Guoying Feng

Response of risperidone treatment may be associated with polymorphisms of HTT gene in Chinese schizophrenia patients.

Serotonin transporter (5-HTT) is a key component of the serotonergic neurotransmitter system. Few studies have focused on polymorphisms of the serotonin transporter and antipsychotic response and, in particular, there have so far been no published studies on the association between the serotonin transporter and response to risperidone. This study examined the relationship between two polymorphisms of the serotonin transporter and the efficacy of risperidone treatment in 129 patients with schizophrenia. Our results revealed that patients with l allele of HTTRLP showed a greater improvement than those without l allele on the overall brief psychiatric rating scale (BPRS) (P=0.025). But no such relationship was found for the HTTVNTR. In haplotype analysis, the frequency of L-12 haplotype showed a significant difference between the responder group and the non-responder group (P=0.005). Our study has, for the first time, produced evidence that the potential for therapy in patients with schizophrenia is related to the HTTRLP polymorphism in the HTT gene and haplotype L-12 may help to predict risperidone treatment efficiency.

RGS4 polymorphisms and risk of schizophrenia : An association study in Han Chinese plus meta-analysis

Recently, several researches based on expression analysis, genetic linkage and association studies have suggested that the regulator of G-protein signaling 4 (RGS4) might be a schizophrenia susceptibility gene. However, these linkage and association studies have been conducted using different ethnic samples, and have therefore tended to produce inconsistent results. To help to clarify this inconsistency, we used non-family based samples to carry out a case-control analysis on six single nucleotide polymorphisms (SNPs) (including four widely investigated SNPs, SNP1, 4, 7, 18 and another two SNPs, rs2842030 and rs2344671) in a Chinese Han sample set comprising 288 schizophrenia patients and 288 normal controls. All genotypings were conducted by direct sequencing and all SNPs were in Hardy-Weinberg equilibrium. We found no individual SNPs or haplotypes to be associated with schizophrenia. We also performed a meta-analysis based on all published population-based association studies on the topic including our own. The results of both our case-control study in the Chinese Han population and the meta-analysis yield no significant evidence for association, which suggests that the genetic polymorphisms within RGS4 are unlikely to confer an increased susceptibility to the etiology of schizophrenia.

Evidence for association between the 5' flank of the NOS1 gene and schizophrenia in the Chinese population

Nitric oxide (NO) plays an important role in the dopaminergic and serotonergic system as the second messenger of the NMDA receptor and has possible roles in neurotransmission, neurosecretion, synaptic plasticity, and tissue injury in many neurological disorders, including schizophrenia. There is also genetic evidence to support the human NOS1 (neuronal nitric oxide synthase 1) gene as a promising candidate gene associated with schizophrenia. In this paper we conducted a case-control association study involving 1705 Chinese subjects and 12 genetic markers [11 single nucleotide polymorphisms (SNPs) and 1 microsatellite] mainly in the 5 flank region of the gene by direct sequencing and capillary electrophoresis. We identified SNP rs3782206 and several haplotypes derived from it as being significantly associated with schizophrenia and, specifically, in a paranoid subgroup. Our results strongly support a previous hypothesis that NOS1 contributes to the genetic risk of schizophrenia and suggest that further research on more NOS1 variants and its regular elements are warranted.

Interleukin-10 −1082 promoter polymorphism is associated with schizophrenia in a Han Chinese sib-pair study

The interleukin-10 (IL-10) gene has been identified as a susceptibility gene for schizophrenia in Caucasians. A previous case-control study conducted by our group revealed a weak association between polymorphism, -592C/A, of the IL-10 gene promoter and schizophrenia. Our present study was aimed at confirming the association of the IL-10 promoter with schizophrenia using 197 Han Chinese sib-pair families. A family-based association test (FBAT) and haplotype analysis was undertaken using the FBAT v1.5.5. The global TDT was significant for a different polymorphism, -1082G/A (chi2=13.16, P=0.000285) and that the allele -1082G was preferentially transmitted to schizophrenia-affected children. Furthermore, haplotype TDT analysis showed that haplotype GCC was significantly associated with the disease (chi2=8.1, P=0.00443). Our results also indicate that the IL-10 gene may play a significant role in the etiology of schizophrenia among Han Chinese.

Positive association between OLIG2 and schizophrenia in the Chinese Han population

A recent study reported that OLIG2 had a significant association with schizophrenia in the UK population. We genotyped three variants scattered among the genomic region of OLIG2, namely rs1005573, rs762178 and rs1059004 in a sample consisting of 329 schizophrenia patients and 288 controls. The results provide further evidence that the SNP rs762178 in OLIG2 seems to be a potential candidate in altering risk for schizophrenia in the Chinese Han population and worthy of further replication and functional study.

