Exon 3 polymorphisms of dopamine D4 receptor (DRD4) gene and attention deficit hyperactivity disorder in Chinese children.

Dopamine D4 receptor (DRD4) gene is implicated in the pathogenesis of attention deficit hyperactivity disorder (ADHD). The 7-repeat allele of the variable-number-of-tandem-repeat (VNTR) polymorphism in exon 3 has been reported to be associated with ADHD. However, studies in Chinese populations have yielded conflicting results. We therefore perform another study to investigate the association between ADHD and DRD4 gene polymorphism in Chinese children in Hong Kong. In this prospective family-based and case-control study during January-June 2004, we recruited consecutive Chinese children diagnosed with ADHD by DSM-IV and sex-matched controls admitted for acute upper respiratory infection, excluding those with perinatal brain insults, mental retardation, or neurological deficits. VNTR polymorphisms of the DRD4 gene were determined by standard PCR followed by agarose gel electrophoresis. Sixty-four ADHD cases (52 boys, 12 girls), their family members, and 64 normal controls were recruited. The 4-repeat allele (84.4%) and the 4/4-repeat genotype (70.3%) were the most prevalent. Both family-based and case-control analyses showed no association between ADHD and DRD4 gene polymorphisms (transmission dysequilibrium test (TDT): P = 0.91 and P = 0.33 for the 7-repeat and 4-repeat alleles, respectively; OR for the 7-repeat allele = 2.01 (95% CI 0.07-60.4, P = 0.66), OR for the 4-repeat allele = 1.51 (95% CI 0.80-2.85, P = 0.2)). However, the longer repeat alleles had a positive trend association with ADHD (P = 0.01) in the case-control analysis. We concluded that ADHD is not associated with a particular VNTR polymorphism of the DRD4 gene. Further studies are needed to clarify the role of repeat length of the VNTR region of the DRD4 gene in the pathogenesis of ADHD.     

Family-based association study between brain-derived neurotrophic factor gene polymorphisms and attention deficit hyperactivity disorder in UK and Taiwanese samples.

Brain-derived neurotrophic factor (BDNF) plays an important role in normal neuronal development. Several lines of evidence implicate the involvement of BDNF in attention-deficit hyperactivity disorder (ADHD). This study investigated the role of two common BDNF variants (Val66Met, C270T) in two samples of ADHD probands from the United Kingdom (n = 180) and Taiwan (n = 212). We found evidence of increased transmission of the C allele of the C270T in Taiwanese samples (TDT: chi(2) = 6.78, P = 0.009) and the two samples pooled together (TDT: chi(2) = 7.24, P = 0.007). No association was found between the Val66Met polymorphism and ADHD in either of the two populations. Analysis of haplotypes demonstrated a significant decreased transmission of haplotypes containing the Val66 allele and the 270T allele in the Taiwanese samples (TDT: chi(2) = 4.57, P = 0.032) and the pooled sample set (TDT: chi(2) = 5.82, P = 0.016). This study provides evidence for the possible involvement of BDNF in susceptibility to ADHD.     

Family-based association study between bipolar disorder and DRD2, DRD4, DAT, and SERT in Sardinia.

Association analysis of candidate genes may represent a strategy for clarifying the genetic components involved in bipolar disorder. Polymorphism at dopamine receptor genes DRD2, DRD4, and dopamine and serotonin transporter genes (DAT, SERT) has been used in previous association studies. Some authors have reported positive association between certain alleles and bipolar disorder, using the case-control design. In this family-based association study of DRD2, DRD4, DAT, and SERT, the distribution of parental nontransmitted alleles was compared with that of alleles transmitted to 53 Sardinian probands suffering from bipolar disorder. The transmission disequilibrium test (TDT) was used to detect any disproportionate transmission of alleles by heterozygous parents to affected children. No differences were found between the allele distribution of polymorphisms at DRD2, DRD4, DAT, and SERT in probands and parental nontransmitted chromosomes. TDT did not reveal any difference between transmitted and nontransmitted alleles. Our results do not support the hypothesis of a role for DRD2, DRD4, DAT, or SERT in bipolar disorder. Previously reported positive associations between DRD2 or SERT and bipolar disorder were conceivably due to stratification dependent on the case-control design, even though our sample might have failed to detect small associations due to limited power.     

