Circadian genetic vulnerability shapes trauma-related inflammation and white matter integrity in bipolar disorder

Background and aim. Bipolar disorder (BD) is characterized by circadian dysregulation, immune-inflammatory activation, and increased vulnerability to the long-term effects of adverse childhood experiences [1]. Peripheral inflammatory markers are often elevated in BD, suggesting a state of low-grade systemic inflammation [2;3]. BD is also a prototypical circadian disorder, with evidence of vulnerability in clock genes, including CLOCK, and rhythmic modulation of inflammatory indices [4]. Elevated cytokines and cytotoxic cell counts correlate with reduced white matter integrity, which predict poorer cognitive outcomes and diminished antidepressant responsiveness in BD [5]. We hypothesized that CLOCK 3111T/C polymorphisms may moderate both the association between childhood trauma and peripheral inflammation and the relationship between peripheral inflammation and white matter microstructure.

Methods. We enrolled 137 patients with BD experiencing a depressive episode according to DSM-5 criteria. All participants underwent 3T MRI, venous blood samples for CLOCK 3111T/C genotyping and assessment of peripheral inflammatory indices - including Baso-Lymphocyte Ratio (BLR), Platelet-Lymphocyte Ratio (PLR), Neutrophil-Lymphocyte Ratio (NLR), Systemic Immune-Inflammation Index (SII), and Systemic Inflammation Response Index (SIRI) - and completed the Childhood Trauma Questionnaire (CTQ). Generalized linear model (GLM) analyses were performed to test the interaction between CTQ scores and CLOCK genotype on peripheral inflammatory markers, as well as the interaction between peripheral inflammatory markers and CLOCK genotype on DTI-derived microstructural metrics, including fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD). Analyses were then conducted separately for each CLOCK genotype.

Results. GLM analyses revealed significant interactions between emotional abuse and CLOCK genotype on inflammatory indices, including NLR (p= .011), SII (p< .001), and SIRI (p< .001). Genotype-stratified analyses showed that higher levels of emotional abuse were associated with increased NLR (b= .164, p< .001), PLR (b= .048, p< .001), SII (b= .007, p < .001), and SIRI (b= .086, p= .001), specifically among CLOCKC-allele carriers. GLM analyses also revealed a significant interaction between BLR and CLOCK genotype on FA (p=.033); genotype-stratified analyses indicated that higher BLR (b= −.367, p= .005) and higher SIRI (b= -.018; p= .035) were associated with widespread lower FA, exclusively in CLOCKC-allele carriers.

Conclusions. The present study suggests that CLOCKC-allele carriers exhibit a distinct sensitivity to the immune-inflammatory consequences of childhood adversity, particularly emotional abuse, as reflected by elevated peripheral indices, such as NLR, PLR, SII and SIRI. These results align with and extend the immune-circadian hypothesis, suggesting that individuals with specific genetic variations in the CLOCK gene are more prone to a chronic, low-grade systemic inflammatory state when exposed to childhood trauma [1;3]. The moderation effect of CLOCK on the relationship between trauma and systemic inflammation highlights a potential pathway through which environmental stressors are biologically embedded into the system in a genotype-dependent manner [4]. Furthermore, our data link this immune dysregulation directly to structural brain changes. The observation that BLR and SIRI significantly predict lower FA - a marker of white matter microstructural integrity - exclusively in CLOCKC-allele carriers, but not in CLOCK T/T homozygotes, suggests a genotype-dependent neuro-inflammatory mechanism underlying white matter alterations [2;5].

References

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