Impact of the CACNA1G rs757415 polymorphism on grey matter volume in patients with bipolar disorder

BackgroundBipolar disorder is a severe mental disorder characterized by cycling between mania/hypomania and depression， yet its underlying pathophysiological mechanism remains unclear. Several prior studies have suggested a potential role for voltage-gated calcium channel subunit genes in the etiology of bipolar disorder， particularly in their influence on brain structure.ObjectiveTo investigate the differences in grey matter volume （GMV） for individuals with bipolar disorder compared to healthy controls， and to explore the potential influence of calcium channel voltage-dependent T-type α1 G subunit （CACNA1G） rs757415 polymorphism on GMV in bipolar disorder and clarify the specific brain regions associated with this genetic variation， thus offering a new opportunity to gain insight into the pathophysiological mechanism of bipolar disorder.MethodsA cohort of 289 patients who met the Diagnostic and Statistical Manual of Mental Disorders， fourth edition （DSM-IV） criteria for bipolar disorder were selected for participation. These patients were either admitted to hospital or examined in outpatient clinic for bipolar disorder at the Mental Health Center of West China Hospital， Sichuan University between September 2013 and December 2022. Another 322 healthy individuals were concurrently recruited as a control group from Sichuan University and surrounding communities. All participants underwent brain imaging using a 3.0 T magnetic resonance scanner to acquire data on GMV. Additionally， the presence of the CACNA1G rs757415 polymorphism was validated using the imLDRTM technique. Spearman correlation analysis was utilized to investigate potential relationship between abnormal brain regions identified through GMV data and clinical characteristics of the patients. Then the genotype-by-diagnosis interaction effect for CACNA1G rs757415 on GMV was observed using the full factor method.ResultsThe study successfully enrolled 173 patients with bipolar disorder and 207 healthy controls who completed all the necessary procedures. Analyses revealed decreased GMV for patients with bipolar disorder compared to healthy controls in the left cerebellar declive extending to cerebellar anterior/posterior lobe， fusiform gyrus， parahippocampal gyrus and inferior occipital gyrus （t=5.664， P<0.05）； in the right cerebellar anterior/posterior lobe， fusiform gyrus， parahippocampal gyrus extending to lingual gyrus （t=4.583， P<0.05）； in the bilateral anterior cingulate/paracingulate gyri， superior frontal gyrus and precuneus （t=7.543， P<0.05）； in the left lingual gyrus and superior temporal gyrus （t=6.593， P<0.05）； and in the right insula entending to central operculum （t=7.153， P<0.05）. Correlation analysis indicated that the duration of bipolar disorder was positively correlated with cerebrospinal fluid volume （r=0.258， P=0.003）， whereas negatively correlated with the GMV in the left cerebellar declive extending to cerebellar anterior/posterior lobe， inferior occipital gyrus and parahippocampal gyrus （r=-0.204， P=0.019）， in the right cerebellar anterior lobe extending to right cerebellar posterior lobe， fusiform gyrus， parahippocampal gyrus and lingual gyrus （r=-0.238， P=0.006）， in the bilateral superior frontal gyrus extending to anterior cingulate/paracingulate gyri and precuneus （r=-0.219， P=0.012）， in the left lingual gyrus extending to superior temporal gyrus （r=-0.296， P=0.001）， and in the right insula extending to central operculum （r=-0.257， P=0.003）. A significant genotype-by-diagnosis interaction effect for CACNA1G rs757415 on GMV was observed in the right parahippocampal gyrus - fusiform gyrus - cerebellum 4-5 （F=19.967， P<0.05） . In the control group， individuals carrying the non-risk allele showed increased GMV in the right parahippocampal gyrus - fusiform gyrus - cerebellum 4-5 compared to those carrying the risk allele. In contrast， within the patient group， risk allele carriers exhibited increased GMV in the same brain regions when compared to non-risk allele carriers. Moreover， the GMV in the right parahippocampal gyrus - fusiform gyrus - cerebellum 4-5 of patients with bipolar disorder carrying risk alleles was increased compared to healthy controls.ConclusionCACNA1G rs757415 polymorphism may affect the GMV in the right parahippocampal gyrus， fusiform gyrus and cerebellum 4/5 of patients with bipolar disorder. ［Funded by National Natural Science Fundation of China， （number， 82071524）］