Family-based association study between bipolar disorder and DRD2, DRD4, DAT,and SERT in Sardinia

Association analysis of candidate genes may represent a strategy for clarifying the genetic components involved in bipolar disorder. Polymorphism at dopamine receptor genes DRD2, DRD4, and dopamine and serotonin transporter genes (DAT, SERT) has been used in previous association studies. Some authors have reported positive association between certain alleles and bipolar disorder, using the case-control design. In this family-based association study of DRD2, DRD4, DAT, and SERT, the distribution of parental nontransmitted alleles was compared with that of alleles transmitted to 53 Sardinian probands suffering from bipolar disorder. The transmission disequilibrium test (TDT) was used to detect any disproportionate transmission of alleles by heterozygous parents to affected children. No differences were found between the allele distribution of polymorphisms at DRD2, DRD4, DAT, and SERT in probands and parental nontransmitted chromosomes. TDT did not reveal any difference between transmitted and nontransmitted alleles. Our results do not support the hypothesis of a role for DRD2, DRD4, DAT, or SERT in bipolar disorder. Previously reported positive associations between DRD2 or SERT and bipolar disorder were conceivably due to stratification dependent on the case-control design, even though our sample might have failed to detect small associations due to limited power. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:522–526, 1999. © 1999 Wiley-Liss, Inc.     

Family-based association study of serotonin transporter gene polymorphisms in attention deficit hyperactivity disorder: no evidence for association in UK and Taiwanese samples.

Five independent studies have reported associations between serotonin transporter gene (5-HTT) polymorphisms and attention deficit hyperactivity disorder (ADHD). Four studies found evidence for association between the long-allele of a 44-base pair insertion/deletion polymorphism (5-HTTLPR), one of the studies found association to a variable number tandem repeat within intron 2, another to the T-allele of a single base pair substitution in the 3'-untranslated regions and another reported preferential transmission of a haplotype of the three markers (long-allele/10-repeat-allele/T-allele). One further study found no evidence for these associations. We investigated the association of these three markers in two samples of ADHD patients from the United Kingdom (n = 197) and Taiwan (n = 212), using within-family tests of association. No association was found between any of the three markers in either of the two populations. Although we found some evidence for the preferential transmission of a rare haplotype (long-allele/9-repeat-allele/T-allele; chi2 = 4.5, P = 0.034), we concluded that this most likely occurred by chance factors alone.     

Association of dopamine D4 receptor (DRD4) polymorphisms with attention deficit hyperactivity disorder in Indian population.

Attention deficit hyperactivity disorder (ADHD) is a childhood onset neurobehavioral disorder. Several studies worldwide have implicated a possible association between ADHD and transmission of different polymorphisms of the dopamine D4 receptor gene (DRD4) in different ethnic groups. However, this is the first report on the transmission of different polymorphisms of DRD4 in Indian subjects. Association of 5' flanking 120-bp duplication, exon 1 12-bp duplication, and exon 3 48-bp variable numbers of tandem repeats (VNTR) were analyzed in 50 ADHD cases. Haplotype-based haplotype relative risk (HHRR) analysis and transmission disequilibrium test (TDT) were carried out to ascertain the association of these polymorphisms with the disorder. Linkage disequilibria (LD) between the polymorphisms were calculated using EH+ and 2LD programs. Our preliminary data showed lack of association between ADHD and transmission of the 5' flanking 120-bp duplication and exon 1 12-bp duplication. But, the transmissions of 6 and 7 repeat alleles of exon 3 48-bp VNTR showed significant association with ADHD. We have also examined the haplotype frequencies and biased transmission of one haplotype was observed in ADHD probands. LD analysis showed very strong disequilibrium between exon 1 12-bp duplication and exon 3 48-bp VNTR. Strong LD was also observed between the 5' flanking 120-bp duplication and exon 1 12-bp duplication. The observed association between higher repeat alleles of exon 3 48-bp VNTR and Indian ADHD children is consistent with some of the earlier reports.     

No association between VNTR polymorphisms of dopamine transporter gene and attention deficit hyperactivity disorder in Chinese children.

