Human dopamine transporter gene: coding region conservation among normal, Tourette's disorder, alcohol dependence and attention-deficit hyperactivity disorder populations

Vandenbergh, David J.; Thompson, Miles D.; Cook, Edwin H.; Bendahhou, E; Nguyen, Toan Van; Krasowski, Matthew D.; Zarrabian, D; Comings, David E.; Sellers, E. A.; Tyndale, Rachel F.; George, Susan R.; O’Dowd, Brian F.; Uhl, George R.

doi:10.1038/sj.mp.4000701

Cited by 127 publications

(94 citation statements)

References 41 publications

(44 reference statements)

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“…Repeated mutation screens and resequencing efforts have shown that nonsynonymous DAT1 SNPs are too infrequent to explain the ADHD linkage signal on 5p. [27][28][29][30] We summarize the major findings of our current study: (1) rs463379 (SNP 20) located in intron-4of DAT1 was significantly associated with ADHD (P = 0.0046) in our 329 families upon correction for multiple testing. (2) Furthermore, the global P-value for association to haplotypes in block two, which includes intron 4, was significant upon correction for all three tested blocks (P = 0.0048).…”

Section: Discussionmentioning

confidence: 71%

“…[27][28][29][30] Two of these studies, 29,30 that also included ADHD patients in addition to patients with other neuropsychiatric disorders, described novel synonymous and intronic variants; however, polymorphisms associated with ADHD were not detected. Mazei-Robinson et al 30 observed the nonsynonymous mutation A559V that had been described previously in an individual with bipolar disorder 28 in two affected sibs with ADHD.…”

Section: Introductionmentioning

confidence: 99%

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Association and linkage of allelic variants of the dopamine transporter gene in ADHD

et al. 2007

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Previously, we had reported a genome-wide scan for attention-deficit/hyperactivity disorder (ADHD) in 102 families with affected sibs of German ancestry; the highest multipoint LOD score of 4.75 was obtained on chromosome 5p13 (parametric HLOD analysis under a dominant model) near the dopamine transporter gene (DAT1). We genotyped 30 single nucleotide polymorphisms (SNPs) in this candidate gene and its 5 0 region in 329 families (including the 102 initial families) with 523 affected offspring. We found that (1) SNP rs463379 was significantly associated with ADHD upon correction for multiple testing (P = 0.0046); (2) the global P-value for association of haplotypes was significant for block two upon correction for all (n = 3) tested blocks (P = 0.0048); (3) within block two we detected a nominal P = 0.000034 for one specific marker combination. This CGC haplotype showed relative risks of 1.95 and 2.43 for heterozygous and homozygous carriers, respectively; and (4) finally, our linkage data and the genotype-IBD sharing test (GIST) suggest that genetic variation at the DAT1 locus explains our linkage peak and that rs463379 (P < 0.05) is the only SNP of the above haplotype that contributed to the linkage signal. In sum, we have accumulated evidence that genetic variation at the DAT1 locus underlies our ADHD linkage peak on chromosome 5; additionally solid association for a single SNP and a haplotype were shown. Future studies are required to assess if variation at this locus also explains other positive linkage results obtained for chromosome 5p.

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Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Association and linkage of allelic variants of the dopamine transporter gene in ADHD

et al. 2007

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“…26,27 This is consistent with suggestions that this polymorphism may affect the translational efficiency and thus the amount of protein expressed, resulting in less in vivo availability of the transporter. 28 In addition, the DAT1 10R has been associated with poor response to methylphenidate (MPH) in ADHD. 29,30 MPH has been shown to block the dopamine transporter in vivo, 31,32 and may therefore be more effective in those individuals who have more in vivo availability of the transporter.…”

