[Show abstract][Hide abstract] ABSTRACT: 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.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 08/2008; 32(5):1210-3. · 3.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exposure to prenatal undernutrition or malnutrition increases the risk of schizophrenia, although little is known about the mechanism. Pro-inflammatory factors are critical in brain development, and are believed to play an important role in neurodevelopmental disorders associated with prenatal exposure to infection, including schizophrenia. However it is not known whether pro-inflammatory factors also mediate the effects on the fetus of prenatal malnutrition or undernutrition. In this study, we established a new prenatal undernourished rat model induced by maternal exposure to a diet restricted to 50% of the low (6%) protein diet (RLP50). We observed the disappearance of maternal nest-building behavior in the RLP50 dams, increased levels of TNFA and IL6 in the placentas (P<0.001; P=0.879, respectively) and fetal livers (P<0.001; P<0.05, respectively), and a decrease in the fetal brains (P<0.05; P<0.01, respectively). Our results are similar to previous studies of maternal infection, which implies that a common pathway mediated by pro-inflammatory factors may contribute to the brain development, consequently increasing the risk of schizophrenia and other psychiatric diseases programmed by varied maternal adversities. We also provide a new prenatal undernourished model for researching prenatal problems, which differs from previous malnourished model in terms of the maternal behavior of dams and of observed pro-inflammatory factor levels in fetal tissues.
Schizophrenia Research 02/2008; 99(1-3):48-55. · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report here the clinical, genetic, and molecular characteristics of a large Chinese family exhibiting non-syndromic, late-onset autosomal dominant sensorineural hearing loss. Clinical evaluation revealed variable phenotypes of hearing loss in terms of severity and age-at-onset of disease in these subjects. Genome-wide linkage analysis mapped the disease gene to the DFNA5 locus with a maximum two-point log odds score of 5.39 at [theta] = 0 for marker D7S2457. DNA sequencing of DFNA5 revealed a novel heterozygous IVS8+4 A>G substitution in the splice donor site of intron 8. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed skipping of exon 8 in the mutant transcript. This mutation faithfully cosegregated with hearing loss in the family. In addition, the mutation was absent in 100 unrelated control DNA samples of Chinese origin. The IVS8+4 A>G mutation is predicted to create a shift in the reading frame and introduce a stop codon at position 372, thereby resulting in a prematurely truncated DFNA5 protein. Up to date, a total of four mutations in DFNA5 have been reported to lead to hearing impairment, all of them result in skipping of exon 8 at the mRNA level. Our findings provide further support for the hypothesis that DFNA5-associated hearing loss is caused by a very specific gain-of-function mutation.
[Show abstract][Hide abstract] ABSTRACT: This study aims to identify the effects of antipsychotics on plasma proteins, and on the proteins associated with schizophrenia. We applied proteomics technology to screen protein aberrations in Sprague-Dawley rats treated with antipsychotics and schizophrenic patients undergoing medication. ApoA-I was found significantly increased in the chlorpromazine-treated rats and decreased in the patients with treatment-resistant schizophrenia, which suggest that decreased levels of apoA-I might be associated with the pathology of schizophrenia and that chlorpromazine increases apoA-I levels as part of its therapeutic action.
Journal of Neural Transmission 02/2007; 114(5):657-63. · 3.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recently, the nested genes G72 and G30 on chromosome 13q32-q33 have been implicated in the etiology of schizophrenia. We genotyped six single-nucleotide polymorphisms (SNPs: rs3916965, rs3916967, rs2391191, rs778294, rs779293 and rs3918342), which span approximately 82.5 kb in the region encompassing the G72/G30 genes in 1176 Han Chinese subjects (588 cases and 588 controls) and 365 Scottish subjects (183 cases and 182 controls). Significant association between an allele of marker rs778293 and schizophrenia was found in our Chinese samples (P = 0.0013), and was replicated in the Scottish samples (P = 0.022). LD analysis revealed that four SNPs between rs3916965 and rs778294 were in LD, called block I, and the two distal SNPs (rs778293 and rs3918342) constituted a block II in both the Chinese and Scottish samples. We selected one SNP from each block (rs778294 from block I and rs778293 from block II), and then analyzed the haplotypes. A significant difference was observed for the common haplotype GC in the Chinese sample (P = 0.0145), and was replicated in the Scottish sample (P = 0.003). On meta-analysis, we separately analyzed the studies in Asian and European populations because of significant heterogeneity in the homogeneity test. We found a statistically significant association between rs778293 and schizophrenia in Asian populations, but no difference was found between cases and controls in the European populations. Overall, our data give further support to the existing evidence that G72/G30 genes are involved in conferring susceptibility to schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: Recently, Pimm et al. identified Epsin 4 on chromosome 5q33 as a susceptibility gene for schizophrenia in the British population, based on linkage and association evidence. In Pimm's case-control study, both the single polymorphisms and the individual haplotypes at the 5' end of the gene showed genetic association with schizophrenia. Here, we report the first study evaluating the relevance of Epsin 4 and schizophrenia outside the British population. Markers showing positive results in the original work as well as two additional polymorphisms were genotyped in 308 Han Chinese family trios. Transmission disequilibrium analysis was used to test for association of single-locus markers and multi-locus haplotypes with schizophrenia. Although no individual marker was significant at the P=0.05 level, the haplotypes detected in our samples, different from those previously reported, showed strong evidence of association (most significant global P=0.0021). Our results indicate the presence of a locus near the 5' end of Epsin 4 conferring susceptibility to the disease and provide further support for Epsin 4 as an important potential contributor to genetic risk in schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Neurotransmitter-based hypotheses have so far led to only moderate success in predicting new pathogenetic findings in etiology of schizophrenia. On the other hand, the more recent oligodendroglia hypotheses of this disorder have been supported by an increasing body of evidence. For example, the expression level of the myelin associated glycoprotein (MAG) gene has been shown to be significantly lower in schizophrenia patient groups compared to control groups. Such an effect might be a result of genetic variations of the MAG gene. In order to test this hypothesis, we genotyped four markers within the MAG locus in 413 trios sample of the Han Chinese using allele-specific PCR. None of the four markers revealed noticeable allelic significance. However, the four-marker and two-marker haplotypes covering components rs720309 and rs720308 were observed to be significantly associated with schizophrenia (P < 0.0001) in this study. In addition, we identified one common risk haplotype TA (rs720309-rs720308, present in 78.5% of the general population) that showed increased evidence of overtransmission from parents to affected offspring (P = 0.0001). The results demonstrated MAG might play a role in genetic susceptibility to schizophrenia. Furthermore, our finding of a possible association between the MAG locus and schizophrenia is in agreement with the hypotheses of oligodendrltic and myelination dysfunction.
