| Background Bipolar disorder is a group of major mental disorders characterized by recurrent episodes of mania/hypomania and depression, the underlying pathophysiological mechanism of which remains unclear. Prior studies have suggested a potential role for voltage-gated calcium channel genes in the etiology of bipolar disorder, particularly in their influence on brain structure. Objective The current study aims to investigate differences in grey matter volume (GMV) between individuals with bipolar disorder and healthy controls, and explore the potential influence of calcium voltage-gated channel subunit α1 G (CACNA1G) gene rs757415 polymorphism on GMV in bipolar disorder. By identifying abnormal brain regions associated with this genetic variation, the study may contribute to a better understanding of the pathophysiological mechanism of bipolar disorder. Methods A cohort of 289 patients with bipolar disorder who met the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), were selected for participation. These patients were either hospitalized or received treatment at the Mental Health Center of West China Hospital, Sichuan University, between September 2013 and December 2022. During the same time, 322 healthy individuals were recruited as a control group from Sichuan University and surrounding communities. All participants underwent brain imaging using a 3.0T magnetic resonance scanner to acquire data on grey matter volume (GMV). Additionally, the presence of the CACNA1G gene rs757415 polymorphism was detected using the imLDRTM method. Spearman correlation analysis was used to investigate potential relationships between abnormal brain regions identified through GMV data and clinical characteristics of the patients. The interaction between CACNA1G rs757415 polymorphism and diagnosis in GMV was analyzed using the full factor method. Results The study successfully enrolled 173 patients with bipolar disorder and 207 healthy controls who completed all the necessary procedures. Compared with healthy controls, the GMV of left cerebellar summit/slope, anterior/posterior cerebellar lobe, fusiform gyrus, parahippocampal gyrus, suboccipital gyrus (t=5.664, P<0.05), right anterior/posterior cerebellar lobe, fusiform gyrus, parahippocampal gyrus, lingual gyrus (t=4.583, P<0.05), bilateral anterior/parascingulate gyrus, superior frontal gyrus and anterior cuneate gyrus in bipolar disorder group were significantly higher than those in healthy control group (t=7.543, P<0.05), left lingual gyrus and superior temporal gyrus (t=6.593, P<0.05), right insula and central operculum (t=7.153, P<0.05) were decreased in patients with bipolar disorder. There was a significant interaction between CACNA1G rs757415 polymorphism and bipolar disorder in GMV of right parahippocampal - fusiform gyrus - cerebellum 4 5 (t=19.967, P＜0.05) . In the control group, individuals carrying the non-risk allele (TT genotype) showed increased GMV in the right parahippocampal gyrus - fusiform gyrus - cerebellum 4 5 compared to those carrying the risk allele (CC or CT genotypes). In contrast, within the patient group with bipolar disorder, individuals carrying the risk allele exhibited increased GMV in the same brain regions when compared to non-risk allele carriers. Moreover, the GMV of the right parahippocampal gyrus - fusiform gyrus - cerebellum 4 5 in patients with bipolar disorder carrying risk alleles was increased compared to healthy controls. Correlation analysis revealed that the duration of bipolar disorder was positively correlated with cerebrospinal fluid volume (r=0.258, P=0.003), but negatively correlated with the GMV of left cerebellar summit/slope, anterior/posterior cerebellar lobe, fusiform gyrus, parahippocampal gyrus, suboccipital gyrus (r=-0.204，P=0.019), right anterior/posterior cerebellar lobe, fusiform gyrus, parahippocampal gyrus, lingual gyrus (r=-0.238，P=0.006), bilateral anterior/parascingulate gyrus, superior frontal gyrus and anterior cuneate gyrus in bipolar disorder group were significantly higher than those in healthy control group (r=-0.219，P=0.012), left lingual gyrus and superior temporal gyrus (r=-0.296，P=0.001), right insula and central operculum (r=-0.257，P=0.003). Conclusion CACNA1G rs757415 polymorphism affects the GMV in the right parahippocampal gyrus, fusiform gyrus and cerebellum 4 5 of patients with bipolar disorder, which may contribute to the pathogenic mechanism of bipolar disorder. |