Dopamine transporter haplotype and attention-deficit hyperactivity disorder

Galili-Weisstub, Esti; Levy, Sharon; Frisch, Amos; Gross‐Tsur, Varda; Michaelovsky, Elena; Kosov, A; Meltzer, A; Goltser, T; Serretti, Alessandro; Cusin, Cristina; Darvasi, Ariel; Inbar, E; Weizman, Abraham; Segman, Ronnen H.

doi:10.1038/sj.mp.4001655

Cited by 25 publications

(15 citation statements)

References 16 publications

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“…Our results support the notion that VNTR alleles may either reflect LD with another functional variation or affect the regulation of DAT1 in combination with another functional variation. This is in line with previous reports showing that additional marker information is superior to VNTR single marker genotyping in detecting association with other neuropsychiatric disorders including ADHD [Galili-Weisstub et al, 2005], and bipolar disorder [Greenwood et al, 2001[Greenwood et al, , 2006.A prominent finding of this study is the role of traumatic life experience as risk factor for both SI and ND and its moderation, in the case of ND, by a C-9 haplotype derived from the DAT1_E15þ274 SNP and DAT1_VNTR. We previously reported a similar interaction between life experience and a polymorphism in the 5-HT6 receptor gene in which C267T genotype modified the effect of trauma on SI.…”

supporting

confidence: 89%

Why do young women smoke? IV. Role of genetic variation in the dopamine transporter and lifetime traumatic experience

Segman

Kanyas

Karni

et al. 2007

American J of Med Genetics Pt B

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Cigarette smoking is a complex behavior to which environmental, psychological, and genetic factors contribute. Applying a multifactorial model, we examined the role of genetic variation in the dopamine transporter (DAT1) in smoking initiation (SI) and nicotine dependence. The participants were female college students who had never smoked (n = 148) or had smoked daily for at least a year (n = 242). All participants provided extensive background information and completed a series of psychological instruments. Five SNPs were genotyped in the 3' and 5' regions of DAT1. Data were analyzed by logistic regression. The best fitting model for SI (P = 1.9 x 10(-17), Nagelkerke R2 = 0.33) revealed novelty seeking (OR = 1.14, P = 0.000004) and lifetime traumatic experience (OR = 2.3, P = 0.001) as risk factors and a DAT1_E15 + 274-DAT1_VNTR G-9 haplotype as protective (OR = 0.57, P = 0.03). In the model for nicotine dependence (P = 1.4 x 10(-8), Nagelkerke R2 = 0.27) novelty seeking was a risk factor (OR = 1.07, P = 0.03); the DAT1_E15+274-DAT1_VNTR G-9 haplotype (OR = 0.37, P = 0.001) and the interaction between trauma and a DAT1_E15 + 274-DAT1_VNTR C-9 haplotype (OR = 0.15, P = 0.01) were protective. Lifetime experience of trauma was associated with high nicotine dependence among non-carriers of the C-9 haplotype but not among carriers of this haplotype. These findings indicate that in the context of a multifactorial model, haplotypes in the 3' region of DAT1 influence the propensity of young women to initiate smoking as well as the severity of nicotine dependence once the habit is established. A haplotype in the 3' untranslated region of DAT1 modifies the effect of lifetime traumatic experience on the severity of nicotine dependence.

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supporting

confidence: 89%

Why do young women smoke? IV. Role of genetic variation in the dopamine transporter and lifetime traumatic experience

Segman

Kanyas

Karni

et al. 2007

American J of Med Genetics Pt B

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“…This hypothesis is supported by recent studies that found a stronger association of haplotypes containing the 10R rather than with the 10R allele alone, suggesting that the VNTR might not be the optimum polymorphism to ADHD investigations in all populations [Barr et al, 2001;Hawi et al, 2003;Feng et al, 2005;Galili-Weisstub et al, 2005]. Moreover, these approaches also suggest that the 3 0 -untranslated region of the DAT1 gene may play a role in gene functionality.…”

Section: Discussionmentioning

confidence: 55%

“…Despite this gene being highly polymorphic [Mazei-Robison et al, 2005;Greenwood et al, 2006] most association studies have concentrated on the 3 0 -untranslated region of the gene (3 0 -UTR) mainly in a variable number of tandem repeat (VNTR) polymorphism. Cook et al [1995] was the first who demonstrated an association between the 10 repeat allele of this VNTR and ADHD, a finding that has been replicated in several studies [Gill et al, 1997;Waldman et al, 1998;Daly et al, 1999;Rowe et al, 2001;Chen et al, 2003;Hawi et al, 2003;Galili-Weisstub et al, 2005]. However, around half of the investigations of this VNTR in ADHD have found no support for the association [Palmer et al, 1999;Holmes et al, 2000;Swanson et al, 2000;Todd et al, 2001;Smith et al, 2003;Feng et al, 2005;Langley et al, 2005;Hebebrand et al, 2006], including our own previous study [Roman et al, 2001].…”

mentioning

confidence: 84%

A promoter polymorphism (−839 C > T) at the dopamine transporter gene is associated with attention deficit/hyperactivity disorder in Brazilian children

