Testing the role of genetic variation of the MC4R gene in Chinese population in antipsychotic-induced metabolic disturbance

Antipsychotic-induced metabolic disturbance(AIMD) is a common adverse effect of antipsychotics with genetics partly underpinning variation in susceptibility among schizophrenia patients. Melanocortin4 receptor(MC4 R) gene, one of the candidate genes for AIMD, has been under-studied in the Chinese patients. We conducted a pharmacogenetic study in a large cohort of Chinese patients with schizophrenia. In this study, we investigated the genetic variation of MC4 R in Chinese population by genotyping two SNPs(rs489693 and rs17782313) in 1,991 Chinese patients and examined association of these variants with the metabolic effects that were often observed to be related to AIMD. Metabolic measures, including body mass index(BMI), waist circumference(WC), glucose, triglyceride, high-density lipoprotein(HDL), and low-density lipoprotein(LDL) levels were assessed at baseline and after 6-week antipsychotic treatment. We found that interaction of SNP×medication status(drug-na?ve/medicated) was significantly associated with BMI, WC, and HDL change %, respectively. Both SNPs were significantly associated with baseline BMI and WC in the medicated group. Moderate association of rs489693 with WC, Triglyceride, and HDL change % were observed in the whole sample. In the drug-na?ve group, we found recessive effects of rs489693 on BMI gain more than 7%, WC and Triglyceride change %, with AA incurring more metabolic adverse effects. In conclusion, the association between rs489693 and the metabolic measures is ubiquitous but moderate. Rs17782313 is less involved in AIMD. Two SNPs confer risk of AIMD to patients treated with different antipsychotics in a similar way.

The Human MSI2 Gene is Associated with Schizophrenia in the Chinese Han Population

It has been suggested that altered neurogenesis may be involved in the etiology of schizophrenia,so genes impacting on neurogenesis could be potential candidates for schizophrenia.A member of the Musashi family,the human MSI2 gene plays a substantial role in stem-cell maintenance,asymmetric division,and differentiation during neurogenesis.Our previous genome-wide association study（GWAS）implied an association of MSI2 with schizophrenia in a Han Chinese population.To further explore this association,three single-nucleotide polymorphisms（SNPs）,rs9892791,rs11657292,and rs1822381,were selected for a replication study involving 921 schizophrenia cases and 1244 controls.After rigorous Bonferroni correction,two of the SNPs（rs9892791 and rs11657292） displayed significant differences in allele and genotype distribution frequencies between the case and control groups.When our GWAS and replication samples were combined,the three MSI2 SNPs were all strongly associated with schizophrenia（rs9892791：allelic P = 1.07E-5;rs11657292：allelic P = 1.95E-12;rs1822381：allelic P = 1.44E-4）.These results indicate that the human MSI2 gene might be a susceptibility gene forschizophrenia and encourage future research on the functional relationship between this gene and schizophrenia.

Interaction Between Variations in Dopamine D2 and Serotonin 2A Receptor is Associated with Short-Term Response to Antipsychotics in Schizophrenia

Dear Editor,Schizophrenia is a chronic and debilitating brain disorder,which has a strong genetic component with heritability ranging from 66%to 85%[1,2].Currently,antipsychotic drugs remain the most effective treatment for the psychotic symptoms of schizophrenia[3].Because of the severe sideeffects of first-generation antipsychotics(FGAs),secondgeneration antipsychotics(SGAs)have become more widely used in the treatment of schizophrenia.

Association of ABCB1 Gene Polymorphisms with Efficacy and Adverse Reaction to Risperidone or Paliperidone in Han Chinese Schizophrenic Patients

Dear editor, P-glycoprotein （P-gp, also known as ATP-binding cassette transport sub-family B member 1, ABCB1） is a potent ATP-dependent efflux pump for a wide variety of drugs. Although studies of its substrates are abundant [ 1, 2], and ABCB1 is a well-conserved gene, there is increasing evi- dence that its polymorphisms affect substrate specificity [3]. A previous study reported that the synonymous single nucleotide polymorphism （SNP） C3435T （rs1045642） affects the timing of co-translational folding and insertionof P-gp into the membrane,

STON2风险变异通过影响Syt1转运和突触功能导致精神分裂症样行为

Synaptic dysfunction is a core component of the pathophysiology of schizophrenia.However,the genetic risk factors and molecular mechanisms related to synaptic dysfunction are still not fully understood.The Stonin 2(STON2)gene encodes a major adaptor for clathrin-mediated endocytosis(CME)of synaptic vesicles.In this study,we showed that the C-C(307Pro-851Ala)haplotype of STON2 increases the susceptibility to schizophrenia and examined whether STON2 variations cause schizophrenia-like behaviors through the regulation of CME.We found that schizophrenia-related STON2 variations led to protein dephosphorylation,which affected its interaction with synaptotagmin 1(Syt1),a calcium sensor protein located in the presynaptic membrane that is critical for CME.STON2307Pro851Ala knockin mice exhibited deficits in synaptic transmission,short-term plasticity,and schizophrenia-like behaviors.Moreover,among seven antipsychotic drugs,patients with the C-C(307Pro-851Ala)haplotype responded better to haloperidol than did the T-A(307Ser-851Ser)carriers.The recovery of deficits in Syt1 sorting and synaptic transmission by acute administration of haloperidol effectively improved schizophrenia-like behaviors in STON2307Pro851Ala knockin mice.Our findings demonstrated the effect of schizophreniarelated STON2 variations on synaptic dysfunction through the regulation of CME,which might be attractive therapeutic targets for treating schizophrenia-like phenotypes.