Haplotype-based Haplotype Relative Risk Research Articles

No association between the Ser9Gly polymorphism of the dopamine receptor D3 gene and schizophrenia: a meta-analysis of family-based association studies

BackgroundPrevious studies found that Ser9Gly (rs6280) might be involved in the occurrence of schizophrenia. However, no consist conclusion has yet been achieved. Compared to the case-control study, the family-based study took into account stratification bias. Thus, we conducted a meta-analysis of family-based studies to measure a pooled effect size of the association between Ser9Gly and the risk of schizophrenia.MethodsThe relevant family-based studies were screened using the electronic databases by the inclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to measure the correction between Ser9Gly polymorphism and schizophrenia susceptibility. Subgroup analysis was performed by stratification of ethnicity (i.e., East Asian, Caucasian, and other populations). Additionally, publication bias was evaluated by the funnel plot.ResultsAfter literature searching, a total of 13 family-based association studies were included, which contained 11 transmission disequilibrium test (TDT) studies with 1219 informative meiosis and 5 haplotype-based haplotype relative risk (HRR) studies. No statistical significance of the heterogeneity was detected in TDT and HRR studies. Thus, the pooled effect size was calculated under the fixed effect model. The results found that the association was significantly protective in East Asian in TDT studies (204 informative meiosis, OR = 0.744, 95% CI = 0.564–0.980, Z-value = − 2.104, p = 0.035).ConclusionsThe meta-analysis based on the family study found a protective association of Ser9Gly in East Asian. In future, large sample molecular epidemiology studies are needed to validate our findings.

The role of SLITRK6 in the pathogenesis of Tourette syndrome: From the conclusion of a family-based study in the Chinese Han population.

Tourette syndrome (TS) is a complex neuropsychiatric disorder coupled with obvious genetic heterogeneity. Studies in recent years have confirmed the association of SLITRK genes with sensory and neuropsychiatric diseases. To detect whether SLITRK6 is involved in the progress of TS, a family-based association study was performed to explore the possible genetic association between SLITRK6 and TS in the Chinese Han population. We genotyped 399 TS nuclear families trios, and then analyzed three tag SLITRK6 single nucleotide polymorphisms using the transmission disequilibrium test (TDT) haplotype relative risk (HRR) and haplotype-based haplotype relative risk (HHRR) methods. The TDT showed no statistically significant allele transfer for the three polymorphisms. The HRR and HHRR also showed a negative association. Despite the results suggesting that these polymorphisms may not be associated with susceptibility to TS in the Chinese Han population, we are still unable to determine the potential role of SLITRK6 in the pathogenesis of TS. Furthermore, the results still need to be confirmed in a larger sample size and in different populations.

Family-Based Analysis Combined with Case-Controls Study Implicate Roles of PCNT in Tourette Syndrome.

ObjectiveTourette syndrome (TS) is a childhood-onset neuro-developmental disorder and the genetic factors play an important role in its etiology. As pericentrin (PCNT) binds to disruption-in-schizophrenia 1 (DISC1) and is a risk factor for many mental illnesses, we aimed to investigate the effect of PCNT on TS in the Chinese Han population.MethodsFive tag single nucleotide polymorphisms (SNPs) (rs17371795, rs2839227, rs2839228, rs6518291 and rs9983522) in PCNT were screened in 407 TS nuclear family trios and 506 healthy persons by the TaqMan assays real-time. A common case–control study was designed to recognize differences in the genetic distributions. Additionally, we conducted a family based association study including transmission disequilibrium test, haplotype relative risk, and haplotype-based haplotype relative risk for these SNPs.ResultsThe allele frequencies revealed a significant difference of rs17371795, rs2839227 and rs2839228 between TS patients and controls (for rs17371795: P=0.002, OR=0.691, 95% CI=0.547–0.874; for rs2839227: P=0.001, OR=0.682, 95% CI=0.540–0.860; for rs2839228: P=0.028, OR=0.775, 95% CI=0.618–0.973) and genotypic distributions showed a positive association only in rs17371795 and rs2839227 (for rs17371795: P=0.010; for rs2839227: P=0.008). Moreover, only rs2839227 remained significant after Bonferroni correction (P<0.01).ConclusionOur study suggested genetic variability at the PCNT locus may be associated with TS risk in the Chinese Han population.

