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Epigenetic signatures of the FKBP5 Gene as predictor for depressive disorders

FKBP5 基因的表观遗传特征作为抑郁症的预测因子

基本信息

批准号：
253233213
负责人：
Professor Dr. Hans Jörgen Grabe
金额：
--
依托单位：
Poliklinik für Zahnärztliche Prothetik, Alterszahnheilkunde und medizinische Werkstoffkunde
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/253233213?language=en
关键词：
Epigenetic signatures FKBP5 Gene predictor

项目摘要

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.

重度抑郁症（MDD）影响全球高达15%的受试者，并造成高的个人和社会经济负担。因此，早期识别MDD高风险受试者至关重要。生物和环境因素相互作用，调节MDD的个体风险。我们的研究小组已经证明，FKBP 5基因内的风险多态性（rs 1360780），糖皮质激素受体复合物的共伴侣，与儿童虐待相互作用，使MDD的风险增加8倍。最近，已经确定了与FKBP 5风险多态性相关的DNA低甲基化的长期模式，该多态性响应于内含子7 bin 2的特定CpG位点处的儿童期虐待。这种低甲基化与FKBP 5产生增加、靶组织的相对皮质醇抗性和全血中76个皮质醇依赖性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。我们项目的目的有两个：第一，复制和验证儿童虐待与一般人群中FKBP 5低甲基化的关联。第二，将FKBP 5低甲基化与风险基因型相互作用与临床终点MDD相关联。我们将在我们的一般人群研究（SHIP-TREND; n=4422）中建立FKPB 5内含子7 bin 2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）中验证灵敏度、特异性和阳性预测值的最佳阈值。总之，我们检验了以下假设：FKBP 5内含子7 bin 2的低甲基化与风险基因型（rs 1360780）的相互作用是一般人群中MDD高风险受试者的新生物学标志物。