Molecular Genetic Studies Of Major Mental Disorder Based On The Hypothesis Of Abnormal Synaptic Plasticity

Mental disorders are characterized by the abnormal mental functions and disturbed behaviors with the low mortality and high disability.Common mental disorder included schizophrenia,depression,bipolar disorder,autism and so on.Several lines of evidence suggest that genetic factors are likely to play an essential role in developing of mental disorder.Now,the main challenge to genetic study is how to screen the predisposing genes of mental disorders.Many hypotheses had been raised to explain the etiology of the symptoms. However the genes evoking mental disorder remain unclear.People began to evaluate the existent hypotheses.Now,more and more evidences suggest that there be some relationship between the abnormality of synaptic plasticity and mental disorder.In addition,clinical heterogeneity has been one of the obstacles in the study of the etiology of mental disorders.To solve this problem,the concept of endophenotype has been introduced to the present studies.Many evidences indicate Cognitive impairments maybe a representative endophenotype for mental disorders.There are two parts in our work.In the first part,we carried out the study of the predisposing genes related to the NMDAR-LTP pathway.We performed a two-step analysis.In the analytical step,we genotyped 43 reported single nucleotide polymorphisms(SNPs) present in 14 genes related to the NMDAR-LTP pathway among 96 paranoid schizophrenics and 96 normal controls.The results showed that five susceptibity SNPs sites were found to be associated with schizophrenia.The five SNPs were:rs3916965,rs3916966 and rs9558562 of the G72 gene;rs1295645 and rs6759 of the PSEN2 gene.The second step was to validate the initial findings in a larger sample size(454 schizophrenics and 484 controls).The G72 gene and the PSEN2 gene were also showed positive association with the disorder.In addition,analysis of gene expression demonstrated that G72 mRNA levels were significantly higher in the patient group than in control group.The expression levels of the G72 gene were not correlated to its genotypes;the PSEN2 mRNA levels were significantly lower in the patient group than in control group and that expression levels of the PSEN2 gene were significantly correlated to its genotypes.In addition,the combined effect of G72 and PSEN2 was found with the conditional test. In the second part,we took the cognitive deficits as the endophenotype and carried out the study of the predisposing genes related to the NMDAR-LTP pathway,we collected the general and clinical data of 50 patients(25) and the general data of 50 normal controls.Then all the subjects are required to complete three sets of neuropsychological tests(19 items).The results show that there was significant difference between patients and normal controls in almost all of their performances of neuropsychological test,including intelligence,memory and executive functioning.Then combined with the 14 candidate genes on the NMDAR-LTP,the quantitive trait analysis of cognitive impairments was taken.The results show that there were 9 genes associated with cognitive impairments.The susceptibility genes were:AKT1,BDNF,CNTF, DISC1,EGF,G72,NOS1,NTF3å’ŒPSEN2.In this part,the G72 gene and the PSEN2 gene were detected again.The genes of AKT1,BDNF,CNTF,DISC1,EGF,NOS1 and NTF3 were caught,which indicated that the endophenotype were more sensitive.Our study suggested that the NMDAR-LTP pathway is correlated with the susceptibility of mental disorder.With cognitive deficits as the endophenotype, susceptibility genes can be found with the cognitive deficits as the endophenotype.Our results may supply new clues for the study of the pathogenesis of major mental disorders.