Investigation of a Possible Role for the Histidine Decarboxylase Gene in Tourette Syndrome in the Chinese Han Population: A Family-Based Study.

Tourette syndrome (TS) is a polygenic neuropsychiatric disease. Previous studies have indicated that dysregulation in the histaminergic system may play a crucial role in disease onset. In this study, we investigated the role of the histidine decarboxylase gene (HDC) in TS susceptibility in the Chinese Han population. After genotyping 241 TS nuclear families trios, we analyzed three tag HDC single nucleotide polymorphisms (rs854150, rs854151, and rs854157) in a family-based study using the transmission disequilibrium test (TDT) and haplotype relative risk (HRR). TDT showed no over-transmission in these SNPs across the HDC region (for rs854150: χ2 = 0.472, P = 0.537, OR = 1.097, 95%CI = 0.738–1.630; for rs854151: χ2 = 0.043, P = 0.889, OR = 1.145, 95%CI = 0.767–1.709; for rs854157:χ2 = 0.984, P = 0.367, OR = 1.020, 95%CI = 0.508–2.049). HRR also showed the same tendency (for rs854150: χ2 = 0.211, P = 0.646, OR = 1.088, 95%CI = 0.759–1.559; for rs854151: χ2 = 0.134, P = 0.714, OR = 0.935, 95%CI = 0.653–1.339; for rs854157:χ2 = 0.841, P = 0.359, OR = 1.206, 95%CI = 0.808–1.799). Additionally, the haplotype-based haplotype relative risk showed a negative association. Although these findings indicate an unlikely association between HDC and TS in the Chinese Han population, a potential role for HDC cannot be ruled out in TS etiology. Future research should investigate this more thoroughly using different populations and larger samples.

Association of rs1013940 polymorphism in SLC5A7 with Tourette syndrome in Chinese Han population

Objective To investigate the association between rs1013940 in SLC5A7 and Tourette Syndrome (TS) in Chinese Han population. Methods Polymorphism was genotyped in 401 TS nuclear families trios from china by real-time fluorescent quantitive PCR. Transmission disequilibrium test (TDT) and Haplotype relative risk (HRR) were used to analyze the association between the genetic distrbution of rs1013940 and TS and the results were verified by haplotype-based haplotype relative risk(HHRR). Results No transmission disequilibrium was found between rs1013940 in SLC5A7 and TS by TDT and HRR(TDT: χ2 =0.268, P=0.657, OR=0.728, 95%CI=0.366-1.451; HRR: χ2=0.111, P=0.739, OR=0.959, 95%CI=0.762-1.466). HHRR also indicated the same result (HHRR: χ2=0.276, P=0.599, OR=1.082, 95%CI=0.806-1.453). Conclusion The result reveals that there is no significant association between rs1013940 in SLC5A7 and TS in Chinese Han population. However, the results need to be further validated in different populations. Key words: SLC5A7; Tourette syndrome; Single nucleotide polymorphism; Transmission disequilibrium test

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.

Association between the polymorphism of C861G (rs6296) in the serotonin 1B receptor gene and Tourette syndrome in Han Chinese people.