Dopamine transporter (DAT) gene is implicated in the pathogenesis of attention deficit hyperactivity disorder (ADHD). Previously a meta-analysis concluded no association between the variable-number-of-tandem-repeats (VNTR) polymorphisms of the DAT gene and ADHD. However, significant heterogeneity was present among studies and no conclusion can be drawn about the association in any single ethnicity given the small number of studies. There were also conflicting results in Chinese populations. We therefore perform the present study to investigate the association in Chinese children in Hong Kong. In this prospective family-based and case-control study during January to June 2004, we recruited consecutive Chinese children diagnosed with ADHD by DSM-IV criteria, their family members, and sex-matched controls admitted for acute upper respiratory infection, excluding those with perinatal brain insults, mental retardation, or neurological deficits. VNTR polymorphisms of the DAT gene were determined by standard PCR followed by agarose gel electrophoresis. Sixty-four ADHD cases (52 boys, 12 girls), their family members and 64 normal controls were recruited. The 10-repeat allele (92.6%) and the 10/10 repeat genotype (85.2%) were the most prevalent. Both family-based and case-control analyses showed no association between the DAT gene polymorphisms and ADHD (transmission dysequilibrium test: P = 0.99; odds ratio of 10-repeat allele = 0.89 (95%CI 0.35-2.28), P = 0.81; odds ratio of 10/10 repeat genotype = 0.69 (95%CI 0.26-1.84), P = 0.46). We concluded that VNTR polymorphism of the DAT gene is not associated with ADHD in Chinese children, and further studies are needed to clarify the polygenic and environmental influences for pathogenesis of ADHD.     

Investigation of dopamine receptor (DRD4) and dopamine transporter (DAT) polymorphisms for genetic linkage or association to panic disorder

Clinical and animal studies suggest a role for the neurotransmitter dopamine in anxiety states. In humans, one such condition is panic disorder, which is typified by recurrent panic attacks accompanied by anticipatory anxiety. Family, segregation, and twin studies imply a genetic component to the pathophysiology of panic disorder. In this study, we examined the genes for the D4 dopamine receptor (DRD4) and the dopamine transporter (DAT) using three common sequence polymorphisms. Two of these polymorphisms were in DRD4, a 12 base-pair insertion/deletion in exon 1 and a 48 base-pair repeat in exon 3, and the third was a 40 base-pair repeat in the 3' untranslated region of DAT. We employed a family-based design, using 622 individuals in 70 families, as well as 82 haplotype relative risk "trios". Subjects were genotyped at the polymorphic loci, and the data were analyzed for genetic association and linkage. There were no significant differences in allele frequencies or occurrence of genotypes within the triads for any of the three polymorphisms. No significant linkage between the DRD4 or DAT polymorphisms and panic disorder was observed in the multiplex families, using a variety of simulations for dominant and recessive models of inheritance. However, LOD scores of approximately 1.1 and 1.05 were observed for the DAT and DRD4 exon 1 loci, respectively. The results reported here provide little support for the role of these polymorphisms in panic disorder.     

No association of the dopamine DRD4 receptor (DRD4) gene polymorphism with attention deficit hyperactivity disorder (ADHD) in the Irish population

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent childhood-onset syndromes affecting 3%-6% of school-age children worldwide. Although the biological basis of ADHD is unknown, a dopaminergic abnormality has long been suggested. The dopamine D4 receptor gene (DRD4) has been mapped to chromosome 11p15.5 and has been implicated in predisposition to ADHD. Several independent genetic association studies have demonstrated increased frequency of the DRD4 7-repeat allele in ADHD cases compared with controls or excess transmission of the 7-repeat allele from parents to affected offspring. However, there have also been few negative studies. In this study we investigated 78 ADHD parent proband trios and 21 parent proband pairs for the transmission of the DRD4 alleles in HHRR and case control design. We found no significant differences in the frequency of the DRD4 alleles transmitted or not transmitted to ADHD cases from their parents nor when comparing case allele frequencies to ethnically matched controls. Therefore, it is unlikely that the DRD4 7-repeat allele is associated with ADHD in the Irish population.     

Genotypic interaction between DRD4 and DAT1 loci is a high risk factor for attention-deficit/hyperactivity disorder in Chilean families.

