Association Of DISC1 Gene Polymorphism And The White Matter Network Alterations In Patients With Schizophrenia

Objective: Schizophrenia(SCZ)is a chronic degenerative psychiatric disorder,which can cause serious disease burden,yet its pathology is still unclear.Most scholars believe that SCZ is associated with decreased integrity of brain white matter,and it has a high genetic susceptibility.Network analysis using graph theory is a novel and effective method to study the white matter lesions in SCZ patients.Disrupted-in-Schizophrenia-1(DISC1)is associated to the white matter lesions,and is recognized as one of the most significant genetic susceptibility factors of SCZ.However,there is no report on the association between DISC1 gene polymorphism and abnormal white matter network in schizophrenic patients.In this study,we intend to apply Diffusion Tensor Imaging(DTI)and graph theory analysis to study the alterations of white matter network in SCZ from the view of topological analysis.Our study provided new supplement for the studies of pathophysiological mechanism of SCZ and new experimental support for the study of association between the pathology of SCZ and DISC1 gene polymorphism.Methods: 123 SCZ patients aged 18-45 who met the DSM-IV diagnostic criteria were collected from the outpatient department of the First Affiliated Hospital of China Medical University and the outpatient department of Shenyang Mental Health Center.209 health control(HC)were recruited through advertisements.Demographic data collection,clinical symptoms assessment,magnetic resonance imaging scanning,blood sample collection and DISC1 genotyping were performed for the participant.PNADA was used to construct the white matter network of every subject,and GRETNA was used to calculate the network topological parameters.Then,SPSS was used to analyze the topological parameters of two groups.Analysis of covariance(ANCOVA)(age and gender as covariates)was implemented to find out the network alterations in SCZ patients,partial correlation analysis was used to study the associations between network alterations and psychiatric symptoms.Two-way ANCOVA was used to study the main effects of DISC1 genotype and the interaction between DISC1 genotype and diagnosis on the topological parameters.Results: 1.ANCOVA demonstrated that compared to HCs,SCZ patients showed several reduced topological metrics of white matter network,including the global efficiency(F = 5.80,P = 0.017),the local efficiency(F = 27.75,P < 0.001),the nodal efficiency of the left inferior triangle frontal gyrus(F = 12.52,P = 0.041 Bofferoni corrected),the nodal efficiency of the right superior occipital gyrus(F = 12.67,P = 0.0038 Bofferoni corrected),the nodal efficiency of the right middle occipital gyrus(F = 13.64,P = 0.001 Bofferoni corrected)and the nodal efficiency of the right postcentral gyrus(F = 21,P < 0.001 Bofferoni corrected).2.Two-way ANCOVA showed that the diagnosis × genotype interactions had significant effect on the local efficiency(F = 7.35,P = 0.007).The results of Post Hoc showed that the local efficiency of G allele carriers in SCZ patients was significantly lower than that of the other three groups.3.In SCZ group,the total score of Brief Psychiatric Rating Scale(BPRS)was negatively correlated with the local efficiency(r =-0.193,P = 0.039).The factor score of depression and anxiety was negatively correlated with the local efficiency(r =-0.192,P = 0.041).The factor score of depression and anxiety was also negatively correlated with the nodal efficiency of the left lower frontal gyrus(r =-0.206,P = 0.028).Conclusion: 1.Several kinds of topological alterations of white matter network are founded in SCZ patients,suggesting topological alterations of white matter network might be some neurobiological factors of SCZ.2.DISC1 rs2738880 polymorphism is associated with topological alterations of white matter network in SCZ patients: the local efficiency of G allele carriers in SCZ patients is significantly lower than that of the other three groups,suggesting that G allele might be a risk allele correlated with topological alterations in SCZ patients.3.In SCZ patients,the topological alterations of white matter network correlate with the severity of psychotic symptoms: the local efficiency negative correlate with the total severity of psychotic symptoms,as well as the severity of depression and anxiety symptoms;the nodal efficiency of the left inferior triangle frontal gyrus also negative correlate with the severity of depression and anxiety symptoms.