpG位点。这种低甲基化与FKBP5的产生增加、靶组织的相对皮质醇抵抗以及全血中76个皮质醇依赖基因的转录改变有关。因此，这种DNA低甲基化似乎反映了对儿童虐待的生物学长期反应的重要机制。我们的项目有两个目的：首先，在普通人群中复制和验证儿童虐待与FKBP5低甲基化的关系。其次，将FKBP5低甲基化与风险基因型相互作用与临床终点MDD联系起来。我们将在我们的一般人群研究（SHIP-TREND, n=4422）中建立FKPB5 7 bin 2的甲基化与MDD之间的剂量-反应关系，并在第二个独立样本（SHIP-LEGEND, n=2400）中验证关于敏感性、特异性和阳性预测值的最佳阈值。总之，我们验证了FKBP5内含子7 bin 2与风险基因型（rs1360780）相互作用的低甲基化是普通人群中重度抑郁症高风险受试者的一个新的生物学标记。

Major depressive disorders (MDD) affect up to 15 % of all subjects worldwide and are responsible for high individual and socioeconomic burden. Therefore the early identification of subjects being at high risk for MDD is of utmost importance. Biological and environmental factors interact modulating the individual risk of MDD. Our group has demonstrated that a risk polymorphism (rs1360780) within the FKBP5 gene, a co-chaperone of the glucocorticoid receptor complex, interacts with childhood abuse increasing the risk of MDD up to 8-fold. Recently, a long-lasting pattern of DNA hypomethylation associated with the FKBP5 risk polymorphism in response to childhood abuse at specific CpG sites at intron 7 bin 2 have been identified. This hypomethylation was associated with increased FKBP5 production, a relative cortisol resistance of target tissues and an altered transcription of 76 cortisol-dependent genes in whole blood. Thus, this DNA hypomethylation seems to reflect an important mechanism of the biological long-term response to childhood abuse. The aim of our project is 2-fold: First, to replicate and validate the association of childhood abuse with the FKBP5 hypomethylation in the general population. Second, to associate the FKBP5 hypomethylation in interaction with the risk genotype with the clinical endpoint MDD. We will establish a dose-response relationship between FKPB5 methylation at intron 7 bin 2 and MDD in our general population study (SHIP-TREND; n=4422) and validate optimal thresholds with regard to sensitivity, specificity and positive predictive value in a second independent sample (SHIP-LEGEND, n=2400). In all, we test the hypothesis that hypomethylation at FKBP5 intron7 bin 2 in interaction with the risk genotype (rs1360780) is a new biological marker for subjects being at high risk for MDD in the general population.