Attention-deficit/hyperactivity disorder, ADHD [MIM 126452], is a common, highly heritable neurobiological disorder of childhood onset, characterized by hyperactivity, impulsiveness, and/or inattentiveness. As part of an ongoing study of ADHD, we carried out a family-based discordant sib-pair analysis to detect possible associations between dopamine receptor D4 (DRD4) and dopamine transporter 1 (DAT1) polymorphisms and ADHD in Chilean families. Both loci individually classified as homozygotes or heterozygotes for the DRD4 7-repeat and DAT1 10-repeat alleles, did not exhibit genotype frequency differences between affected children and their healthy siblings (Fisher's exact test P > 0.25 in both cases). However, the simultaneous presence of both DRD4 7-repeat heterozygosity and DAT1 10 allele homozygosity were significantly higher (34.6%) in cases (26), compared with their unaffected siblings (25) (4%; Fisher's exact test P = 0.0096; odds-ratio, OR = 12.71). Increased density of dopamine transporter in ADHD brains, along with abundance of 7-repeat D4 receptors in prefrontal cortex, which is impaired in ADHD patients, make the observed gene-gene interaction worthy of further incisive studies.     

Association between tryptophan hydroxylase gene polymorphisms and attention deficit hyperactivity disorder in Chinese Han population.

Attention deficit hyperactivity disorder (ADHD) is a severe behavioral disorder in children known to have a substantial genetic component. Prior studies have implicated serotonin genes in the etiology of ADHD but have not examined tryptophan hydroxylase (TPH), which is a rate-limiting enzyme in serotonin biosynthesis. The current study examined the relationship between the A218C and A-6526G polymorphisms of the TPH gene and ADHD. Three hundred sixty-two unrelated ADHD probands and their biological parents were recruited to participate in this study. No biased transmission of any allele of the two polymorphisms was observed using TDT analysis. However, haplotype analyses found that the rare 218A/-6526G haplotype was significantly not transmitted to probands with ADHD (chi(2) = 4.4995, P = 0.034), regardless of subtype. Although this finding for ADHD in the Chinese Han population.     

The serotonin receptor HTR1B: gene polymorphisms in attention deficit hyperactivity disorder.

Serotonin plays an essential role in cognition, locomotor activity, and the regulation of sleep, pain, mood, and aggression. Polymorphisms of the HTR1B gene have been implicated in a variety of psychiatric disorders including attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). The objectives of this study were to: (i) expand our original investigation of the relationship between the HTR1B receptor gene and attention deficit/hyperactivity and; (ii) to investigate a possible association of obsessive behaviors/perfectionism and the HTR1B gene in a sample of 203 families with an ADHD proband. Six single nucleotide polymorphisms (SNPs) of the HTR1B receptor gene were genotyped using standard methods. Evidence for an association between the HTR1B gene and ADHD as a qualitative diagnosis, or the inattentive and hyperactive-impulsive quantitative traits was not supported by either TDT single marker analysis or haplotype analysis. In addition we did not find evidence to suggest an association between HTR1B and perfectionism in this sample of ADHD families.     

Meta-analysis of family-based association studies between the dopamine transporter gene and attention deficit hyperactivity disorder

INTRODUCTION: Molecular genetic research has mainly focused on the D4 dopamine receptor (DRD4) and the dopamine transporter (DAT) genes in attention-deficit hyperactivity disorder (ADHD). A recent meta-analysis showed that the DRD4 gene has a significant role in the vulnerability to ADHD. OBJECTIVES: With an equal number of positive and negative association studies between the 10-repeat of the DAT gene and ADHD, a meta-analysis is required for this other candidate gene. METHODS: We re-analysed the 13 published family-based association studies between ADHD and the DAT gene. Following recent recommendations, different biases were specifically assessed, such as the sample-size effect and the time effect. RESULTS: The meta-analysis showed no significant association between ADHD and the DAT gene (P = 0.21), but an important between-samples heterogeneity (P = 0.0009). Odds ratios above 1 are mostly observed in studies with a small number of informative transmissions, and decrease with larger sample size. CONCLUSIONS: Contrary to what was found for the DRD4 gene, the 10-repeat allele of the DAT gene has at most a minor role in the genetic susceptibility of ADHD. The different biases detected herein probably explain the initial impression of a significant impact of the DAT gene on hyperactivity.     

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.