Shiwei Duan

Positive association of the DIO2 (deiodinase type 2) gene with mental retardation in the iodine-deficient areas of China

Background: Iodine deficiency is the commonest cause of preventable mental retardation (MR) worldwide. However, in iodine-deficient areas not everyone is affected and familial aggregation is common. This suggests that genetic factors may also contribute. Thyroid hormone (TH) plays an important role in fetal and early postnatal brain development. The pro-hormone T4 (3,3′,5,5′-triiodothyronine) is converted in the brain to its active form, T3, or its inactive metabolite, reverse T3, mainly by the action of deiodinase type 2 (DIO2). Methods: To investigate the potential genetic contribution of the DIO2 gene, we performed a case-control association study using three common SNPs in the gene (rs225014, rs225012, and rs225010) that were in strong linkage disequilibrium with each other. Results: Single marker analysis showed a positive association of MR with rs225012 and rs225010. Particularly with rs225012, TT genotype frequency was significantly higher in MR cases than in controls (χ2u200a=u200a9.18, pu200a=u200a0.00246). When we compared the distributions of common haplotypes, we also found significant differences between mental retardation and controls in the haplotype combination of rs225012 and rs225010 (χ2u200a=u200a15.04, df 2, global pu200a=u200a0.000549). This association remained significant after Bonferroni correction (pu200a=u200a0.0016470). Conclusion: We conclude that allelic variation in the DIO2 gene may affect the amount of T3 available and in an iodine-deficient environment may partly determine overall risk of MR.

Further evidence for the association between G72/G30 genes and schizophrenia in two ethnically distinct populations

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 82.5u2009kb 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.

Polymorphisms of the ABCB1 gene are associated with the therapeutic response to risperidone in Chinese schizophrenia patients

P-glycoprotein, a product of the ATP-binding cassette B1 (ABCB1) gene, plays an important role in absorption and distribution of drugs. The brain entry of risperidone and 9-OH-risperidone is greatly limited by P-glycoprotein, which implies that the functional polymorphisms of ABCB1 in humans may be a factor contributing to the variability in response to risperidone. The present study was therefore designed to examine whether polymorphisms of the ABCB1 gene are related to therapeutic response. For this purpose, 130 Chinese schizophrenia patients undergoing risperidone treatment were recruited. Plasma drug concentrations were monitored and clinical symptoms were evaluated using the Brief Psychiatric Rating Scale (BPRS) before and 8 weeks after the treatment. Association tests between genotypes and percentage improvement in total BPRS scores were performed using analyses of variance. Our results show that genotyping C1236T may help to predict the efficacy of risperidone treatment on the basis that patients with the TT genotype showed greater improvement than those with other genotypes on the overall BPRS (F = 3.967, p = 0.021), while other polymorphisms, including rs13233308, G2677T/A and C3435T polymorphism, did not show any association with the response to risperidone. These results showed suggestive evidence that genetic variation in the ABCB1 gene may influence the individual response to risperidone.

A family-based study of the association between the G72/G30 genes and schizophrenia in the Chinese population

Studies have shown a strong positive association between schizophrenia and G72/G30, demonstrated by both individual markers and haplotypes. A further functional study also supports the role of G72 in the etiology of schizophrenia. In this study, we have replicated these results of transmission/disequilibrium testing (TDT) and haplotype analysis in the Han Chinese population, showing P values of 0.0018 and 0.00007 for individual markers and haplotypes, respectively. Hence, our data supports the hypothesis that G72/G30 are important candidate genes for explaining schizophrenia in the Han Chinese population.

The relationship between the therapeutic response to risperidone and the dopamine D2 receptor polymorphism in Chinese schizophrenia patients

Antipsychotic drugs exert both therapeutic and adverse effects through dopamine D2 receptor (DRD2) antagonism. Genetic variants of this receptor may be responsible for individual variations in neuroleptic response and may therefore be useful in predicting response. In this study we evaluated the role of six polymorphisms of the DRD2 gene in 125 risperidone-treated Chinese schizophrenia patients following the hypothesis that variation in the DRD2 gene could affect drug response. Response was categorized as a change of >40% on the Brief Psychiatric Rating Scale (BPRS). Our results show that genotyping A-241G may help to predict the efficacy of risperidone treatment on the basis that patients with the A allele showed greater improvement than those with the G allele on the overall BPRS (chi2=7.19, p=0.007, p=0.031 after correction by the program SNPSpD), while other polymorphisms, including -141C Ins/Del, TaqIB, rs1076562, T939C and TaqIA, did not show any association with the response to risperidone. These data suggest that the DRD2 A-241G polymorphism or, alternatively, another genetic variation that is in linkage disequilibrium, may influence response to risperidone in schizophrenia patients.

Insulin-degrading enzyme and Alzheimer disease: a genetic association study in the Han Chinese.

Background: 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 β-protein and the intracellular amyloid precursor protein (APP) domain released by γ-secretase processing. Objective: To examine the association of IDE with AD in the Han Chinese. Methods: 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. Results: 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 ε4 status indicated that the association between IDE2 and AD was confined to APOE ε4 carriers only. No association was found between all variants studied and AD within APOE ε4-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. Conclusions: These results suggest a possible synergic interaction between IDE and APOE ε4 in the risk to develop late-onset sporadic AD. IDE might modify the effect of the APOE ε4 risk factor in the Han Chinese population.