Clinical, neuroimaging and other studies provided evidence that the dysfunction of the serotonin neurotransmitter system were found in Tourette syndrome (TS). This study is to explore the association between the polymorphism of C861G (rs6296) in HTR1B and TS in Han Chinese people. Two hundred ninety-nine TS patients (260 TS trios and 39 TS patients) and 388 healthy controls were collected. The genotype of HTR1B C861G was detected using Taqman probes. The case-control study and family-based study was used separately to study association between HTR1B C861G and TS in Han Chinese people. In case-control study, no statistically significant difference was found in the distribution of HTR1B C861G polymorphism between TS patients and controls (for genotype: χ2 = 3.408, P = 0.182; for allele: χ2 = 0.395, P = 0.530, OR = 0.934, 95%CI: 0.754-1.156). In family-based study, we observed nonsignificant over-transmission of the G861 allele in HTR1B to TS offspring using the transmission disequilibrium test (TDT), haplotype relative risk (HRR) and haplotype-based HRR (HHRR) (TDT χ2 = 0.410, P = 0.560; HRR = 1.151, χ2 = 0.421, P = 0.517, 95% CI: 0.753-1.759; HHRR = 0.919, χ2 = 0.467, P = 0.495, 95%CI: 0.720-1.172). Our study suggested that the polymorphism of HTR1B C861G is not a risk factor for TS in Han Chinese population. However, the result should be replicated in larger sample and different population.

Rs2043211 polymorphism in CARD8 is not associated with Tourette syndrome in a family-based association study in the Chinese Han population.

Previous studies showed that postinfectious autoimmunity and immune deficiency played an important role in the pathogenesis of Tourette syndrome. CARD8 can suppress activity of NF-ΚB activated by inflammatory mediators. To study the association between the rs2043211 polymorphism in CARD8 and susceptibility to Tourette syndrome in Chinese Han population. We recruited 279 patients diagnosed with Tourette syndrome and their parents for the study. Genotyping for CARD8 rs2043211 single-nucleotide polymorphism was performed using predesigned TaqMan single-nucleotide polymorphism genotyping assay. The genetic contribution of this single-nucleotide polymorphism was evaluated using transmission disequilibrium test and haplotype relative risk and the haplotype-based haplotype relative risk. The results of the allelic and genotypic distribution of rs2043211 polymorphism in CARD8 showed that both the Tourette syndrome patients group and the parents group are in Hardy-Weinberg equilibrium. No significant differences were observed in the mutant allele transmission (transmission disequilibrium test = 1.107, df = 1, p = 0.322). Results of haplotype relative risk analysis showed that no statistical significant difference was found in the genotypic frequency (AA/AT/TT) of Tourette syndrome patients passed from parents (haplotype relative risk = 1.152, χ(2 )= 0.494, p = 0.482, 95% CI = 0.777-1.708). Similarly, the analysis of haplotype-based haplotype relative risk was also not to support a statistically significant association in allelic frequency (A/T) of Tourette syndrome patients passed from parents (haplotype-based haplotype relative risk = 1.130, χ(2 )= 1.037, p = 0.308, 95% CI = 0.893-1.429). Our results suggest CARD8 might not play a role in the pathogenesis of Tourette syndrome in Chinese Han population. However, the results still need to be tested in a larger sample and different populations.

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.

Genetic association study between methyl-CpG-binding domain genes and schizophrenia among Chinese family trios.

This study investigates the genetic association between methyl-CpG-binding domain (MBD) gene polymorphisms and schizophrenia. A total of 200 family trios consisting of fathers, mothers, and affected offspring with schizophrenia were recruited as our participants. Four tag SNPs on MBD1 (rs125555, rs140689, rs140687, and rs140686), three tag SNPs on MBD2 (rs3876254, rs7614, and rs1145317), and three tag SNPs on MBD3 (rs7252741, rs4807934, and rs4807122) genes were tested using the PCR-based ligase detection reaction (PCR-LDR). The transmission disequilibrium test showed that rs1145317 on the MBD2 gene was significantly overtransmitted from parents to schizophrenic offspring (P=0.026). The haplotype-based haplotype relative risk test revealed that the haplotype rs7614-rs1145317 (A-G) was associated with schizophrenia (P=0.029). Our finding suggests that the MBD2 gene may be a susceptibility gene for schizophrenia.

