Abstract
Attention-deficit hyperactivity disorder (ADHD) has been postulated to associate with dopaminergic dysfunction, including the dopamine transporter (DAT1). Several meta-analyses showed small but significant association between the 10-repeat allele in the DAT1 gene in 3′-untranslated region variant number tandem repeat polymorphism and child and adolescent ADHD, whereas in adult ADHD the 9-repeat allele was suggested to confer as risk allele. Interestingly, recent evidence indicated that the long-allele variants (10 repeats and longer) might confer to lower expression of the transporter in comparison to the short-allele. Therefore, we assessed here the association in samples consisting of families with child and adolescent ADHD as well as a case–control sample, using either the 10- versus 9-repeat or the long- versus short-allele approach. Following, we conducted a systematic review and meta-analysis, including family and case–control studies, using the two aforementioned approaches as well as stratifying to age and ethnicity. The first approach (10-repeat) resulted in nominal significant association in child and adolescent ADHD (OR 1.1050 p = 0.0128), that became significant stratifying to European population (OR 1.1301 p = 0.0085). The second approach (long-allele) resulted in significant association with the whole ADHD population (OR 1.1046 p = 0.0048), followed by significant association for child and adolescent ADHD (OR 1.1602 p = 0.0006) and in Caucasian and in European child and adolescent ADHD (OR 1.1310 p = 0.0114; OR 1.1661 p = 0.0061; respectively). We were not able to confirm the association reported in adults using both approaches. In conclusion, we found further indication for a possible DAT1 gene involvement; however, further studies should be conducted with stringent phenotyping to reduce heterogeneity, a limitation observed in most included studies.
Highlights
Attention-deficit hyperactivity disorder (ADHD), characterized by persistent symptoms of inattention, hyperactivity and impulsivity, is one of the most common psychiatric and behavioural disorders in children and adolescents, with more1 3 Vol.:(0123456789)than 5% of the paediatric population affected worldwide, and ADHD often persists into adulthood with a prevalence of 2.5–4.9% in adults (Thomas et al 2015; Polanczyk et al 2014)
In the case–control study a nominal significant association between DAT1 3′-untranslated region (UTR) variable number tandem repeats (VNTRs) long-allele and ADHD was observed
Family-based association analyses of the DAT1 3′-UTR VNTR long-allele as well as the 10-repeat versus 9-repeat allele yielded no significant association in the Zurich sample
Summary
Attention-deficit hyperactivity disorder (ADHD), characterized by persistent symptoms of inattention, hyperactivity and impulsivity, is one of the most common psychiatric and behavioural disorders in children and adolescents, with more1 3 Vol.:(0123456789)than 5% of the paediatric population affected worldwide, and ADHD often persists into adulthood with a prevalence of 2.5–4.9% in adults (Thomas et al 2015; Polanczyk et al 2014). A recent genome-wide association study of over 20,000 ADHD patients has identified 12 independent loci to be genome-wide significantly associated with ADHD (Demontis et al 2019) Genetic variations such as variable number tandem repeats (VNTRs) cannot be captured on such arrays, and conventional gene association studies may provide further information. One of these VNTRs (rs28363170), located on the dopamine transporter gene (SLC6A3 / DAT1) in the 3′ untranslated region (UTR), with the 10- and 9-repeat alleles that are most common (Doucette-Stamm et al 1995), were found to be associated with ADHD. No association has been detected in child and adolescent ADHD both in European and Asian ethnicity (Li et al 2006), whereas in adult ADHD a trend for association was found for 9-repeat allele carriers following a recent meta-analysis (Bonvicini et al 2016)
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