Transmission Disequilibrium Test Analysis Research Articles

Association Studies Between Regulatory Regions of IRF6/TP63 Genes and Nonsyndromic Oral Clefts.

To evaluate genetic variants within the regulatory regions of interferon regulatory factor 6 (IRF6) and TP63 for the etiology of nonsyndromic oral clefts risk factors. We performed allelic transmission disequilibrium test analysis on 5 eligible single-nucleotide polymorphisms (SNPs) and SNP haplotypes using the Family-Based Association Test. The study sample consisted of 334 case-parent trios of nonsyndromic oral clefts from Taiwanese population, separated into nonsyndromic cleft lip/palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO) groups. We found all 3 selected SNPs of the IRF6 gene show significant association with nonsyndromic oral clefts (rs2235371, P = 5.10E-07; rs642961, P = .00194; and rs77542756, P = 9.08E-07). Haplotype analyses identified 3 possible SNP combination haplotypes in the IRF6 gene and found that C-G-G showed significant undertransmission (P = .058), whereas 2 other haplotypes, T-G-A and C-A-G (P = 2.71E-06 and P = 5.00E-04, respectively), were significantly overtransmitted to the NSCL/P children but not to the NSCPO children. For the TP63 gene, we failed to detect evidence of nonsyndromic oral cleft association in the 2 SNPs within the TP63 large intron 1 region. We used a family-based analysis in 334 Taiwanese case-parent trios to evaluate selected SNPs of IRF6 genes and TP63 genes for a risk of orofacial clefting. This study provides additional evidence for an association between IRF6 and NSCL/P, including the genetic variants within the 5'-noncoding region of the gene. We also confirmed that NSCL/P and NSCPO individuals belong to different groups. For the TP63, our data did not favor the direct involvement of TAp63 isoforms during orofacial development.

OR4 High resolution haplotype analyses of classical HLA genes in families with multiple sclerosis

Aim HLA alleles are observed in specific haplotypes because of linkage disequilibrium between particular alleles. Multiple sclerosis (MS) has been associated with HLA genes and haplotypes. Our goal was to identify candidate HLA gene alleles and haplotypes that are susceptible or protective to MS. Methods We applied a high-throughput, high-resolution NGS method to type 11 HLA loci in 481 trio families comprising of 962 unaffected parental controls and 481 children diagnosed with MS. We developed an in-house computer program named HaplObserve that builds haplotypes by comparing offspring and parents HLA genotypes from nuclear families. HLA haplotypes were built from the trio families using HaplObserve that also allows tracing HLA allele/haplotype transmissions from the parents to the offspring. We dissected the extended haplotypes generated into smaller haplotypes and alleles, then explored associations with MS using standard transmission disequilibrium test (TDT) and multiallelic TDT analyses. Results We built a pipeline to systematically analyze HLA alleles and various segments of haplotypes using standard TDT and multiallelic TDT tests. Standard TDT and multiple allelic TDT showed that the DRB5∗01:01:01 ∼ DRB1∗15:01:01:01 haplotype was significantly predisposing (standard TDT: p 2.2e−16). We identified that DRB1∗01:01:01 ∼ DQB1∗05:01:01:03 (standard TDT: p = 8.63e−06), C∗04:01:01:01 ∼ B∗35:01:01:02 (p = 0.001645) and A∗02:01:01:01 ∼ C∗03:04:01:01 ∼ B∗40:01:02 (p = 0.008318) haplotypes were protective. Our analysis indicated that DRB1∗11:01:01:01 (p = 0.001738), B∗27:05:02 (p = 0.0004531), B∗38:01:01 (p = 0.0031953) and C∗07:04:01:01 (p = 0.004126) were protective. Conclusions We have shown the suitability of the HaplObserve to efficiently build haplotypes from NGS data in a large number of families, as well as the efficacy and power of TDT analysis for MS association studies. By comparing statistical significance of various haplotype segments, we were able to fine-map MS candidate alleles/haplotypes while eliminating false signals resulting from ‘hitchhiking’ alleles.

Association between a common missense variant in LOXL3 gene and the risk of non-syndromic cleft palate.

