Association Between Ca²⁺ Channel Gene Polymorphism And The Amplitude Of Low-frequency Fluctuation In Patients With Mood Disorder

Objective:Mood disorder（MD）is a series of common complex diseases,which are with a characteristic of significant and lasting changes in mood.It mainly includes major depressive disorder（MDD）and bipolar disorder（BD）.With the development of science and technology,people gradually discovered that it was more similar clinical symptoms in MDD and BD,and more similar susceptibility genes and brain functional imaging.A recent cross-disease genome-wide association analysis showed that the patients diagnosed with MDD and BD,it was similar in chromosome 3p21 and 10q24,and the single nucleotide polymorphisms of two L-type voltage-gated calcium channel subunits（CACNA1C and CACNB2）.The results show that there is some association between the pathological mechanism of independent diseases,which may be shared common genetic factors.Although currently classified as different diseases in clinical manifestations,genetic studies have shown that Ca2+channel gene polymorphism may be a common biomarker for the pathogenesis of a wide range of psychiatric diseases,and so the diseases in MDD and BD may be some similarities with clinical phenotypes.At present,it has not been found that resting low-frequency amplitude（rs-ALFF）technique is used as an intermediate phenotype to explore the effects of CACNA1C and CACNB2gene polymorphisms.Therefore,we use rs-ALFF method to explore the relationship between CACNA1C or CACNB2 gene polymorphisms and activation of the brain,and to identify the abnormal brain regions associated with genetic risk of affective disorders,and provide evidence and support for the study of the pathogenesis and treatment of MD.Methods:A total of 155 MD patients and 173 healthy controls were collected for demographic data collection,clinical symptom score,magnetic resonance scanning and blood sample collection.All subjects were scanned by resting-state functional magnetic resonance imaging（rs-fMRI）using GE 3.0T magnetic resonance machine.The collected image data were processed by DPARSF and SPM software based on MATLAB platform.The ALFF values of each subject were calculated through analysis.The A/G allele polymorphism at rs1006737 locus of CACNA1C gene and the A/C allele polymorphism at rs11013860 locus of CACNB2 gene were detected by imLDRTM Method.Based on genotype,they were separately divided into GG group vs risk gene A-carrier group and CC group vs risk allele A-carrier group.Hardy-Weinberg Equilibrium（HWE）test was performed in MD group and healthy control group.We are adopting 2*2 factorial design variance analysis to research the main effects of diagnostic and gene and the interaction effect using ALFF values.Results:1.CACNA1C:There were significant differences in age and education years between MD and HC groups,but no significant differences in gender and handedness.The gene frequencies of MD group and HC group accorded with H-W equilibrium.Two-factors ANOVA showed that there was significant main effect of diagnosis in the right middle temporal gyrus（t=3.43,P=0.001）and the right cuneus（t=2.60,P=0.01）.There was significant main effect of genotype in right caudate nucleus（t=4.58,P<0.001）,right superior temporal gyrus（t=4.22,P<0.001）and right superior temporal gyrus（t=4.22,P<0.001）.Additionally,a significant diagnosis×genotype interaction was noted in the right fusiform gyrus（F=10.19,P<0.001）,left orbital superior frontal/middle gyrus（F=9.40,P<0.001）and bilateral medial superior frontal gyrus（F=8.74,P<0.001）.2.CACNB2:There were significant differences in age and education years between MD and HC groups,but no significant differences in gender and handedness.The gene frequencies of MD group and HC group accorded with H-W equilibrium.Two-factors ANOVA showed that there was significant main effect of diagnosis in the bilateral cingulate gyrus and bilateral medial superior frontal gyrus（t=4.61,P<0.001）and left pars triangularis（t=3.54,P<0.001）.There was also significant main effect of genotype in right superior frontal gyrus of orbit（t=3.85,P<0.001）.Additionally,a significant diagnosis×genotype interaction was noted in the right hippocampus and parahippocampal gyrus（F=4.28,p=0.006）and right postcentral gyrus（F=5.73,p=0.001）.3.The MD group was divided into three group including AA group,AG/AC group and GG/CC group according to the degree of genetic risk,and there was no difference among groups.Conclusion:In our study,the ALFF values combined with genetic information（CACNA1C and CACNB2 gene polymorphisms）were used to identify the association between brain activation and Ca²⁺channel gene polymorphism in MD patients.CACNA1C gene polymorphisms was related to abnormal activation of visual cortex,default network and attention network.CACNB2 gene polymorphisms was related to abnormal activation of limbic system and primary sensory cortex,which would provide a new way to explore the pathophysiological mechanism of MD.