Association Studies Of Psychiatic And Stroke Diseases And The Pathogenesis In Chd7 Mutation Mouse

Schizophrenia?SCZ?and major depressive disorder?MDD?are two of the most common and severe mental disorders,which place a large burden not only on affected individuals and their families but also on society and health services.The prevalence of SCZ is up to 1%worldwide,and the lifetime risk of MDD ranges from 5%to 25%.And substantial heritability of SCZ and MDD were 80%and 37%,respectively.Strikingly,the pathogenesis underlying these disorders still needs to be elucidated.In addition,there is large body of evidence that overlaps exist among biological mechanisms underlying mental illnesses such as SCZ,MDD and bipolar disorder.Stroke,as another severe common disease,is recognized as one of the leading causes of death and severe neurological disability worldwide.Data from family-based studies,twin studies,and animal experiments indicate that genetic factors play a major role in stroke,while the etiologies of stroke is not yet clearly elucidated.Therefore,in this study,we aimed to investigate the possible genetic association between candidate genes and SCZ,MDD and stroke in the Han Chinese Population,as well as to examine the potential susceptibility of gene-gene interaction and common genetic risk backgroud in the two psychiatric diseases.Abnormal glutamatergic neurotransmission is one of main hypotheses of psychiatric diseases.Metabotropic glutamate receptor type 7?GRM7?and type 8?GRM8?are involved in the neurotransmission of glutamate which is supposed to play an important role in the development of schizophrenia?SCZ?and major depressive disorders?MDD?in previous studies.We designed this study to investigate whether common DNA variants or their genetic interactions within GRM7 and GMR8 genes were associated with these disorders in the Han Chinese population.Fourteen SNPs in GRM7 and GRM8 were selected within a sample set comprising1235 SCZ patients,1045 MDD patients and 1235 normal controls.Significant association in SCZ case-control subjects was observed for rs2229902(permutated P_allele=0.0005,OR=1.492)and rs9870680(permutated P_allele=0.0023,OR=1.262)in GRM7 and rs2237781(permutated P_allele=0.0027,OR=1.346)in GRM8.Association analysis for MDD case-control subjects revealed positive results in rs779706(permutated P_allele=0.0099)of GRM7 and in rs1361995(permutated P_allele=0.0017,OR=1.488)of GRM8.Moreover,a three-locus model,constituted by polymorphisms in GRM7 and GRM8 significantly correlated with MDD in the gene-gene interaction analysis.Meta-analysis and haplotype analysis further confirmed our significant results.We demonstrated the genetic association of GRM7 and GRM8 with SCZ and MDD in the Han Chinese population.We also found susceptibility interactive effects of these two genes with both psychiatric disorders.Acyl-CoA synthetase medium-chain family member 1?ACSM1?,has medium-chain fatty acid:CoA ligase activity with major role lying in the degradation of medium-chain fatty acids for the production of energy.Previous research has shown that genetic polymorphisms in the acyl-CoA synthetase gene family have contributed to multiple risk factors,especially hypertriglyceridemia.Notably,accumulating evidence has suggested that individuals with schizophrenia have high levels of metabolic disorders and cardiovascular risk factors.The significant association between ACSM1and schizophrenia was first found in Europeans.However,up to now,there has been no replication of the association between ACSM1 and neuropsychiatric diseases in the Han Chinese population.In this study,we not only undertook analysis to validate the associations of the common variants of ACSM1 with SCZ previously reported in European population but also genotyped those polymorphisms in MDD patients to reveal potential cross-disorder associations.In the second part of this paper,six single nuclear polymorphisms?SNPs?in ACSM1 were genotyped to test their associations with SCZ and MDD in the sample same of part 1.SNP rs163234 was found to be significantly associated with both SCZ(permutated P_allele=0.0017,OR=1.350)and MDD(permutated P_allele=0.0048,OR=1.329).SNP rs433598 showed a strong association with SCZ(permutated P_allele=0.0043,OR=1.303).Haplotype analysis of the blocks containing the two positive markers also revealed a significant association.Our data are the first to suggest a positive association of the ACSM1 gene with a genetic susceptibility for SCZ and MDD in the Han Chinese population.The third part of the paper focused on the association study between paraoxonase?PON?gene family including PON1,PON2 and PON3 and stroke in a Han Chinese sample set with 508 healthy controls and 498patients?328 with ischemic stroke and 170 with hemorrhagic stroke?.PON gene family was implicated as potential risk factors of cerebrovascular disease and can prevent oxidative modification of low-density lipoproteins and atherosclerosis.Other studies have demonstrated a positive association between single nucleotide polymorphisms?SNPs?in PON genes and stroke susceptibility,although conflicting results have been seen in different ethnic groups.In our study,a total of 11 single nucleotide polymorphisms?SNPs?covering the PON genes were genotyped for statistical analysis.The presence of rs705381?-162?in the promoter region of PON1 was significantly associated with total stroke(P_adjusted=0.0007,OR=0.57[95%CI=0.41-0.79])and ischemic stroke(P_adjusted=0.0017,OR=0.54[95%CI=0.37-0.79])when analyzed using a dominant model,but was not associated with hemorrhagic stroke.There was also a nominal association between rs854571?-824?and total stroke.These findings indicate that polymorphisms of PON1 gene may be a risk factor of stroke.The fourth part of the paper is about studying the underlying pathogenesis of a Chd7 gene mutation mouse created in our lab.In this study,we identified different phenotypes of this mouse model and undertook a genome-wide microarry expression analysis on wild-type mouse embryos and embryos with heterogeneous or homozygous Chd7gene mutation at day 10.5,a time point of middle gestation and when the homozygous mutations die.We foud that the Chd7 gene mutation mouse showed features of CHARGE syndrome disorder,which included circling,growth retardation,coloboma,short lower jaw,protruding tongue,oedema and maldevelopment of the pinna in the embryo.Moreover,whole-genome microarry expression analysis pointed out some interesting candidate genes closely related to the phenotypes,such as Epha3,Trpm3,Aldh1a3,Fgf3,Pbx4,Nkx2-6,and Tbx15.Although these results gave us lots of hints of how Chd7 gene contributes to the phenotypes of the CHARGE syndrome like phenoypes in our mouse model,further endeavor is needed in finding the convincing functional evidence and in illustrating the mechanism of how Chd7 gene play its role in ochiestrating the candidate genes.