To investigate possible association between functional common variants in the lysyl oxidase like 3 gene and non-syndromic cleft palate we selected a common missense variant p.Ile615Phe (rs17010021), which was predicted to have a probably damaging effect on the lysyl oxidase like 3 enzyme. We genotyped 258 non-syndromic cleft palate case-parent triads of European origin and tested genetic association using the transmission disequilibrium test and log-linear regression analyses of genotypic relative risks and of parent-of-origin effects. The observed genotype frequency in parents was in Hardy-Weinberg equilibrium. Compared with wild-type Ile/Ile homozygotes, the relative risks for Phe/Phe homozygote infants was 6.87 (P value 3.0 × 10-3 ), while that for Ile/Phe heterozygotes was not significant. Assuming an autosomal recessive model, the relative risks for Phe/Phe genotype resulted 10.54 (P value 2.9 × 10-5 ), with a 3.6% population attributable risk. No parent-of-origin effect was observed. The identification in lysyl oxidase like 3 of a missense variant which under a recessive model associates with 10-fold increased risk of non-syndromic cleft palate supports the hypothesis that the genetic etiology of this congenital anomaly includes relatively uncommon recessive variants with moderate penetrance and located in genes which are also involved in syndromes that include cleft palate as part of the phenotype. Our findings require functional validation and replication in a larger independent genetic association study.

Study of genetic variants in the BDNF, COMT, DAT1 and SERT genes in Colombian children with attention deficit disorder

BackgroundAttention deficit and hyperactive disorder (ADHD) is highly prevalent among children in Bogota City. Both genetic and environmental factors play a very important role in the etiology of ADHD. However, to date few studies have addressed the association of genetic variants and ADHD in the Colombian population. ObjectivesTo test the genetic association between polymorphisms in the DAT1, HTTLPR, COMT and BDNF genes and ADHD in a sample from Bogota City. MethodsWe genotyped the most common polymorphisms in DAT1, SERT, COMT and BDNF genes associated with ADHD using conventional PCR followed by restriction fragment length polymorphism (RFLP) in 97 trios recruited in a medical center in Bogota. The transmission disequilibrium test (TDT) was used to determine the association between such genetic variants and ADHD. ResultsThe TDT analysis showed that no individual allele of any variant studied has a preferential transmission. ConclusionsOur results suggest that the etiology of the ADHD may be complex and involves several genetic factors. Further studies in other candidate polymorphisms in a larger sample size will improve our knowledge of the ADHD in Colombian population.

The rs10757278 Polymorphism of the 9p21.3 Locus in Children with Arterial Ischemic Stroke: A Family-Based and Case-Control Study

The association of 9p21.3 locus single nucleotide polymorphisms with arterial ischemic stroke in adults was demonstrated in many studies, but there are no studies in pediatric arterial ischemic stroke patients. We investigated whether the 9p21.3 locus polymorphism, namely rs10757278, is associated with the arterial ischemic stroke risk in children. The study group consisted of 335 individuals: 80 children with arterial ischemic stroke, their biological parents (n = 122), and 133 children (age and sex matched) without any symptoms of arterial ischemic stroke as a control group. The rs10757278 polymorphism was genotyped using the TaqMan® Pre-designed SNP Genotyping Assay (Applied Biosystems). Two different study design models were used: family-based association test (transmission-disequilibrium test) and case-control model. There were no statistically significant differences in the distribution of genotypes and alleles of the rs10757278 polymorphism between groups of children with arterial ischemic stroke and controls. The frequency of both transmitted alleles in transmission-disequilibrium test analysis was identical (50%). The A allele carrier state (AA+AG genotype) was more frequent in arterial ischemic stroke children with hemiparesis than in patients without this symptom (94.5% versus 68.0%, P = .004). There is no evidence to consider the 9p21.3 locus polymorphism as a risk factor for childhood arterial ischemic stroke.