An investigation of the dihydropyrimidinase-like 2 (DPYSL2) gene in schizophrenia: genetic association study and expression analysis

Several linkage studies support a susceptibility locus for schizophrenia on chromosome 8p21-22. In this study, we investigated a gene mapping to 8p21, dihydropyrimidinase-like 2 (DPYSL2). DPYSL2 plays an important role in axonal formation and dysfunction of DPYSL2 may result in neurodevelopmental abnormalities. In previous studies, the expression of the gene has been shown to display alteration in the brain of schizophrenia patients compared with those of healthy controls. Recently, Nakata and colleagues found polymorphisms in the 3-end of DPYSL2 to be associated with schizophrenia, especially the paranoid type, in a Japanese population. In this study, we genotyped four SNPs in DPYSL2 in 2552 Chinese Han specimens. Case-control and TDT analyses were performed to detect association of DPYSL2 with schizophrenia. However, no allele, genotype or haplotype association was found. We investigated the expression of DPYSL2 in 29 schizophrenia patients and 54 healthy controls using quantitative real-time PCR and no difference was found between the two groups. In a comparative allele-specific expression test, we used two SNPs as markers. Only a small proportion of heterozygotes revealed a significant difference (>20%) in allele representation. The results indicated the mRNA level did not contribute mainly in the altered expression of the gene in schizophrenia patients. Although our results provided no evidence for DPYSL2 itself as a susceptibility gene for schizophrenia, recent findings have indicated that DPYSL2 may interact with other candidate genes for schizophrenia and be worthy of further studies.

Family-based association studies of CAPON and schizophrenia in the Chinese Han population.

Although there is evidence pointing to CAPON as a susceptible gene for schizophrenia, the results of independent association studies have so far been inconsistent. A recent case-control study by Zheng et al. supported CAPON as a susceptible site for the disease in the Chinese Han population. In their study both the single polymorphism (rs348624) and individual haplotypes showed significant association with schizophrenia. Our study further investigates this relationship this time using a family-based association. We selected 5 SNPs including rs348624 and performed a Transmission Disequilibrium Test (TDT) in 319 Chinese Han trios. Our results identified no single marker nor haplotype associated with schizophrenia, which did not suggest that CAPON was a susceptible site in the Chinese Han population, or it appeared unlikely that the CAPON played a major role in the aetiology of schizophrenia. Since there is consistent evidence pointing to 1q21-22 as a positional candidate region for schizophrenia, we suggest that further research should focus on other genes located in this region.

The PIP5K2A gene and schizophrenia in the Chinese population — A case-control study

Results from a number of molecular and pharmacological studies suggest that the phosphatidylinositol-4-phosphate 5-kinase IIalpha (PIP5K2A) gene may be involved in the development of schizophrenia. A recent family-based transmission disequilibrium test in the German and Israeli populations found that four single nucleotide polymorphisms, rs1417374, rs10828317, rs746203 and rs8341 in this gene or nearby intergenic regions are significantly associated with schizophrenia. The objective of our study was to investigate whether these four SNPs are also associated with schizophrenia in the Chinese population. Our study found that SNP rs8341 (p=0.0045, Odds Ratio=1.415, 95%CI=1.113-1.799 for the minor allele) and a haplotype (p=0.0039, Odds Ratio=1.440, 95%CI=1.123-1.845) are significantly associated with schizophrenia. Our results confirm that the PIP5K2A gene merits further study as a susceptible gene for schizophrenia.

Missense mutations in IHH impair Indian Hedgehog signaling in C3H10T1/2 cells: Implications for brachydactyly type A1, and new targets for Hedgehog signaling.

Heterozygous missense mutations in IHH result in Brachydactyly type A1 (BDA1; OMIM 112500), a condition characterized by the shortening of digits due to hypoplasia/aplasia of the middle phalanx. Indian Hedgehog signaling regulates the proliferation and differentiation of chondrocytes and is essential for endochondral bone formation. Analyses of activated IHH signaling in C3H10T1/2 cells showed that three BDA1-associated mutations (p.E95K, p.D100E and p.E131K) severely impaired the induction of targets such as Ptch1 and Gli1. However, this was not a complete loss of function, suggesting that these mutations may affect the interaction with the receptor PTCH1 or its partners, with an impact on the induction potency. From comparative microarray expression analyses and quantitative real-time PCR, we identified three additional targets, Sostdc1, Penk1 and Igfbp5, which were also severely affected. Penk1 and Igfbp5 were confirmed to be regulated by GLI1, while the induction of Sostdc1 by IHH is independent of GLI1. SOSTDC1 is a BMP antagonist, and altered BMP signaling is known to affect digit formation. The role of Penk1 and Igfbp5 in skeletogenesis is not known. However, we have shown that both Penk1 and Igfbp5 are expressed in the interzone region of the developing joint of mouse digits, providing another link for a role for IHH signaling in the formation of the distal digits.

No genetic association between polymorphisms in the kainate-type glutamate receptor gene, GRIK4, and schizophrenia in the Chinese population

BACKGROUNDnSchizophrenia is a chronic psychiatric disorder with a strong genetic component. Several studies have suggested that dysfunctions in the glutamatergic transmission are linked to the pathogenesis of schizophrenia, and that the kainate ionotropic glutamate receptors are involved in this mechanism. A recent study provides cytogenetic and genetic evidence to support a role for the kainate-type glutamate receptor gene (GRIK4), in schizophrenia. A systematic case-control association study of GRIK4 involving a Scottish population found that three SNPs, rs4935752, rs6589846 and rs4430518, were associated with schizophrenia.nnnMETHODSnHere, we investigated rs4935752, rs6589846, rs4430518 and other 2 SNPs within the GRIK4 gene in an association study of the Chinese population. Our sample consisted of 288 schizophrenia and 288 control subjects. All recruits were Han Chinese drawn from the city of Shanghai.nnnRESULTSnNo individual SNP nor any haplotype was associated with schizophrenia in our study.nnnCONCLUSIONnThese results suggest that the five SNPs within the GRIK4 gene are unlikely to play a major role in the susceptibility to schizophrenia in the Chinese population.