Relationship between genetic polymorphism of MTHFR C677T and nonsyndromic cleft lip with or without cleft palate in Shanxi Province of China

To assess the association between polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene C677T locus and nonsyndromic cleft lip with or without cleft palate (NSCL/P) in Shanxi Province of China. Blood samples from 150 patients and their parents and 150 controls and their mothers were collected. The polymorphism of MTHFR gene C677T locus were analyzed by the methods of polymerase chain reaction and restriction fragment length polymorphism technique(PCR-RFLP). Case-control analysis, transmission-disequilibrium test(TDT) and haplotype-based haplotype relative risk analysis(HHRR) were used to study the correlation between the gene mutation and NSCL/P. Hardy-Weinberg equilibrium test results showed that, the offspring and mother genotype in the case group and the control group was not deviated from the Hardy-Weinberg law of genetic equilibrium (P > 0.05). The distribution of genotype CC, CT and TT in offspring had significant difference between the two groups (P < 0.05). In the offspring and mother of case group and the control group, the carriers of the TT genotype compared to CC genotype, the OR are greater than 1 and 95% CI do not contain 1 (offspring OR: 2.692, 95% CI: 1.319-5.495; mother OR: 2.469, 95% CI: 1.136-5.363). The distribution of C allele and T mutation gene were significantly different in the offspring and mother between the two groups (P < 0.05). The TDT test showed: chi2 = 4.507, P < 0.05. The HHRR test showed: P < 0.05. The single nucleotide polymorphism of MTHFR C677T locus is associated with the development of NSCL/P in Shanxi Province.

Associations of histone deacetylase-2 and histone deacetylase-3 genes with schizophrenia in a Chinese population

To explore the association between histone deacetylase-2 (HDAC2) and histone deacetylase-3 (HDAC3) gene polymorphisms and schizophrenia. A total of 208 family trios consisting of fathers, mothers and affected offspring with schizophrenia were recruited as our subjects. Four tag SNPs on HDAC2 (rs10499080, rs6568819, rs2499618 and rs13204445) and two tag SNPs on HDAC3 (rs11741808, rs2530223) genes were selected. The Mass ARRAY Assay Design software (Sequenom) was used to design amplification and allele specific extension primers. The Hardy-Weinberg equilibrium (HWE) for genotypic distributions was tested using the chi-square goodness-of-fit test. Allelic association for a single tag SNP was analyzed by using family-based association tests including the haplotype-based haplotype relative risk (HHRR) test and the transmission disequilibrium test (TDT). The genotypic distributions of HDAC2 SNPs rs6568819, rs2499618 and rs13204445 and HDAC3 SNPs rs11741808 and rs2530223 were all in Hardy-Weinberg equilibrium (P > 0.05). HHRR analysis revealed no associations between the SNPs and schizophrenia (P > 0.05). In addition, the TDT did not show any significant associations between HDAC2 and HDAC3 SNPs and schizophrenia (P > 0.05). HDAC2 and HDAC3 might not be associated with schizophrenia in the Chinese population.

Association between polymorphism of IRF6 rs2235371 locus and nonsyndromic cleft lip with or without cleft palate

To assess the association between polymorphism of interferon regulatory factor 6 (IRF6) gene rs2235371 locus and nonsyndromic cleft lip with or without cleft palate in Chinese population. Blood samples from 106 patients and their parents and 129 controls and their parents were collected. The polymorphism of IRF6 rs2235371 locus was determined with PCR-restriction fragment length polymorphism (PCR-RFLP) method. Case-control analysis, transmission disequilibrium test(TDT), haplotype-based haplotype relative risk analysis (HHRR) and family-based association test (FBAT) were carried out. By case-control analysis, no significant difference was found in the frequencies of GG, GA and AA genotypes of rs2235371 locus between the patient group and control group (P> 0.05), but there was a significant difference in allelic frequencies (P< 0.05). There was also a significant difference in genotype and gene frequencies of rs2235371 variant between family members from cleft lip only group and control group. However, in cleft lip with cleft palate group, no such difference was observed. TDT analysis suggested a linkage in the presence of disequilibrium (chi-square=5.56, P=0.024). Results of HHRR analysis (chi-square=5.115, P=0.024) and FBAT (Z=2.218, P=0.027) also indicated an association between IRF6 rs2235371 variant and the risk of NSCL with or without cleft palate. Genetic polymorphism of IRF6 gene rs2235371 locus is associated with NSCL with or without cleft palate.

