Allele-Specific Epigenetic Modification: A Molecular Mechanism for Gene–environment Interactions in Stress-Related Psychiatric Disorders?

Abstract

As for most common disorders, the pathogenic forces underlying psychiatric disorders are complex, with both environmental and genetic factors contributing to risk [1]. For a series of psychiatric disorders that range from major depression, to post-traumatic stress disorder (PTSD) to anxiety disorders, exposure to stressful life events, especially early in development, has been shown to strongly increase the risk of suffering from these disorders. However, not every individual exposed to adverse life events, even lifethreatening trauma, will experience psychiatric symptoms, suggesting a moderation of environmental effects by genetic predisposition. This has been now supported by both epidemiologic as well as genetic association studies. The number of studies investigating gene–environment interactions (G×E) on psychiatric disorders or phenotypes have increased exponentially ever since the groundbreaking studies by Caspi et al. [2]. Nonetheless, the molecular mechanisms behind these essentially statistical interactions remained elusive for all the examples. We have now reported on a potential molecular mechanism for a G×E between exposure to child abuse and genetic polymorphisms, especially the intronic SNP rs1360780, in the gene encoding the FK506 binding protein 5 (FKBP5) on PTSD [3–5]. This mechanism involves allele-specific epigenetic changes, and could highlight molecular features relevant for G×E in stress-related psychiatric disorders in general. FKBP5 regulates the glucocorticoid receptor (GR)–complex, which is the central part of the stress hormone system directing the systemic response to a stressful stimulus. The GR also mediates the negative feedback of this system to end the stress response once the threat is over. Psychiatric disorders, as well as exposure to early life trauma, have been associated with a dysregulation of this system. FKBP5 alters the function of the GR by diminishing ligand binding and translocation of the receptor complex to the nucleus. As part of an ultra-short feedback loop, GR activation enhances FKBP5 transcription via binding to predominantly intronic glucocorticoid response elements (GRE). FKBP5 is thus at the interface of environmental exposure and the systemic reactions of the individual by being both activated by stress and by regulating the GR.