Family-based association study of synapsin II and schizophrenia.

Synapsin II has been proposed as a candidate gene for vulnerability to schizophrenia on the basis of its function and its location in a region of the genome implicated by linkage studies in families with schizophrenia. We recently reported positive association of synapsin II with schizophrenia in a case-control study (Chen et al. 2004). However, since case-control analyses can generate false-positive results in the presence of minor degrees of population stratification, we have performed a replication study in 366 additional Han Chinese probands and their parents by use of analyses of transmission/disequilibrium for three in/del markers and three single-nucleotide polymorphisms. Positive association was observed for rs2307981 (P =.02), rs2308169 (P =.005), rs308963 (P =.002), rs795009 (P =.02), and rs2307973 (P =.02). For transmission of six-marker haplotypes, the global P value was.0000016 (5 degrees of freedom), principally because of overtransmission of the most common haplotype, CAA/-/G/T/C/- (frequency 53.6%; chi (2) = 20.8; P =.0000051). This confirms our previous study and provides further support for the role of synapsin II variants in susceptibility to schizophrenia.

A family-based association study of schizophrenia with polymorphisms at three candidate genes

Clinical researches have shown that there is a genetic contribution to the pathogenesis of schizophrenia. Recent studies have suggested that three genes neuropeptide Y (NPY), phosphoinositide-3-kinase class 3 (PIK3C3) and 14-3-3 eta chain gene (YWHAH) are probably associated with schizophrenia. To replicate these findings, we carried out a family-based study on a sample of 235 trios. Our results suggest that the polymorphisms at the NPY and YWHAH genes are unlikely to be linked with genetic susceptibility to schizophrenia. However, we found significant evidence of preferential transmission of the -432C allele of the PIK3C3 gene in the entire trios (Z=2.91, d.f.=1, P=0.0036) and the male probands trios (Z=2.66, d.f.=1, P=0.0079).

No association between the promoter variants of tumor necrosis factor alpha (TNF-α) and schizophrenia in Chinese Han population

Abstract An increasing amount of evidence suggests that the pathophysiology of schizophrenia is associated with activation of the immune system. Four studies have established an association of −308G/A polymorphism of tumor necrosis factor alpha (TNF-α), a cytokine involved in inflammatory processes, with schizophrenia [Mol. Psychiatry 6 (2001) 79; Mol. Psychiatry 8 (2003) 718; Schizophr. Res. 65 (2003) 19; Biol. Psychiatry 54 (2003) 1205]. In the present study, however, no significant positive association has been found between any individual SNP or haplotype constituted of the five promoter polymorphisms (−1031T/C, −863C/A, −857C/T, −308G/A and −238G/A) in the human TNF-α gene and schizophrenia (314 Chinese Han schizophrenic patients and 340 healthy control). A meta-analysis we did in this work, which is based on previous nine studies plus our own unpublished data including a total of 2399 schizophrenic patients (sporadic cases 2099, familial cases >505) and more than 3261 controls, failed to show significant difference of −308G/A distribution between patients and controls in both the whole sample and the pooled Asian sample. By contraries, the significant results in the pooled Caucasian sample imply an ethnic heterogeneity in −308G/A variation in the TNF-α gene in schizophrenia.

Comprehensive analysis of polymorphisms throughout GAD1 gene: a family-based association study in schizophrenia

Summary.Studies suggest that GAD1 gene is a functional candidate susceptibility gene for schizophrenia. In order to investigate the contribution of GAD1 gene to the etiology of schizophrenia in Chinese, we carried out a family-based association study between GAD1 gene and schizophrenia in 235 Chinese Han family trios. The GAD1 gene is comprehensively analyzed using a systematic mutation scan and the following-up association studies between common SNPs and schizophrenia in both single-locus and haplotype levels. Altogether, we have found 17 variants including 10 SNPs in 5′-flanking regions, 4 SNPs and one novel in-del in intronic regions and 2 SNPs (one novel SNP) in the 3′-untranslated region (UTR). Using the transmission disequilibrium test of the 9 common SNPs out of 17 variants, Significant evidence of SNP rs3791878-G allele in 5′-flanking region of GAD1 was preferentially transmitted to both the all offsprings of the trios (P = 0.0063, respectively; odds ratio = 1.83; 95% confidence interval: 1.26–2.65) and the male offsprings the trios (P = 0.0045, respectively; odds ratio = 2.21; 95% confidence interval: 1.37–3.56). Haplotype analysis suggested that rs3762556(C)–rs3791878(G)–rs6755102(C) is the major risky haplotype preferentially transmitted in both all the trios and male-offspring trios (Global P = 0.016 and 0.012, respectively). The gender-dependent of the risk of SNP rs3791878 suggest the complexity of GAD1 gene in schizophrenia. Given that the switch from G to T in SNP rs3791878 might cause the loss of ARNT and XBP1 transcriptional factor binding sites using a bioinformatics approach, our positive findings of this SNP support the hypothesis that the abruption of GAD1 gene is important to the risk of schizophrenia.