Shaoping Huang

An association study between cathechol-O-methyltransferase gene and mental retardation in the Chinese Han population.

Cathechol-O-methyltransferase (COMT) regulates the amount of dopamine in the prefrontal cortex (PFC). Substantial studies indicate a close relationship between COMT and several human psychotic disorders. The case-control method was used to study the association between mental retardation (MR) and genetic variants of COMT. Three single nucleotide polymorphisms (SNPs: rs4680, rs165656 and rs165774), in the cathechol-O-methyltransferase (COMT) gene, were genotyped by PCR-RFLP method. Individual SNP analysis shows significant differences only at SNP rs165656 for both genotype and allele frequency when comparing MR cases and controls (p=0.023, 0.011, respectively). Further haplotype analysis indicates that there are two haplotype sets, rs165656-rs4680 and rs165656-rs165774, which show statistical differences between MR cases and controls (global p=0.047, p=0.033, respectively). Our results suggest a positive association between the genetic variants of the COMT gene and MR in the Chinese Han population in the Qinba region.

Positive association of neuroligin-4 gene with nonspecific mental retardation in the Qinba Mountains Region of China.

Objective Neuroligin-4 is essential for proper brain function. Some studies indicate a close relationship between neuroligin-4 and several human psychiatric conditions. Methods The case–control method was used to study the association between nonspecific mental retardation (NSMR) and genetic variants of neuroligin-4 gene (NLGN4). Five single nucleotide polymorphisms (SNPs: rs5916271, rs7049300, rs6638575, rs3810686, and rs1882260) were genotyped by PCR-RFLP/SSCP method in the NLGN4. Results Individual SNP analysis shows significant differences at SNPs rs3810686 and rs1882260 for allele frequency when NSMR cases and controls [odds ratio (OR)=1.589, 95% confidence interval (CI)=1.035–2.438, χ2=4.53, df=1, P=0.033; OR=2.050, 95% CI=1.211–3.470, χ2=7.38, df=1, P=0.007, respectively] were compared. Further haplotype analysis indicates that there are two haplotype sets, rs3810686-rs1882260 and rs6638575-rs3810686-rs1882260, which show statistical differences between NSMR cases and controls (χ2=6.79, df=2, global P=0.034; χ2=9.29, df=2, global P=0.0096, respectively). Conclusion The results suggest a positive association between the genetic variants of the NLGN4 and NSMR in the Chinese children from Qinba Mountains Region.

Association Between a Functional COMT Polymorphism, Mental Retardation and Cognition in Qinba Area Children

Catechol-O-methyl transferase (COMT) plays an important role in the metabolism of neurotransmitters. Two alleles of the COMT gene as a result of a G/A transition in the exon 4 can lead to different COMT enzymatic activities. Much genetic research has revealed that this COMT functional polymorphism was related to human psychiatric disorders. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods were used to discern the relationships among the functional polymorphism of COMT, mental retardation (MR), and general cognitive ability of children. The results of the case-control analysis showed that there was no association between the frequencies of genotypes of COMT and MR (chi2=0.776, P>0.05) or between the frequency of COMT alleles and MR (chi2=0.335, P>0.05). COMT polymorphism was found in children whose intelligence quotient (IQ) was above 55. In normal children (IQ> or =85), the frequencies of high-activity allele COMTH and the homozygote genotype COMTHH were 60.98% and 79.28%, respectively. Both were higher than those of the borderline group (46.67% and 70.67%, 0.10 > P>0.05). Therefore, the result of this study suggests that this functional polymorphism is not an important risk factor for MR, but the COMTHH genotype may have a positive effect on cognitive performance in normal children in the Qinba area.

A Family-based Association Study of DIO2 and children mental retardation in the Qinba region of China

Deiodinase enzyme II (DIO2) has an important role in individuals’ thyroid hormones’ level, the development of central and peripheral nervous systems and characterized by mental retardation (MR). The DIO2 gene was genotyped by using five haplotype-tagging single-nucleotide polymorphisms (SNPs) in 157 Chinese MR high-density family pedigrees, including 452 nuclear families and >1460 persons. The single marker and haplotype analyses were performed by Family-based Association Tests (FBAT). Three SNPs had P-values <0.05 in at least one inherited model survived with the correction. Several haplotypes composed of these SNPs were also associated with MR. The in silico analyses identified that one of the SNPs, rs1388378, may be a functional SNP. However, further in vitro studies of this SNP should be considered in elucidating its effect on gene expression and the possible role in MR susceptibility.

A New Role for LOC101928437 in Non-Syndromic Intellectual Disability: Findings from a Family-Based Association Test

Non-syndromic intellectual disability (NSID) is mental retardation in persons of normal physical appearance who have no recognisable features apart from obvious deficits in intellectual functioning and adaptive ability; however, its genetic etiology of most patients has remained unknown. The main purpose of this study was to fine map and identify specific causal gene(s) by genotyping a NSID family cohort using a panel of markers encompassing a target region reported in a previous work. A total of 139 families including probands, parents and relatives were included in the household survey, clinical examinations and intelligence tests, recruited from the Qinba mountain region of Shannxi province, western China. A collection of 34 tagged single nucleotide polymorphisms (tSNPs) spanning five microsatellite marker (STR) loci were genotyped using an iPLEX Gold assay. The association between tSNPs and patients was analyzed by family-based association testing (FBAT) and haplotype analysis (HBAT). Four markers (rs5974392, rs12164331, rs5929554 and rs3116911) in a block that showed strong linkage disequilibrium within the first three introns of the LOC 101928437 locus were found to be significantly associated with NSID (all P<0.01) by the FBAT method for a single marker in additive, dominant and recessive models. The results of haplotype tests of this block also revealed a significant association with NSID (all P<0.05) using 2-window and larger HBAT analyses. These results suggest that LOC 101928437 is a novel candidate gene for NSID in Han Chinese individuals of the Qinba region of China. Although the biological function of the gene has not been well studied, knowledge about this gene will provide insights that will increase our understanding of NSID development.

