CACNA1C Gene rs11832738 Polymorphism Influences Depression Severity by Modulating Spontaneous Activity in the Right Middle Frontal Gyrus in Patients With Major Depressive Disorder

OBJECTIVES: This study aimed to examine whether the CACNA1C gene rs11832738 polymorphism and major depressive disorder (MDD) have an interactive effect on the untreated regional amplitude of low-frequency fluctuation (ALFF) and to determine whether regional ALFF mediates the association between CACNA1C rs11832738 and MDD. METHODS: A total of 116 patients with MDD and 66 normal controls (NCs) were recruited. The MDD and NC groups were further divided into two groups according to genotype: carriers of the G allele (G-carrier group, GG/GA genotypes; MDD, n = 61; NC, n = 26) and AA homozygous group (MDD, n = 55; NC, n = 40). MDD was diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Depression severity was assessed using the Hamilton Depression Scale-24 (HAMD-24) at baseline and follow-up (after 2 and 8 weeks of treatment). All subjects underwent functional MRI (fMRI) scans at baseline, and the ALFF was calculated to reflect spontaneous brain activity. The interactions between MDD and CACNA1C single nucleotide polymorphism rs11832738 were determined using two-way factorial analysis of covariance, with age, sex, education, and head motion as covariates. We performed mediation analysis to further determine whether regional ALFF strength could mediate the associations between rs11832738 and depression severity, MDD treatment efficacy. RESULTS: MDD had a main effect on regional ALFF distribution in three brain areas: the right medial frontal gyrus (MFG_R), the left anterior cingulate cortex (ACC_L), and the right cerebellum posterior lobe (CPL_R); CACNA1C showed a significant interactive effect with MDD on the ALFF of MFG_R. For CACNA1C G allele carriers, the ALFF of MFG_R had a significant positive correlation with the baseline HAMD-24 score. Exploratory mediation analysis revealed that the intrinsic ALFF in MFG_R significantly mediated the association between the CACNA1C rs11832738 polymorphism and baseline HAMD-24 score. CONCLUSIONS: A genetic variant in CACNA1C rs11832738 may influence depression severity in MDD patients by moderating spontaneous MFG_R activity.