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confidence: 99%

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

et al. 2005

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Genetic influences on behavior are complex and, as such, the effect of any single gene is likely to be modest. Neuroimaging measures may serve as a biological intermediate phenotype to investigate the effect of genes on human behavior. In particular, it is possible to constrain investigations by prior knowledge of gene characteristics and by including samples of subjects where the distribution of phenotypic variance is both wide and under heritable influences. Here, we use this approach to show a dissociation between the effects of two dopamine genes that are differentially expressed in the brain. We show that the DAT1 gene, a gene expressed predominantly in the basal ganglia, preferentially influences caudate volume, whereas the DRD4 gene, a gene expressed predominantly in the prefrontal cortex, preferentially influences prefrontal gray matter volume in a sample of subjects including subjects with ADHD, their unaffected siblings, and healthy controls. This demonstrates that, by constraining our investigations by prior knowledge of gene expression, including samples in which the distribution of phenotypic variance is wide and under heritable influences, and by using intermediate phenotypes, such as neuroimaging, we may begin to map out the pathways by which genes influence behavior. Investigators interested in the effect of genes on behavior face a challenge in that behavior is complex, and is likely affected by multiple genes, as well as gene-gene and gene-environment interactions. As such, the effect of any single gene on behavior is probably only small. Indeed, studies investigating the effect of genotype on behavior have reported modest associations. For example, Fossella et al 1 described the influence of four genes related to dopamine function on measures of executive attention and report small effect sizes. Furthermore, their effects were subtle in that not all aspects of executive attention were affected and that genes had differential effects. 1

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“…Several attempts have been made to characterize the variation within the DAT gene and to use the resultant SNPs to assess association with disease. 5,18,19 We have previously reported the analysis of 14 SNPs that span the gene from the distal promoter through the 3Ј UTR in a study of LD between DAT and bipolar disorder, which implicates the 3Ј end of DAT as the region of interest. 19 This study illustrates the inherent strengths and pitfalls of such LD studies using SNPs and SNPbased haplotypes and highlights the utility of characterizing the LD relationships between SNPs prior to assessing association with disease.…”

Section: Introductionmentioning

confidence: 99%

“…3 The DAT gene has been mapped to chromosome 5p15.3, 4 and its entire sequence, spanning nearly 60 kb, has recently been elucidated. 5 DAT has been pursued as a candidate gene in numerous disorders, and DAT sequence variants have been analyzed in attempts to determine its possible genetic contribution to these disorders. Studies of a 40-bp variable number of tandem repeats (VNTR) in the 3Ј untranslated region have revealed an allelic or genotypic association with bipolar disorder, 6 ADHD, 7,8 schizophrenia, 9 cocaine-induced paranoia, 10 alcoholism, 11 the severity of alcohol withdrawal, 12,13 and Parkinson's disease.…”

Section: Introductionmentioning

confidence: 99%

Segmental linkage disequilibrium within the dopamine transporter gene

et al. 2002

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The dopamine transporter gene (DAT) has been implicated in a variety of disorders, including bipolar disorder, attention-deficit hyperactivity disorder, cocaine-induced paranoia, Tourette's syndrome, and Parkinson's disease. As no clear functional polymorphism has been identified to date, studies rely on linkage disequilibrium (LD) to assess the possible genetic contribution of DAT to the various disorders. A better understanding of the complex structure of LD across the gene is thus critical for an accurate interpretation of the results of such studies, and may facilitate the mapping of the actual functional variants. In the process of characterizing the extent of variation within the DAT gene, we have identified a number of single nucleotide polymorphisms (SNPs) suitable for LD studies, 14 of which have been analyzed, along with a 3Ј repeat polymorphism, in a sample of 120 parent-proband triads. Calculations of pairwise LD between the SNPs in the parental haplotypes revealed a high degree of LD (P Ͻ 0.00001) in the 5Ј (distal promoter through intron 6) and 3Ј (exon 9 through exon 15) regions of DAT. This segmental LD pattern is maintained over approximately 27 kb and 20 kb in these two regions, respectively, with very little significant LD between them, possibly due to the presence of a recombination hotspot located near the middle of the gene. These analyses of the DAT gene thus reveal a complex structure resulting from both recombination and mutation, knowledge of which may be invaluable to the design of future studies.

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Human dopamine transporter gene: coding region conservation among normal, Tourette's disorder, alcohol dependence and attention-deficit hyperactivity disorder populations

Cited by 127 publications

References 41 publications

Association and linkage of allelic variants of the dopamine transporter gene in ADHD

Association and linkage of allelic variants of the dopamine transporter gene in ADHD

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

Segmental linkage disequilibrium within the dopamine transporter gene

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