The relative contribution of genetic and environmental factors in the etiology of psychiatric disorders has long been a hotly debated area of investigation. Considerable evidence from a variety of studies suggests a preeminent role of early adverse experiences in the development of mood and anxiety disorders. One study¹ composed of almost 2000 women revealed that those with a history of childhood sexual or physical abuse exhibited more symptoms of depression and anxiety and had more frequently attempted suicide than women without a history of childhood abuse. Women who have been abused in childhood are 4 times more likely to develop syndromal major depression in adulthood than women who have not been abused, and the magnitude of the abuse is correlated with the severity of depression.²

Gene-environment interactions of FKBP5 and early trauma predict adult stress-related psychiatric disorders. In this study, the authors reveal the molecular mechanism of how transcriptionally active variants interact with early trauma leading to long-term allele-specific changes in DNA methylation in glucocorticoid response elements of FKBP5. Although the fact that genetic predisposition and environmental exposures interact to shape development and function of the human brain and, ultimately, the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not yet been elucidated. We found that a functional polymorphism altering chromatin interaction between the transcription start site and long-range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increased the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma–dependent DNA demethylation in functional glucocorticoid response elements of FKBP5. This demethylation was linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global effect on the function of immune cells and brain areas associated with stress regulation. This identification of molecular mechanisms of genotype-directed long-term environmental reactivity will be useful for designing more effective treatment strategies for stress-related disorders.