Tingwei Guo

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 (χ2 = 9.18, p = 0.00246). 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 (χ2 = 15.04, df 2, global p = 0.000549). This association remained significant after Bonferroni correction (p = 0.0016470). 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.

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.

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.

Evidence for association between single nucleotide polymorphisms in T complex protein 1 gene and schizophrenia in the Chinese Han population

Schizophrenia (MIM 181500) is a severe, common, and heterogeneous psychiatric disorder that affects 1% of the world’s population. The disorder is characterised by hallucinations, delusions, disorganised thoughts, and various cognitive and affective impairments. As a leading cause of psychiatric admissions, schizophrenia accounts for a considerable portion of healthcare expenditure and is a major public health concern. Family, twin, and adoption studies have shown that a genetic factor is associated with susceptibility to schizophrenia.1–4 The number and nature of genes that influence susceptibility to schizophrenic illness, as well as their interaction with environmental factors, are unknown. Despite decades of research on anatomical, physiological, and biochemical changes possibly associated with schizophrenia, insight into the aetiology is only fragmentary. Mapping of genes that contribute to the development of schizophrenic disorders by means of linkage and association studies may help identify and characterise causal factors. Although no single causative gene has been identified to date, several chromosomal loci with positive linkage results are under investigation as tentative susceptibility loci for schizophrenia, including chromosomes 6, 8, 10, 13, and 22 to remove obstacles of locus heterogeneity among sampled populations.5 Cao et al first reported possible linkage to 6q21–22 in two independent American samples of patients with schizophrenia: at locus D6S474 using sibling pair analysis in 63 independent sibling pairs (p = 0.00018) and at D6S424, which is about 14 centimorgan (cM) near D6S474 in a second sample of 87 independent sibling pairs (p = 0.00095).6 The same group reported modest support for linkage to D6S424 in a third sample in 1999 that consisted of 54 American and Australian sibling pairs.7 In a study with combined samples (141 independent sibling pairs), they obtained a non-parametric likelihood of odds (LOD) score of 3.82 (p = 0.000014).7 Several other studies also supported a susceptibility locus for schizophrenia on …

Distribution of apolipoprotein E allele frequencies of the Han Chinese in an iodine-deficient mountainous area

Background: Iodine deficiency is common in the Qinba mountainous area and fetal iodine deficiency disorder (FIDD) is endemic. Our previous study demonstrated that apolipoprotein E (ApoE) was a genetic risk factor for FIDD in the local area. Aim: In order to achieve a better understanding of the aetiology of iodine deficiency-based mental retardation in the Qinba mountainous area, we conducted further studies of ApoE allele frequencies obtained from the local population. Subjects and methods: A total of 818 samples from four counties in the iodine-deficient area were recruited for the study of the ApoE genotype and allele frequencies using the PCR-RFLP method, and were subsequently confirmed by sequencing. Results: The frequencies of ϵ2, ϵ3 and ϵ4 alleles of Han Chinese in Qinba were 9.67%, 81.30% and 9.03%, respectively. Furthermore, no significant differences in the distribution of ApoE (either genotype or allele frequencies) between any two subgroups divided according to location, sex and age (p > 0.05) were found. Surprisingly, however, we found a significant difference in the genotype and allele frequencies between Qinba and Shanghai (genotype: χ2 = 14.91, p = 0.0096; allele: χ2 = 15.07, p = 0.0009). Conclusion: The currently documented allele frequencies of ApoE in the Han Chinese population living in the open areas of China do not represent the distribution in the isolated Qinba mountainous area. The higher level of ϵ2 and ϵ4 allele frequencies in the Han Chinese living in the isolated Qinba area arise by chance or may result from genetic adaptation to an environment characterized by malnutrition and iodine deficiency, which may also contribute to the high incidence of mental retardation in these regions.

Variants in the RAB3A gene are not associated with mental retardation in the Chinese population

Mental retardation is a common form of cognitive impairment among children. The underlying causes of mental retardation are extremely heterogeneous, and include significant genetic factors. The coexistence of neuropathology and cognitive deficits supports the view that mental retardation is a disorder of brain development and plasticity. Rab3A, a member of the Rab small G protein family, is a key molecule in modulating basal neurotransmission and contributes to synaptic plasticity. The RAB3A gene is located on chromosome 19p13.11, near a region shown by a linkage study to be involved in the etiology of mental retardation. Because of both its function and chromosomal location, RAB3A is a potential candidate susceptibility gene for mental retardation. To investigate the possible genetic contribution of the RAB3A gene, we performed a case-control association study focused on the Han population of northwestern China using four common SNPs in the gene (rs7259012, rs17683539, rs2271882, and rs874628). Pairwise linkage disequilibrium analysis showed that the four SNPs were in linkage disequilibrium. However, there were no significant differences of either allele or genotype frequencies at any of the SNPs nor any significant differences in haplotype distributions between cases and controls. In conclusion, we have found no evidence for RAB3A conferring susceptibility on mental retardation in the Han Chinese population.

No observable relationship between the ACE gene insertion/deletion polymorphism and psychometric IQ and psychomotor ability in Chinese children.

The primary aim of this study was to investigate the impact of the angiotensin I-converting enzyme gene (ACE) on general cognitive ability, specific cognitive ability and psychomotor function in Chinese children. In total, 450 children completed both C-WISC tests and ACE I/D genotyping. Of these, 320 children were examined using psychomotor tests. The quantitative traits of psychometric IQ and psychomotor abilities were calculated to determine whether there were any significant differences related to their ACE genotypes on the basis of an analysis of variance. F test results showed no significant differences with regard to any aspect of intelligence or psychomotor performance relative to the various ACE I/D genotypes (all p > 0.05). Our study suggests that ACE I/D do not have a measurable impact on any aspects of IQ or psychomotor ability and that psychomotor ability correlates well with IQ in Chinese children.