Introduction: CACNA1C gene encodes the L-type voltage dependent calcium channels and its variants are associated with susceptibility to psychiatric disorders. We recently provided evidence of a genotype-by-environment interaction of the CACNA1C rs1006737 polymorphism, suggesting that the cortisol awakening response (CAR), an indicator of HPA-axis function, might be increased in non-risk allele carriers (GG) who have experienced childhood trauma (CT). In these individuals a heightened CAR may be indicative of mental health resilience. We subsequently investigated if epigenetic changes could modulate the genotype-conferred resilience in relation to reported CT.
Methods: Genomic DNA was extracted from saliva (n=114, male). We analysed 11 CpGs of CACNA1C gene, previously investigated in the context of suicide attempt. 2×2 ANCOVAs with CACNA1C genotype (AA/AG or GG) and CT (yes/no) as main factors and age as a covariate were conducted. In addition, the relation between the methylation levels and the CAR, current perceived stress (PSS-14) and depression (HADS) were investigated using multiple linear regression.
Results: No significant differences between the CACNA1C gene rs1006737 AA/AG and GG groups in terms of age, years of education, current perceived stress (PSS-14) and depression (HADS) (P>0.05) were found. Individuals homozygous for the non-risk allele (GG) showed decreased methylation levels at CpGs 3, 4 and 7. GG genotype individuals who experienced CT showed lower methylation across most of the CpG sites. Conversely, risk allele A carriers had increased methylation levels in comparison to non-risk homozygotes (GG). Regression analysis revealed that lower methylation at CpG2 (B=−0.270, P=0.043) and CpG 3 (B=−2.75, P=0.041) was associated with a greater CAR (subset n=66).
Conclusion: The findings suggest there may be a relation between decreasing CACNA1C methylation and increased CAR, a measure of psychological resilience. This could be a mechanism for conferring resilience and healthy adaptation to the trauma experience in these individuals.