Research On The Pathogenesis Of Schizophrenia Based On Magnetic Resonance Imaging Genetics

Schizophrenia is considered as a chronic and disabling mental disorder with high heritability rate characterized by symptoms such as delusion,hallucinations,blunted affect,disorganized communication,reduced motivation and poor planning.After more than one century of research,the neuropathology of schizophrenia is still not fully understood.Genetic factors,environment factors,psychosocial factors and neurobiology factors play crucial roles in the aetiology of schizophrenia.Studies using in vivo magnetic resonance imaging techniques have reported brain functional and structural abnormalities in schizophrenia patients.In addition,brain needs a variety of neurotransmitters to function properly.As an important neurotransmitter in brain,abnormal dopamine activities can directly lead to onset of psychiatric disorders,such as schizophrenia.Catechol-O-methyltransferase(COMT)gene has found to be related to dopaminergic regulation.COMT gene is one of the candidate genes for susceptibility of schizophrenia.Investigating genetic influence of COMT on brain function and structure may contribute to improve our understanding of the pathophysiology of schizophrenia.In the present study,using imaging genetic method,we investigated the effect of COMT genotype on brain function and structure of drug-na?ve first episode schizophrenia(FES)and age-,gender-,education-matched healthy controls(HC).Our results may help to improving the understanding of relationships between COMT genotypes,brain function and structure and schizophrenia pathogenesis.In addition,based on magnetic resonance imaging data,multivariate pattern analysis was used to establish an individualbased diagnostic model to classify FES and HC,and to find potential imaging markers that can distinguish FES patients.The main contents and the innovation points in the present study are as follows: 1.We explored the effect of COMT val158 met genotype on the resting-state functional connectivity of dorsolateral prefrontal cortex(DLPFC).To do so,seeds of bilateral DLPFC were defined by area 46 of Brodmann's atlas.Functional connectivity of DLPFC was calculated by seed-based voxel wise functional connectivity analysis.A two-ways analysis of covariance(ANCOVA)was conducted to explore the main effect of disease state and the interaction effect of COMT val158 met genotype and disease state on the functional connectivity of DLPFC.The results from main effect of disease state suggested that,compared with HC,FES patients showed significant increased functional connectivity between left DLPFC and left anterior cingulate cortex(ACC),left precuneus and right superior parietal gyrus.We found these three DLPFC-related pathways were influenced by the interaction effect of disease state and COMT val158 met genotype.Post hoc analysis was used to explore the details of the interaction effect.Compared with the met carriers of FES patients,we found the FES with val/val genotype showed significantly increased functional connectivity in these three DLPFC-related pathways.These three DLPFC-related pathways showed significantly positive correlation with the affective blunting scores in FES patients with val homozygotes,but not with met carriers.2.We investigated the effect of COMT val158 met genotype on the resting-state functional connectivity of frontostriatal circuits.Firstly,regions of interest in frontostriatal circuits were defined by the result of meta-analysis using the Neurosynth database.Then,the functional connectivity between the regions of interest was calculated.A two-ways ANCOVA analysis was used to investigate the main effect of disease state and the interaction effect of COMT val158 met genotype and disease state on the functional connectivity of frontostriatal circuits.Compared with HC,FES patients showed significant increased functional connectivity between bilateral ACC and bilateral caudate.The functional connectivity between bilateral ACC and right caudate was influenced by interaction effect of disease state and val158 met genotype.The functional connectivity between right ACC and right caudate showed significantly negative correlation with the avolition apathy scores in FES patients with met carriers,but not with val homozygotes.3.We investigated the effect of COMT val158 met genotype on the functional connectivity and cortical thickness of triple networks(salience network,central executive network,default mode network).Firstly,independent component analysis was conducted to identify the triple networks.Free Surfer software was used to calculate the cortical thickness of the key nodes of triple networks.The resting state functional connectivity between the key nodes of the triple networks was calculated.A two-ways ANCOVA analysis was used to investigate the main effect of disease state and the interaction effect of COMT val158 met genotype and disease state on the functional connectivity and cortical thickness of triple networks.We found the cortical thickness of left DLPFC was significantly thinner and the functional connectivity between salience network and central executive network was significantly decreased in FES compared with HC.The cortical thickness of left DLPFC was influenced by interaction effect of disease state and val158 met genotypes.4.We investigated the effect of COMT rs4633 genotype on the resting-state functional connectivity density and cortical thickness.A two-ways ANCOVA analysis was used to investigate the main effect of disease state and the interaction effect of COMT rs4633 genotype and disease state on the functional connectivity density and cortical thickness.Compared with HC,the FES patients showed abnormal functional connectivity density in hub regions,such as precuneus,occipital cortex and frontal cortex.Local and long functional connectivity density of orbitofrontal cortex and cortical thickness of right middle frontal gyri were influenced by interaction effect of rs4633 genotype and disease state.Compared with met carriers in patients,we found significant thinner cortical thickness in patients with CC genotype,and the HC group showed the reverse pattern.We found significant association between speed of processing and right middle frontal gyri cortical thickness in FES patients with the CC genotype.5.We used multivariate pattern analysis based on resting state functional magnetic resonance imaging to classify FES and HC.Functional connectivity density maps were used as classification features.Liner support vector machine is employed to classify the FES and HC.We used a leave-one-out cross validation strategy to estimate the generalization ability of the classifiers.FES patients can be distinguished from HCs using local and long functional connectivity density with high classification accuracy.These results indicate that the combine of multivariate pattern analysis with functional magnetic resonance imaging might provide a novel tool to diagnosis of schizophrenia.In summary,relationships between COMT genotype,brain function and structure of FES and HC were explored by means of imaging genetics method.The polymorphism of val158 met and rs4633 in COMT have significant effect on brain function and structure of prefrontal cortex in FES patients.The results of this study will help us to understand the molecular and cellular mechanisms of brain functional and structural changes in schizophrenia from a genetic perspective and to deepen our understanding of the pathogenesis of schizophrenia.In addition,we used multivariate pattern analysis to establish a diagnostic model for FES and to search for objective biological markers of this disease.,which may provide clinical diagnostic tools.