Schizophrenia Research 06/2005; 75(1):11-9. · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Synapsin II encodes a neuron-specific phosphoprotein that selectively binds to small synaptic vesicles in the presynaptic nerve terminal. The expressions of messenger ribonucleic acid and protein of synapsin II have been reported to be significantly reduced in the brains of schizophrenia patients. The synapsin II gene is located on 3p25, a region that has been implicated to be associated with schizophrenia by genetic linkage. All these findings suggest synapsin II as a candidate gene for schizophrenia.
In this work, we studied four markers (two single nucleotide polymorphisms (SNPs): rs308963 and rs795009; and two insertion/deletion polymorphisms: rs2307981 and rs2308169) covering 144.2 kilobase pairs (kb) with an average interval of 38 kb in synapsin II in a sample of 654 schizophrenic patients and 628 normal control subjects to explore the mechanism underlying schizophrenia.
We found significant differences in allele frequency distribution of SNP rs795009 (p =.000018, odds ratio 1.405, 95% confidence interval 1.202-1.641) between patients and control subjects. The T allele was significantly higher in patients than in control subjects. Moreover, the overall frequency of haplotype showed significant differences between patients and control subjects (p <.000001).
This study suggests a positive association between synapsin II and schizophrenia, implying that synapsin II is involved in the etiology of schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: The gene for insulin-degrading enzyme (IDE) represents a strong positional and biologic candidate for late-onset Alzheimer disease (LOAD) susceptibility. IDE is located on chromosome 10q23.3 close to a region of linkage for LOAD. In addition, many studies have identified a possible role of IDE in the degradation of amyloid beta-protein and the intracellular amyloid precursor protein (APP) domain released by gamma-secretase processing.
To examine the association of IDE with AD in the Han Chinese.
Four IDE polymorphisms (three in 5'-untranslated region and one in intron 21) were analyzed, using a population of 210 patients with LOAD and 200 control subjects well matched for age, sex, and ethnic background.
Among the four polymorphisms studied, only the C allele of single-nucleotide polymorphism (SNP) IDE2 showed association with AD (p = 0.005). Stratification of the data by APOE epsilon4 status indicated that the association between IDE2 and AD was confined to APOE epsilon4 carriers only. No association was found between all variants studied and AD within APOE epsilon4-negative subjects. The global haplotype frequencies showed significant differences between AD patients and control subjects. Furthermore, overrepresentation of GCTG haplotype in the AD group was found. It may be a risk haplotype for AD.
These results suggest a possible synergic interaction between IDE and APOE epsilon4 in the risk to develop late-onset sporadic AD. IDE might modify the effect of the APOE epsilon4 risk factor in the Han Chinese population.
[Show abstract][Hide abstract] ABSTRACT: Polymorphisms at positions -491, -427 and -219 in the promoter region of the Apolipoprotein E APOE gene have been variously reported to confer an increased risk of developing Alzheimer's disease (AD) independent of the effect of epsilon 2, 3 or 4 alleles in exon 4. In order to assess APOE promoter polymorphisms as independent risk factors in AD we have compared results in 183 definite or probable AD cases with 133 controls. We assayed markers at sites -491, -427, -219, and +113 in APOE gene and a polymorphic Hha1 site in the nearby APOC1 gene. We found that APOE promoter polymorphisms and APOC1 insertion alleles were significantly associated with AD. However, after stratification for epsilon 4 allele, only the A allele at -491 in APOE remained significantly associated with AD. The effects of the other markers depended almost entirely upon linkage disequilibrium with epsilon 4 allele, and only trends remained when cases and controls were stratified for the presence or absence of epsilon 4 allele. This occurred irrespective of whether markers were examined separately or together as haplotypes. So in the Chinese population only APOE -491 promoter alleles confer significant risk of AD independent of epsilon 4 status.
[Show abstract][Hide abstract] ABSTRACT: Recently a strong positive association between schizophrenia and Notch4 has been reported. Both individual markers and haplotypes showed association with the disease, with five markers (three microsatellites and two SNPs) being tested. In order to test this finding we genotyped these markers in the Han Chinese population using a sample of 544 cases and 621 controls as well as >300 trios. Analysis of allele, genotype and haplotype frequencies in both samples showed no association between the markers and the disease. Our results would indicate that a significant role for the Notch4 gene in schizophrenia can be ruled out in the Han Chinese. However, similar studies are necessary in the Caucasian population as linkage disequilibrium arrangements and founder effects may differ between these two populations.