Multimodal Associations of FKBP5 Methylation With Emotion-Regulatory Brain Circuits

Area of Science:

• Translational neuroscience
• Molecular psychiatry
• Neuroepigenetics

Background:

• Individual differences in emotion regulation and stress response are crucial for understanding psychiatric disorders.
• The FKBP5 gene is a key regulator of molecular stress signaling implicated in psychiatric conditions.
• The relationship between FKBP5 DNA methylation and neural structure/function in daily stress response remains unclear.

Purpose of the Study:

• To investigate the multimodal correlates of FKBP5 DNA methylation.
• To examine the association between FKBP5 DNA methylation and neural structure and function.
• To explore the relevance of these associations to daily-life stress responsivity.

Main Methods:

• Combined epigenetic data (FKBP5 DNA methylation) with neuroimaging (MRI) and ambulatory assessment.
• Utilized functional magnetic resonance imaging (fMRI) during an emotion-processing task.
• Employed ecological momentary assessment (EMA) for daily stressor measurement in 395 healthy individuals.

Main Results:

• FKBP5 demethylation, a psychiatric risk factor, correlated with reduced gray matter volume in the ventromedial prefrontal cortex (vmPFC), linked to anxiety.
• FKBP5 DNA methylation in blood showed associations with functional differences in prefrontal-limbic circuits during emotion processing.
• These neural differences predicted affective responsivity to daily stressors, as measured by EMA.

Conclusions:

• FKBP5 DNA methylation influences interindividual differences in neural structure and function within prefrontal-limbic circuits.
• These FKBP5-associated neural changes impact real-life affect regulation and stress responsivity.
• The study elucidates a mechanism linking epigenetics, brain circuitry, and behavioral responses to stress.