Epigenetic signatures of the FKBP5 Gene as predictor for depressive disorders

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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.