Choline acetyltransferase may contribute to the risk of Tourette syndrome: Combination of family-based analysis and case–control study

Objectives: Twin and family analyses have revealed a genetic contribution to Tourette syndrome (TS) and post-mortem studies have raised the intriguing possibility of a reduction in cholinergic interneuronsin TS patients.Methods: We selected five tag SNPs (rs100824791, rs12264845, rs1880676, rs3793790 and rs3793798) of choline acetyltransferase (CHAT) from the Han Chinese population Hapmap database. Genotyping was conducted on 401 TS nuclear family trios and 405 control subjects. Transmission disequilibrium test (TDT) and haplotype relative risk (HRR) analyses were used to analyse the family-based study and a case–control study was also used to assess the genetic susceptibility to TS.Results: The results revealed a significant over-transmission of rs3793790 (TDT, χ2 = 9.121, P = 0.003; HRR, χ2 = 6.579, P = 0.01), while case–control analysis found no differences between the two groups (genotype, χ2 = 0.436, P = 0.804; allele, χ2 = 0.149, P = 0.700). Also, rs3793798 also indicated a positive association associated with TS (TDT, χ2 = 5.025, P = 0.028; HRR, χ2 = 0.250, P = 0.617). However, the other three SNPs investigated were found not to be associated with TS in both in the family-based and case–control studies.Conclusions: Our association analysis demonstrates that CHAT may contribute to TS susceptibility in the Han Chinese population. This gives strong support to the involvement of cholinergic interneurons in the aetiology of TS and reveals a potential therapeutic target.

P.1.a.018 - Gene expression in the brain of adult rats with behavioural alterations caused by neonatal exposure to the dipeptidyl peptidase-IV inhibitors diprotin A and sitagliptin

Attention deficit hyperactivity disorder (ADHD) is much more frequent in males than females, so several genes on the X chromosome (e.g., MAOA and MAOB) have been pursued as candidates for influencing risk for the disorder. HTR2C is also located on the X chromosome. In the current study, we examined the relationship between the C-759T and G-697C polymorphisms of HTR2C and ADHD in 488 Han Chinese families. Transmission Disequilibrium Test (TDT) analysis showed that the −759C allele, the −697G allele, and haplotype −759C/−697G were significantly over-transmitted to affected probands, while haplotypes −759C/−697C and −759T/−697C were under-transmitted. When families were divided into three subtypes according to the diagnosis of probands, the −697G allele and haplotype −759C/−697G were significantly over transmitted to ADHD-C probands, while haplotype −759T/−697C was under-transmitted to these individuals; however, no biased transmission of any allele or haplotype was observed for probands with ADHD-I, suggesting that different subtypes of ADHD have different genetic influences. Our findings highlight the need to explore the role of 5-HT2C receptor dysfunction in the pathogenesis of ADHD.

Estudio de variantes de los genes BDNF, COMT, DAT1 y SERT en niños colombianos con déficit de atención

BackgroundAttention deficit and hyperactive disorder (ADHD) is highly prevalent among children in Bogota City. Both genetic and environmental factors play a very important role in the etiology of ADHD. However, to date few studies have addressed the association of genetic variants and ADHD in the Colombian population. ObjectivesTo test the genetic association between polymorphisms in the DAT1, HTTLPR, COMT and BDNF genes and ADHD in a sample from Bogota City. MethodsWe genotyped the most common polymorphisms in DAT1, SERT, COMT and BDNF genes associated with ADHD using conventional PCR followed by restriction fragment length polymorphism (RFLP) in 97 trios recruited in a medical center in Bogota. The transmission disequilibrium test (TDT) was used to determine the association between such genetic variants and ADHD. ResultsThe TDT analysis showed that no individual allele of any variant studied has a preferential transmission. ConclusionsOur results suggest that the etiology of the ADHD may be complex and involves several genetic factors. Further studies in other candidate polymorphisms in a larger sample size will improve our knowledge of the ADHD in Colombian population.

Genetic Modifiers of Patent Ductus Arteriosus in Term Infants

To identify single-nucleotide polymorphisms (SNPs) in specific candidate genes associated with patent ductus arteriosus in term infants. We conducted an initial family-based, candidate gene study to analyze genotype data from DNA samples obtained from 171 term infants and their parents enrolled in the National Birth Defects Prevention Study (NBDPS). We performed transmission disequilibrium testing (TDT) using a panel of 55 SNPs in 17 genes. Replication of SNPs with P<.1 in the NBDPS trios was performed with a case-control strategy in an independent population. TDT analysis of the NBDPS trios resulted in 6 SNPs reaching the predetermined cutoff (P<.1) to be included in the replication study. These 6 SNPs were genotyped in the independent case-control population. A SNP in TGFBR2 was found to be associated with term patent ductus arteriosus in both populations after we corrected for multiple comparisons. (rs934328, TDT P=2×10(-4), case-control P=6.6×10(-5)). These findings confirm the importance of the transforming growth factor-beta pathway in the closure of the term ductus arteriosus and may suggest new therapeutic targets.

