Relationship between VNTR polymorphisms of the human dopamine transporter gene and expression in post‐mortem midbrain tissue

Abstract

Attention deficit hyperactivity disorder (ADHD) is currently one of the most prevalent childhood behavioral disorders. The disorder is found to be highly heritable, suggesting a large genetic component. Association studies have repeatedly implicated the dopamine transporter (DAT1) gene, and in particular the 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism located in the 3'UTR of the gene. Inconclusive data has been generated from several earlier studies on the functional effects of this polymorphism. Therefore, there is call for further investigation and thus the focus on data described here from TaqMan RT-PCR assays. The expression levels of the DAT1 gene from post-mortem midbrain tissue was measured in relation to the polymorphism present at the 3'UTR VNTR, together with a further VNTR marker located within intron 8 of the gene (Int8 VNTR). The findings suggest that the presence of the 10-repeat allele of the 3'UTR VNTR, the 3-repeat of the intron 8 VNTR and both VNTR markers are correlated with increased levels of the DAT1 transcript in midbrain post-mortem tissue. Further work using linear regression (LR) shows agreement with the correlation analysis, and either nominal significance or a trend in that direction. Given the small sample size, bootstrapping-derived confidence intervals were calculated for the LR. These empirical analyses suggest that the 3'UTR VNTR to show a significant main effect on relative DAT1 expression. Furthermore, a significant effect was found for the combined model (3'UTR and Int8 VNTR markers) on expression. These data provide further evidence on the plausible molecular mechanism underlying the aetiology of the disorder.

DAT1 Gene Polymorphism in Children with Attention Deficit Hyperactivity Disorder

“…DAT1 is one of the most studied genes located on chromosome 5 (13). It is one of the main regulators of dopamine transport in the synaptic space, its expression is limited to the central nervous system and is mainly expressed in the midbrain dopamine neurons.…”

COMT and DAT1 genes are associated with hyperactivity and inattention traits in the 1993 Pelotas Birth Cohort: evidence of sex-specific combined effect

“…20 A study has demonstrated that DAT messenger RNA (mRNA) expression in postmortem midbrain tissue is higher for homozygous 10R carriers. 21 However, 2 metaanalyses of neuroimaging studies detected increased DAT activity for 9R carriers in striatal brain regions. 22,23 This result is intriguing, given that 3 meta-analyses have reported a small but significant association between the 10R allele and genetic susceptibility to ADHD.…”

Combination of DAT and DBH gene polymorphisms with a family history of alcohol use disorders increases the risk of withdrawal seizures and delirium tremens during alcohol withdrawal in alcohol-dependent men

“…(VNTR 40) в 3'-регионе гена наиболее изучен, близок к ко-дирующей области и может влиять на экспрессию (функ-циональная активность) гена [23], а вариабельность числа повторов -на уровень белка транспортера дофамина [24] и регулировать экспрессию гена, причем аллель А10 свя-зывают с повышенным уровнем экспрессии [25]. DAT VNTR связывают с алкогольной зависимостью [26,27], СОА -с судорожными припадками и алкогольным дели-рием [12,[28][29][30].…”

“…Показана досто-верная связь СОА с судорожными припадками с аллелем А9 (p=0,009) и группой генотипов (9.9+9.10) (р=0,02) ло-куса DAT 40bp VNTR, что подтверждает данные [28,29], причем частота генотипов (9.9+9.10) у пациентов с судо-рожными припадками оказалась максимальной по срав-нению с остальными вариантами осложнений СОА. С учетом возможной роли этого полиморфизма в регуля-ции экспрессии гена белка трансмембранного переносчи-ка дофамина [25] носительство аллеля А9 может приво-дить к сниженной экспрессии и снижению уровня самого белка трансмембранного переносчика дофамина [24] и, как следствие, уменьшению функциональной активности ДА-нейромедиации. Возможно, такое состояние способ-ствует развитию судорожного синдрома при отмене алко-голя у пациентов с алкогольной зависимостью.…”