Transmission disequilibrium test and haplotype analysis of the MCP-1 -2518G/A polymorphism with Tourette syndrome in Chinese Han trios

The purpose of this study was to investigate the association between MCP-1 -2518G/A polymorphism and Tourette syndrome (TS) in Chinese Hanpopulation. Wecollected 324 Chinese Han individuals from 108 TS nuclear families from Chinese Hanpopulation andemployed polymerase chain reactionand restrictionenzyme digestion for determining thegenotype of MCP-1 -2518G/A polymorphism. The data were analyzed using the transmission disequilibrium test, the genotype haplotype relative risk and haplotype-based haplotype relative risk. No biases were observed in the transmission of either of the two alleles (χ2 = 0.016, df = 1, P = 0.898) to the affected probands in the total sample. The analyses of transmission disequilibrium test, haplotype relative risk and haplotype-based haplotype relative risk did not indicate any associations at MCP-1 -2518G/A with TS. Our results suggest that MCP-1 -2518G/A is not associated with susceptibility of Tourette syndrome in Chinese Han population.

Association of IL8 −251A/T, IL12B −1188A/C and TNF-α −238A/G polymorphisms with Tourette syndrome in a family-based association study in a Chinese Han population

An earlier study indicated a possible relationship between Tourette syndrome (TS) and the cytokines. To explore this further, we analyzed the association of the polymorphisms, IL8 −251A/T, IL12B −1188A/C and TNF-α −238A/G, in the IL8, IL12B and TNF-α cytokine genes with TS in a Chinese Han population. A total of 108 patients diagnosed with TS and their parents were recruited for the study. The genetic contributions of the IL8 −251A/T, IL12B −1188A/C, and TNF-α −238A/G polymorphisms were evaluated using polymerase chain reaction and restriction enzyme digestion (PCR-RFLP) and haplotype relative risk (HRR) and transmission disequilibrium test (TDT) statistics. Our results revealed no significant associations between the IL8 −251A/T, IL12B −1188A/C and TNF-α −238A/G polymorphisms and TS (for IL8 −251A/T, TDT = 0.418, df = 1, P = 0.518; HRR = 2.17, X 2 = 3.000, P = 0.083, 95%CI: 0.900–5.230; for IL12B −1188A/C, TDT = 1.131, df = 1, P = 0.288; HRR = 1.27, X 2 = 0.35, P = 0.549, 95%CI: 0.580–2.790; for TNF-α −238A/G, TDT = 2.793, df = 1, P = 0.095; HRR = 0.27, X 2 = 2.90, P = 0.089, 95%CI: 0.061–1.217). This result was confirmed using haplotype-based haplotype relative risk (HHRR) which allows the two alleles in each genotype to be considered separately. Our data suggests that the IL-8 −251A/T, IL-12B −1188A/C and TNF-α −238A/G polymorphisms may not be associated with susceptibility to TS in the Chinese Han population studied. However, these results need to be replicated using larger datasets collected from different populations.

