Molecular Genetic And Neuroimaging Studies For Genes Related To The Glutamatergic System In The Severe Mental Disorders

Background:Schizophrenia and major depression (MDD) are two of the common severe mental disorders. Compelling evidence suggests an essential role of the genetic factors in the etiology of mental disorders, identification of predisposing candidate genes is one of the key studies for them. Increasing evidence suggests that there may be a relationship between glutamatergic system and severe mental disorders.Because of the clinical heterogeneity, interaction between gene and environmental factors, most of the results from genetic studies in the mental disorders could not be replicated in different samples. By finding endophenotypes, the heterogeneity problem could be resolved and more susceptibility genes could be found out in the studies. Neuroimaging alternation found by functional magnetic resonance imaging (fMRI) is one of the endophenotypes frequently used.Objective:To find out specific neuroimaging alternation and test association of the genes related to glutamatergic system with these two disorders and abnormal brain activities in both patients.Main Outcome Measure:(1). Two-stage association study in454schizophrenic patients,488MDD patients and480control subjects for43SNPspresented in14genes related to the glutamatergic system;(2). fMRI was performed in two group patients and well-matched controls under resting state and n-back condition separately, followed by regional homogeneity (ReHo), default mode network (DMN) and functional connectivity analysis. Differences of the behavior performance and activations in the n-back task were also detected;(3). Association between altered ReHo and SNP genotypes in schizophrenia and MDD;(4).2X2(genotype X disease status) ANOVA for main effects of genotypes, disease status and their interaction.Results:(1). The stage-1study showed association of the DAOA and PSEN2genes with schizophrenia in a small sample; the stage-2study was performed in a larger sample containing patients with schizophrenia and MDD. Allelic association for rs2391191, rs3918341and rs778294with MDD was detected and haplotypic association for2-SNPs and3-SNPs haplotypes in the DAOA gene with both disorders was also reported.(2). A. Schizophrenic patients had lower ReHo in the left superior temporal gyrus than either control subjects or patients with MDD. Increased ReHo was observed in the right superior frontal gyrus in schizophrenic patients compared with control subjects, and a left-less-than-right asymmetry was also found in this region in schizophrenic patients as well;B. Increased activities in the bilateral middle occipital gyrus of schizophrenic patients and decreased activities in the left inferior frontal gyrus, insula, right middle frontal gyrus of patients with MDD were observed in the DMN analysis compared with the control subjects;C. No difference for brain activation was found in the n-back task while reaction time and accuracy were quite different between schizophrenic patients and controls;D. The betweenness of the cuneus, hippocampus, inferior occipital gyrus and middle temporal gyrus in the resting state and cuneus, middle occipital gyrus and superior parietal gyrus in the2-back condition were significantly different between the control and schizophrenic patient groups.(3). The main effect of rs2391191genotypes were found in the right culmen and right middle frontal gyrus of the patients with MDD, and in the left putamen of schizophrenic patients. The left uvula and left middle temporal gyrus in the MDD patients and the left cuneus in the schizophrenic patients showed a genotypes X disease status interaction.Conclusion:Our results suggest that glutamatergic system may play an important role in the etiology of the severe mental disorders. The same susceptibility gene(DAOA) may confer genetic risk and generate specific neuroimaging alternation of schizophrenia and MDD by different alleles and/or their combinations.