A family-based association study of dopamine receptor D4 and mental retardation in Qinba region of China

Dopamine receptor D4 (DRD4) is activated by the neurotransmitter dopamine and links to many neurological and psychiatric conditions because of its close relationship with prefrontal cortex and other important brain regions. To explore the possibility that genetic variants of DRD4 gene predispose to children with mental retardation (MR), five target SNPs of DRD4 were selected and genotyped in the samples of 163 MR pedigrees from the Qinba region of China. Two SNPs (rs752306 and rs3758653) showed weak association with MR (the P values were 0.022 and 0.015 for dominant model, and 0.027 and 0.015 for recessive model, respectively). Although they did not bear the multiple testing corrections, the haplotype which contained rs3758653 exhibited a significant association with MR (global P values were 0.018 for dominant model and 0.028 for recessive model, respectively). The in silico analysis also indicated that rs752306 and rs3758653 would be biologically meaningful SNPs. Therefore, the present study suggested that the genetic variants of DRD4 gene may play an important role in human MR. Further investigations, such as confirmation with other independent samples and functional studies, may elucidate their effect on gene expression and MR susceptibility.

Polymorphisms in the DLG3 gene is not associated with non-syndromic mental retardation in the Chinese Han population of Qin-Ba mountain.

Discs-large-related 3 (DLG3), a member of the membrane-associated guanylate kinases (MAGUKs) protein family, playing an important role in regulating NMDA signal pathway and contributing to synaptic plasticity, may have an influence on the susceptibility of non-syndromic mental retardation (NSMR). To investigate the possible genetic contribution of DLG3 gene to the NSMR of Chinese Han population, we performed an association study of 556 subjects (118 NSMR, 116 borderline NSMR, and 322 controls in 275 males and 281 females) from Qin-Ba mountain region of Shaanxi province in the northwest of China by five common SNPs in the gene. The results showed that there was no positive association between the genetic variations of DLG3 and NSMR. In conclusion, the results of this study indicated that DLG3 did not associate with NSMR in Chinese Han population; however, further studies are needed.

Mental retardation and Xq12-Xq23: candidate loci for nonspecific mental retardation in the male population of the QinBa region.

Objectives The higher prevalence of nonspecific mental retardation (NSMR) presents an important socioeconomic and medical issue for families and the whole QinBa region in China. The obvious family aggregation and high heritability indicated that genetic causes play a role in the NSMR population in QinBa. This study discusses the relationship between Xq12–Xq23 region and NSMR in the QinBa area. Method We chose six short tandem repeats – DXS7132, DXS6979, DXS1191, DXS1230, DXS1072, and DXS6804, located in Xq12–Xq23 – and analyzed the distribution difference of their alleles between the NSMR and control boys. Results A significant allele distribution difference was found between NSMR and control boys (all P<0.05) for DXS7132, DXS1191, DXS1230, DXS1072, and DXS6804 but not for DXS6979. Conclusion Our results suggest that Xq12–Xq23 may be the candidate region where there are one or more loci, linked to NSMR in the QinBa region. Further study needs to be carried out for locating the gene responsible for NSMR in this region and a larger sample size and more genetic markers are needed.

Mutations of ARX and non-syndromic intellectual disability in Chinese population

Mutations of Aristaless-related homeobox (ARX) gene were looked as the third cause of non-syndromic intellectual disability (NSID), while the boundary between true disease-causing mutations and non-disease-causing variants within this gene remains elusive. To investigate the relationship between ARX mutations and NSID, a panel comprising six reported causal mutations of the ARX was detected in 369 sporadic NSID patients and 550 random participants in Chinese. Two mutations, c.428_451 dup and p.G286S, may be disease-causing mutations for NSID, while p.Q163R and p.P353L showed a great predictive value in female NSID diagnosis with significant associations (X2 = 19.60, p = 9.54e−6 for p.Q163R; X2 = 25.70, p = 4.00e−07 for p.P353L), carriers of these mutations had an increased risk of NSID of more than fourfold. Detection of this panel also predicted significant associations between genetic variants of the ARX gene and NSID (p = 3.73e−4). The present study emphasized the higher genetic burden of the ARX gene on NSID in the Chinese population, molecular analysis of this gene should be considered for patients presenting NSID of unknown etiology.

A family-based association study of PRSS12 and mental retardation in the Qinba mountain region of China.

Mental retardation (MR) is one of the most frequent diseases in children and young adults, affecting 2–3% of the general population. Although X-linked MR has been studied extensively in the last decade, little is known about the autosomal nonsyndromic mental retardation (NSMR), which is far more common than X-linked MR (Basel-Vanagaite, 2007). Molinari et al. (2002) reported the first autosomal NSMR gene, PRSS12, an abnormal functional mutation of which was likely involved in synapse maturation and neural plasticity, hence contributing toward NSMR. However, because of population stratification, this hypothesis needs further verification with other independent samples.