FADS1-FADS2 gene cluster confers risk to polycystic ovary syndrome.

Dyslipidemia is common in polycystic ovary syndrome (PCOS). This study was aimed to investigate whether fatty acid desaturase genes (FADS), a dyslipidemia-related gene cluster, are associated with PCOS. We scanned variations of FADS genes using our previous data of genome-wide association study (GWAS) for PCOS and selected rs174570 for further study. The case-control study was conducted in an independent cohort of 1918 PCOS cases and 1889 age-matched controls and family-based study was conducted in a set of 243 core family trios with PCOS probands. Minor allele frequency (allele T) of rs174570 was significantly lower in PCOS cases than that in age-matched controls (P = 2.17E-03, OR = 0.85), even after adjustment of BMI and age. PCOS subjects carrying CC genotype had higher testosterone level and similar lipid/glucose level compared with those carrying TT or TC genotype. In trios, transmission disequilibrium test (TDT) analysis revealed risk allele C of rs174570 was significantly over-transmitted (P = 2.00E-04). Decreased expression of FADS2 was detected in PCOS cases and expression quantitative trait loci (eQTL) analysis revealed the risk allele C dosage was correlated with the decline of FADS2 expression (P = 0.002). Our results demonstrate that FADS1-FADS2 are susceptibility genes for PCOS.

Further Evidence of GWAS Signals in Non-Syndromic Orofacial Clefts from Western Han Chinese

Background Non-syndromic orofacial clefts (NSOCs) are the major human congenital defects with a complex etiology. Several candidate genes and environmental factors, and their interactions were assumed for the susceptibility to NSOCs. Previous GWAS have identified numerous susceptible loci from different populations. However, few loci have been replicated among Western Han Chinese yet. This study aimed to validate this findings in NSOCs from Western Han Chinese population. Methods We selected two SNPs (rs4147811 and rs481931) on 1p22 and recruited 440 case-parent trios with NSOCs for this study. The SNPs were genotyped by using SNPscan method. To evaluate the association, we performed transmission disequilibrium test (TDT), parent-of-origin effect and gene-gene interaction analysis. Results Rs481931 G allele (Z=2.05, P=0.016) and G/G homozygotes (Z=2.62, P=0.009) were over-transmitted for NSCL/P. Rs4147811 C allele (Z=2.16, P=0.030) and C/C homozygotes (Z=2.29, P=0.020) were over-transmitted for NSCL/P. Rs481931 G allele was also paternal over-transmitted for NSCL/P (P=0.030) and maternal over-transmitted for NSCPO (P=0.036). Conclusions Our results confirmed the previous GWAS findings of these two SNPs in the etiology of NSOCs among Western Han Chinese.

Association of Genetic Polymorphisms in Genes Involved at the Branch Point of Nucleotide Biosynthesis and Remethylation with Down Syndrome Birth Risk: A Case-Control Study

DNA methylation and nucleic acid biosynthesis are two crucial phenomena for normal chromosomes segregation. From our earlier studies, MTHFR 677T individually and in combination with other gene polymorphisms, micronutrient deficiency and hyperhomocysteinemia was shown to be associated with risk in Down syndrome (DS) mothers. Remethylation and nucleic acid biosynthesis pathways are dependent on the activity of Methylenetetrahydrofolate reductase (MTHFR) and Thymidylate synthase (TYMS) respectively, competing for common substrate molecule 5,10-methelenetetrahydrofolate (5,10-MTHF). Role of MTHFD1 1958 G>A (affecting synthesis of 5,10-MTHF), MTHFR 677 C>T (affecting methylation), TYMS 5'UTR 28 bp repeat polymorphism and TYMS 3'UTR 6bp deletion polymorphism (affecting nucleic acid biosynthesis) in a cohort of 200 case mothers and 187 control mothers (also 146 case triads: mother, father, and child) were studied. We observed a significant association of MTHFR 677 C>T in a co-dominant model (p=0.0428) and dominant model (0.0194) as well as TYMS 5'UTR 28 bp repeat polymorphism in a recessive model (p=0.0005) and dominant model (0.0161). Genetic combination analysis revealed a significant additive effect of certain genotypic combinations (especially combination of MTHFR 677T and TYMS 2R alleles with other alleles or genotypes) in increasing risk. Weak linkage disequilibrium (LD) was observed between TYMS 5' and 3' UTR regions polymorphism in LD analysis. Transmission disequilibrium test (TDT) analysis revealed a consistent trend of preferential allele's transmission from parents. We concluded that genetic interaction of remethylation pathway and the nucleic acid metabolic pathway was significantly associated with risk factors for DS childbirth. However, replication studies are required to validate our observation in the population.