Family‐based studies indicate association of Engrailed 2 gene with autism in an Indian population

Engrailed 2 (EN2) is a homeobox transcription factor involved in the patterning of cerebellum during brain development. Linkage analysis and studies on knockout mice support EN2, located on chromosome 7q36.3, as a potential risk locus for autism. Candidate gene approach also suggested association of EN2 with autism spectrum disorder (ASD) in various populations. Here, we have investigated the association of five markers [rs3735653 (C/T) in exon 1; rs34808376 (GC/-) and rs6150410 (CGCATCCCC/-) in promoter region; rs1861972 (A/G) and rs1861973 (C/T) in the intron] of the gene with autism and ASD in Indian population using family-based approach. Probands have been recruited using Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) diagnostic criteria. Genotypic distributions conform to Hardy-Weinberg equilibrium. Genotyping analysis showed that the intronic single nucleotide polymorphisms (SNPs) are in complete linkage disequilibrium showing A-C and corresponding G-T allelic association. We observed significant preferential transmission of C allele of rs1861973 from the parents to affected offspring [transmission disequilibrium test (TDT): narrow diagnosis likelihood ratio statistics (LRS) = 6.63, P = 0.006; broad diagnosis LRS = 4.47, P = 0.05]. Interestingly, gender-based investigations showed significant transmission of C allele to the affected females [TDT: LRS = 7.36, P = 0.0025; haplotype-based haplotype relative risk (HHRR): LRS = 7.16, P = 0.02]. A maternal overtransmission for these alleles was also noted (TDT: LRS = 3.65, P = 0.036; HHRR: LRS = 2.81, P = 0.036). Bioinformatic analysis using TFSearch showed generation of Sp1 binding site in the presence of C allele. While Del-T haplotype formed from rs34808376-rs1861973 markers showed increased non-transmission, the Ins-C showed significant transmission suggesting protective effect and risk, respectively, conferred by these haplotypes in autism etiology. These results suggest positive genetic correlation of EN2 with autism in the Indian population.

No association of the A2756G polymorphism of methionine synthase gene with nonsyndromic cleft lip with or without cleft palate

To study the association of the A2756G polymorphism of the methionine synthase (MS) gene with nonsyndromic cleft lip with or without cleft palate (NSCL/P) in Chinese. Ninety-seven NSCL/P case-parent triads were selected as the case group. One hundred and four healthy subjects and their biological parents were selected as control group. For all subjects the A2756G polymorphism of the MS gene was examined by PCR-RFLP method. There was no statistical difference in genotype and allele frequencies for MS A2756G variants among family members between case group and control group. The GG genotype was not detected in the offsprings and mothers. The odds ratio and confidence interval of genotype AG in offspring, father and mother were 1.78(0.74-4.34), 0.80(0.36-1.79) and 1.26(0.54-2.93) respectively. The odds ratio and confidence interval of allele G in offspring, father and mother were 1.70(0.78-3.73), 0.88(0.49-1.75), and 1.23(0.59-2.60) respectively. The G allele did not increase the risk of NSCL/P. Transmission disequilibrium test (TDT) analysis yielded no evidence of linkage disequilibrium (chi-square=0.034,P>0.05). The results of haplotype-based haplotype relative risk (HHRR) analysis (chi-square=0.03,P>0.05) and family-based association tests (FBAT) (Z=0.186, P>0.05) failed to show association between the MS A2756G variant and the risk of NSCL/P. The A2756G polymorphism of the MS gene was not associated with NSCL/P in Chinese in the present study.

No causal role for the G482T and G689T polymorphisms in translation regulation of serotonin transporter (SLC6A4) or association with attention-deficit-hyperactivity disorder (ADHD)