Genro

Zeni

Polanczyk

et al. 2006

American J of Med Genetics Pt B

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The dopamine transporter (DAT) plays a key role in the regulation of dopaminergic neurotransmission and is also the major site of action for methylphenidate which is one of the main drugs used to treat attention deficit hyperactivity disorder (ADHD). Most association studies with ADHD have concentrated on the 3'-untranslated region of the gene (3'-UTR) mainly in a variable number of tandem repeat (VNTR) polymorphism, but these investigations have reported discordant results. In this study, we tested this VNTR polymorphism and an additional promoter polymorphism -839 C>T (Rs: 2652511) using family-based association analyses in a sample of 243 Brazilian ADHD children and adolescents and their parents. No significant linkage disequilibrium between the two polymorphisms was detected in this sample (D' = 0.56; P = 0.22). No evidence of association with the VNTR polymorphism was found. A significant association (P = 0.03) for biased transmission of the C allele at the -839 C>T polymorphism to ADHD children in the total sample was observed, which was strengthened when the analyses were restricted to the ADHD combined type (P = 0.004). Our results suggest a role for the promoter region of DAT1 gene in ADHD susceptibility in this Brazilian sample.

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“…Dropping either VNTR from the analysis led to a significant drop in significance of the haplotype association (3′UTR p=0.002, intron 8 p=0.005), indicating that both markers contribute significantly to the haplotype association. Several other groups have identified haplotype-specific associations with the 10-repeat allele in combination with another allele from a second marker (12)(13)(14), so the finding of haplotype-specific associations in this region is not unique to this study.…”

Section: Discussionmentioning

confidence: 65%

Confirmation That a Specific Haplotype of the Dopamine Transporter Gene Is Associated With Combined-Type ADHD

Asherson¹,

Brookes²,

Franke³

et al. 2007

AJP

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Objective:The primary purpose of this study was to confirm the association of a specific haplotype of the dopamine transporter gene and attention deficit hyperactivity disorder (ADHD), which could be one source of the heterogeneity seen across published studies. Method:The authors previously reported the association of ADHD with a subgroup of chromosomes containing specific alleles of two variable-number tandem repeat polymorphisms within the 3′ untranslated region and intron 8 of the dopamine transporter gene. They now report on this association in a sample of ADHD combined-type probands. Results:The original observations were confirmed, with an overall odds ratio of 1.4 across samples. Conclusions:These data challenge results of meta-analyses suggesting that dopamine transporter variation does not have an effect on the risk for ADHD, and they indicate that further investigation of functional variation in the gene is required. (Am J Psychiatry 2007; 164:674-677)At tention deficit hyperactivity disorder (ADHD) is one of the most prevalent and heritable behavioral disorders of childhood. The disorder is characterized by onset of age-inappropriate hyperactivity, impulsivity, and inattentiveness before the age of 7 years. A familial risk has been established, and twin studies demonstrate the important role of genetic factors, with heritability estimates in the range of 60%-90%. Efforts to identify genes associated with ADHD have been relatively fruitful by focusing on genes that regulate dopamine and related monoamine neurotransmitter systems (1).One of the most prominent findings in ADHD research has been the association between the 10-repeat allele of a 40-base-pair variable-number tandem repeat (VNTR) in the 3′-untranslated (3′UTR) region of the dopamine transporter gene (DAT1). Although the association has been reported in multiple studies since the initial report by Cook et al. in 1995 (2), there have also been many nonreplications (see references 1, 3, and 4 for reviews). Meta-analyses of available data have found the net effect across studies to be very small (3), and one recent study suggested no effect at all (5). However, several authors have also noted that the DAT1 data show significant evidence of heterogeneity across Caucasian data sets (5-7). The reason for this heterogeneity is not well understood.One possible contribution to heterogeneity between data sets might occur if the 10-repeat allele was tagging a nearby functional variant in partial linkage disequilibrium (LD) with the 10-repeat allele, with different levels of LD occurring in different populations. Alternatively, the 10-repeat allele may confer risk for ADHD only in combination with additional DNA variants in the DAT1 gene, and the specific combination might occur at different frequencies in various populations. Data supporting the role of alternative functional sites within DAT1 came from the recent study (8) of two distinct ADHD samples from the United Kingdom and Taiwan in which the association with ADHD was specific to a particular h...

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Dopamine transporter haplotype and attention-deficit hyperactivity disorder

Cited by 25 publications

References 16 publications

Why do young women smoke? IV. Role of genetic variation in the dopamine transporter and lifetime traumatic experience

Why do young women smoke? IV. Role of genetic variation in the dopamine transporter and lifetime traumatic experience

A promoter polymorphism (−839 C > T) at the dopamine transporter gene is associated with attention deficit/hyperactivity disorder in Brazilian children

Confirmation That a Specific Haplotype of the Dopamine Transporter Gene Is Associated With Combined-Type ADHD

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