A Family-Based Association Study of CYP11A1 and CYP11B1 Gene Polymorphisms With Autism in Chinese Trios.

Autism spectrum disorder is a group of neurodevelopmental disorders with the higher prevalence in males. Our previous studies have indicated lower progesterone levels in the children with autism spectrum disorder, suggesting involvement of the cytochrome P-450scc gene (CYP11A1) and cytochrome P-45011beta gene (CYP11B1) as candidate genes in autism spectrum disorder. The aim of this study was to investigate the family-based genetic association between single-nucleotide polymorphisms, rs2279357 in the CYP11A1 gene and rs4534 and rs4541 in the CYP11B1 gene and autism spectrum disorder in Chinese children, which were selected according to the location in the coding region and 5' and 3' regions and minor allele frequencies of greater than 0.05 in the Chinese populations. The transmission disequilibrium test and case-control association analyses were performed in 100 Chinese Han autism spectrum disorder family trios. The genotype and allele frequency of the 3 single-nucleotide polymorphisms had no statistical difference between the children with autism spectrum disorder and their parents (P> .05). Transmission disequilibrium test analysis showed transmission disequilibrium of CYP11A1 gene rs2279357 single-nucleotide polymorphisms (χ(2)= 5.038,P< .001). Our findings provide further support for the hypothesis that a susceptibility gene for autism spectrum disorder exists within or near the CYP11A1 gene in the Han Chinese population.

The role of GRIN2B in Tourette syndrome: Results from a transmission disequilibrium study

BackgroundPrevious studies have indicated that dopamine interacts with glutamatergic projection neurons and that N-methyl-d-aspartate (NMDA) receptors might be involved in the pathogenesis of Tourette syndrome (TS). In this study, we examined whether two functional polymorphisms (rs1805476 and rs1805502) in the 3′UTR of the NMDA receptor 2B subunit gene (GRIN2B) were associated with TS in Chinese Han trios. MethodsDNA samples collected from 261 TS nuclear families were genotyped by PCR and direct sequencing technology. Haplotype relative risk (HRR), transmission disequilibrium test (TDT) and Haplotype-based haplotype relative risk (HHRR) analyses were performed on the genotype data. ResultsWe found an over-transmission of the A allele in rs1805476 and the T allele in rs1805502 from parents to their affected children, using the HRR (rs1805476: HRR=0.696, χ2=4.161, P=0.041, 95% CI: 0.491–0.986; rs1805502: HRR=0.697, χ2=3.954, P=0.047, 95% CI: 0.488–0.995). There was also strong evidence for a linkage between polymorphisms and TS using the TDT (rs1805476: TDT=5.447, df=1, P=0.024; rs1805502: TDT=5.233, df=1, P=0.027). LimitationsThe sample is small and the current population is just limited to the Chinese Han population. ConclusionsThese data support the hypothesis that GRIN2B might play a major role in the pathogenesis of TS in Chinese Han trios. However, these results need to be replicated using larger datasets collected from different populations.

Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder

Objectives. Dysregulation in neurotransmitter signalling has been implicated in the aetiology of attention deficit hyperactivity disorder (ADHD). Polymorphisms of the gene encoding dopamine beta hydroxylase (DBH) have been reported to be associated with ADHD; however, small sample sizes have led to inconsistency. Methods. We conducted transmission disequilibrium test analysis in 794 nuclear families to examine the relationship between DBH and ADHD. The effects of the ADHD-associated polymorphisms on gene expression were assessed by luciferase reporter assays in a human neuroblastoma cell line, SH-SY5Y. Results. A SNP within the 3′ untranslated region of DBH rs129882 showed a significant association with ADHD (χ2 = 9.71, p = 0.0018, OR = 1.37). This association remained significant after Bonferroni correction for multiple testing (p = 0.02). Further, allelic variation in rs129882 significantly impacted luciferase expression. Specifically, the C allele of the ADHD-associated rs129882 SNP produced a 2-fold decrease (p < 0.001) in luciferase activity. Conclusions. These data demonstrate for the first time that a DBH gene variant, rs129882, which confers risk to ADHD is also associated with reduced in vitro gene expression. Reduced DBH expression would be consistent with decreased conversion of dopamine to noradrenaline and thus with a relative hypo-noradrenergic state in ADHD.

Genetic effect of transforming growth factor alpha gene variants on the risk of nonsyndromic cleft lip with or without palate in korean populations.

To identify the contribution of TGFA gene variants to the risk of nonsyndromic cleft lip with or without palate (NS-CL±P). The samples were from 142 Korean NS-CL±P families and 119 control parents having nonaffected children. Minor allele frequency, heterozygosity, and χ(2) test for Hardy-Weinberg equilibrium were calculated for each of 10 selected single-nucleotide polymorphisms (SNPs). Ten SNPs were used to examine the association of case-parent trios with the transmission disequilibrium test (TDT) and conditional logistic regression models (CLRMs). Both allelic and genotypic TDTs for individual SNPs and sliding windows of haplotypes consisting of two to five SNPs were tested using family- and haplotype-based association test programs. Genotypic odd ratios (GORs) were obtained from CLRMs using STATA software. The parent-of-origin effect was evaluated for 10 SNPs, and a comparison between 218 case parents and 119 control parents was performed to investigate paternal and maternal ORs. Family-based TDT and haplotype analysis exhibited no statistical significance, but a relatively meaningful association was shown with rs3771497 (all P < .05; two SNPs, rs3771497 and rs3755377; five SNPs, rs3771497, rs3755377, rs3771485, rs11466212, and rs3771475). G/G homozygotes at rs3771497 have a significant decreased risk of NS-CL±P (GOR = 0.30, P < .01). No SNPs showed parent-of-origin effects. However, in the comparison between case parents and control parents, a single-marker analysis of maternal line showed a significant association with NS-CL±P in rs3771497 (P < .001, recessive model). The association of the TGFA gene with NS-CL±P in Korean populations was not clearly found. However, the etiologic effect of the TGFA gene on NS-CL±P patients should be investigated in terms of maternal genotype influence.

Do obsessive–compulsive disorder and Tourette syndrome share a common susceptibility gene? An association study of the BDNF Val66Met polymorphism in the Chinese Han population

Objectives. We explored the association between the BDNF Val66Met polymorphism and susceptibility to both obsessive–compulsive disorder (OCD) and Tourette syndrome (TS) in the Chinese Han population. Methods. Genotyping for the BDNF Val66Met polymorphism was performed in 321 OCD patients and 426 healthy control subjects and case–control association study data were analysed. Additionally, we evaluated the genetic contribution of this variant in 331 TS patients (including 267 TS trios) and 519 controls using the transmission disequilibrium test (TDT) and case–control study. Results. A statistically significant difference was found in the genetic contribution of the BDNF Val66Met polymorphism between both the OCD (χ2 = 7.50, P = 0.023 by genotype; χ2 = 6.67, P = 0.01 by allele) and TS (χ2 = 6.76, P = 0.03 by genotype; χ2 = 4.27, P = 0.04 by allele), and control groups. TDT and GHRR analysis for TS trios also showed a significant transform disequilibrium of this polymorphism (TDT: χ2 = 3.96, P = 0.05; HHRR: χ2 = 4.33 P = 0.04; GHRR: χ2 = 5.74, P = 0.02; χ2 = 0.98, P = 0.37). There was also a significant gender trend between patients and controls in female cases for OCD and in male cases for TS. Conclusions. Our study supports the involvement of the BDNF Val66Met polymorphism as a common genetic susceptibility for OCD and TS in the Chinese Han population, showing specific gender trends.

Association between Tourette syndrome and the dopamine D3 receptor gene rs6280.