Purpose of the study: The G482T and G689T polymorphisms in the 3′-UTR of serotonin transporter (SLC6A4) are implicated in translational regulation and allelic variants may mediate susceptibility to attention-deficit-hyperactivity disorder (ADHD). Accordingly, we examined influence of allelic variation on stable secondary structure formation and on seed sequences necessary for microRNA-binding. Furthermore, 90 ADHD cases from India were genotyped for these markers and tested for association with ADHD. Methods: The Mfold software was used for secondary structure predictions and miRNA-binding sequences were obtained from the PicTar database. Using a family-based study design we assessed genetic association by means of the haplotype-based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) statistics. With respect to G689T, previously published TDT data were included in pooled analysis. Result: Secondary structure analysis reveals that G482, U482, G689 and U689 conformers are energetically similar. Unlike G482, the U482 change maps within a loop and this conformer differs in free energy by ∼4.4 kcal/mol. While G482T is proximal to various miRNA-binding sequences, it is not part of the seed sequence for any of them. Thus, G482T and G689T polymorphisms do not regulate SLC6A4 translation in cis. From the HHRR ( χ 2 = 0.860, p = 0.353; R.R. = 1.11; 95% C.I. = 0.89–1.65 for G482T; χ 2 = 0.902, p = 0.342; R.R. = 1.17; 95% C.I. = 0.83–1.32 for G689T), TDT ( χ 2 = 1.33, p = 0.25; O.R. = 1.35; 95% C.I. = 0.94–1.94 for G482T; χ 2 = 1.45, p = 0.23; O.R. = 1.44; 95% C.I. = 0.94–2.22 for G689T) and pooled TDT ( χ 2 = 0.52, p = 0.47; O.R. = 1.05; 95% C.I. = 0.96–1.15) statistics we infer that these polymorphisms are not associated with risk of ADHD.

DAT1 3′‐UTR 9R allele: Preferential transmission in Indian children with attention deficit hyperactivity disorder

Genetic alterations in the dopaminergic system are frequently observed in association with attention deficit hyperactivity disorder (ADHD) and a 40 bp variable number of tandem repeats (VNTR) in the 3'-untranslated region (3'-UTR) of the dopamine transporter gene (DAT1) has been investigated in different populations. Both significant association and lack of association with the10 repeat allele (10R) of DAT1 VNTR have been reported. Objective of the present investigation was to examine association of this polymorphism with ADHD in Indian children. Genotypic data obtained from ADHD probands (n = 79), their parents (n = 148) and control individuals (n = 153) were analyzed for haplotype-based haplotype relative risk analysis (HHRR), transmission disequilibrium test (TDT), and family-based association test (FBAT). HHRR analysis revealed significant (P = 0.009) transmission of shorter alleles (< or =9R). TDT analysis of informative ADHD families (n = 32) also exhibited highly significant transmission of the shorter alleles (P = 0.002). Further analysis by FBAT showed preferential transmission (P = 0.019) of the 9R allele from parents to ADHD probands. It can be inferred from the data obtained that the DAT1 3'-UTR 9R allele may confer risk of ADHD in the Indian population.

A meta‐analysis of association studies between the 10‐repeat allele of a VNTR polymorphism in the 3′‐UTR of dopamine transporter gene and attention deficit hyperactivity disorder

The association between the 10-repeat allele of the dopamine transporter gene (DAT) and attention deficit hyperactivity disorder (ADHD) is uncertain. This study aimed to conduct a meta-analysis of the association between the 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region (UTR) of the DAT1 gene and ADHD. We pooled up 18 published transmission disequilibrium test (TDT) studies between the 40-base pair VNTR polymorphism in the3'-UTR of the DAT1 gene and ADHD. It included a total of 1,373 informative meioses, 7 haplotype-based haplotype relative risk (HHRR) studies, and 6 case-control-based association studies. There were statistically significant evidences for heterogeneity of the odds ratio in TDT and HHRR studies (P < 0.10), but not in case-control studies. The results of random effects model showed small but significant association between ADHD and the DAT1 gene in TDT studies (OR = 1.17, 95% CI = 1.05-1.30, chi-square = 8.11, df = 1, P = 0.004), but not in HHRR and case-control studies. The 10-repeat allele of a VNTR polymorphism in the 3'-UTR the DAT1 gene has a small but significant role in the genetic susceptibility of ADHD. These meta-analysis findings support the involvement of the dopamine system genes in ADHD liability variation. However, more work is required to further identify the functional allelic variants/mutations that are responsible for this association.