Multimodal Associations of FKBP5 Methylation with Emotion-Regulatory Brain Circuits

Background Understanding the biological processes underlying individual differences in emotion regulation and stress responsivity is a key challenge for translational neuroscience. The gene FKBP5 is a core regulator in molecular stress signaling that is implicated in the development of psychiatric disorders. Yet it remains unclear how FKBP5 DNA methylation (DNAm) in peripheral blood relates to individual differences in measures of neural structure and function, and their relevance to daily-life stress responsivity. Methods Here, we characterize multimodal correlates of FKBP5 DNAm by combining epigenetic data with neuroimaging and Ambulatory Assessment in a sample of 395 healthy individuals. Results First, we show that FKBP5 demethylation as a psychiatric risk factor relates to an anxiety-associated reduction of gray matter volume in the ventromedial prefrontal cortex (vmPFC), a brain area that is involved in emotion regulation and mental health risk and resilience. This effect of epigenetic upregulation of FKBP5 on neuronal structure is more pronounced where FKBP5 is epigenetically downregulated at baseline. Leveraging 208 functional MRI scans during a well-established emotion processing task we find that FKBP5 DNAm in peripheral blood is associated with functional difference of prefrontal-limbic circuits modulating affective responsivity to daily stressors, which we measured using ecological momentary assessment in daily life. Conclusions Overall, we demonstrate how FKBP5 contributes to interindividual differences in neural and real-life affect regulation via structural and functional changes in prefrontal-limbic brain circuits.