Background:Tourette syndrome (TS) is a complex, heterozygous genetic disorder. The number of molecular genetic studies have investigated several candidate genes, particularly those implicated in the dopamine system. The dopamine D3 receptor (DRD3) gene has been considered as a candidate gene in TS. There was not any report about the association study of TS and DRD3 gene in Han Chinese population. We combined a case–control genetic association analysis and nuclear pedigrees transmission disequilibrium test (TDT) analysis to investigate the association between DRD3 gene rs6280 single nucleotide polymorphisms (SNPs) and TS in a Han Chinese population.Methods:A total of 160 TS patients was diagnosed by the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The DRD3 gene rs6280 SNPs were genotyped by TaqMan SNP genotyping assay technique in all subjects. We used a case–control genetic association analysis to compare the difference in genotype and allele frequencies between 160 TS patients and 90 healthy controls. At the same time, we used TDT analysis to identify the DRD3 gene rs6280 transmission disequilibrium among 101 nuclear pedigrees.Results:The genotype and allele frequency of DRD3 gene rs6280 SNPs had no statistical difference between control group (90) and TS group (160) (χ2 = 3.647, P = 0.161; χ2 = 0.643, P = 0.423) using Chi-squared test. At the basis of the 101 nuclear pedigrees, TDT analysis showed no transmission disequilibrium of DRD3 gene rs6280 SNPs (χ2 = 0; P = 1).Conclusions:Our findings provide no evidence for an association between DRD3 gene rs6280 and TS in the Han Chinese population.

Association of TUSC3 gene polymorphisms with non-syndromic mental retardation based on nuclear families in the Qinba mountain area of China.

TUSC3 interacts with the protein phosphatase 1 and magnesium ion transport system, which plays an important role in learning and memory. Abnormal conditions of learning and memory are common clinical characteristics of mental retardation (MR). However, the association of TUSC3 genetic polymorphisms with MR remains unknown. A total of 456 DNA samples including 174 nuclear families containing MR were collected in the Qinba mountain area of China. The genotypes of eight tag single nucleotide polymorphisms of TUSC3 were evaluated with traditional genetic methods. Family-based association tests, transmission disequilibrium tests (TDTs), and haplotype relative risk (HRR) analyses were performed to investigate the association between genetic variants of the TUSC3 gene and MR. The genetic polymorphisms rs10093881, rs6530893, and rs6994908 were associated with MR (all P values <0.05) based upon the results of single-site TDT and HRR analyses. The haplotype block consisting of rs6530893 and rs6994908, harboring the sixth exon of TUSC3, was also associated with MR (all P values <0.05). This study demonstrated an association between genetic polymorphisms of the TUSC3 gene and MR in the Qinba mountain area, the sixth exon of which might contribute to the risk of MR. However, further studies are needed on the causal mechanisms in this association.

Association of serotonin transporter linked polymorphic region 44 bp variable number of tandem repeat polymorphism with Tourette syndrome

To assess the association between the serotonin transporter linked polymorphic region (5-HTTLPR) 44 bp variable number of tandem repeat (VNTR) polymorphism and Tourette syndrome (TS) in ethnic Han Chinese trios. A total of 252 TS trios (patients and their parents) were recruited. Genetic contribution of the 5-HTTLPR 44 bp VNTR polymorphism was evaluated by genotyping, haplotype relative risk (HRR) analysis and transmission disequilibrium test (TDT) statistics. To enhance the efficiency of the test, haplotype-based HRR (HHRR) was also performed. The TDT, HRR and HHRR analyses have revealed a significant association of the 5-HTTLPR 44 bp VNTR polymorphism with TS, and provided a strong evidence for an over-transmission of L allele from parents to the affected children (TDT: χ² = 6.680, df= 1, P= 0.012; HRR: χ² = 9.345, P= 0.002, OR= 1.739, 95% CI for 1.218-2.483). For 204 male and 48 female TS trios, TDT and HRR were analyzed separately. The results showed a significant association between 5-HTTLPR and male TS (for males. TDT: χ² = 4.643, df= 1, P= 0.038; for females, TDT: χ² = 2.189, df= 1, P= 0.188). 5-HTTLPR may be the susceptibility gene for male TS patients among the Chinese Han population. However, the results need to be replicated in datasets collected from different populations.