Association study and a systematic meta-analysis of the VNTR polymorphism in the 3′-UTR of dopamine transporter gene and attention-deficit hyperactivity disorder

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.

The SLC6A3 gene polymorphism is related to the development of attentional functions but not to ADHD

“…Significant effect of the SLC6A3 genotype showed that subjects with the 9R allele, when compared to those from the 10R group, were characterized by less efficient orienting processes measured with the ANT task and obtained significantly worse results in the TEA-Ch subtests evaluating attentional switching (CL, OA). The association between SLC6A3 10R/10R or 10R/11R genotypes and better performance in cognitive tasks 50 appears counterintuitive, as the 10R allele has been reported as the risk allele for ADHD 51 , and related to poorer performance in cognitive tasks 27,28 . However, the debate on the role of 10R is far from being settled with studies reporting both opposite 29,51 and null 30 effects.…”

“…The association between SLC6A3 10R/10R or 10R/11R genotypes and better performance in cognitive tasks 50 appears counterintuitive, as the 10R allele has been reported as the risk allele for ADHD 51 , and related to poorer performance in cognitive tasks 27,28 . However, the debate on the role of 10R is far from being settled with studies reporting both opposite 29,51 and null 30 effects. In our study, we did not observe effects of genotype on sustained attention neither in the SART nor for the executive attention assessed with the ANT.…”

Genome-wide characterization of human minisatellite VNTRs: population-specific alleles and gene expression differences

“…Among the GO biological processes affected by these genes were neurogenesis (GO:0022008; FDR=3.62e −8 ), neuron differentiation (GO:0030182; FDR=2.52e −7 ), and neuron development (GO:0048666; FDR=4.31e −7 ). These processes are potentially related to other findings that have linked VNTRs to neurodegenerative disorders and cognitive abilities (36,39,51,52,53,54,55,56,57,58) (Supplementary material Population specific Go BP.xlsx). The GO term behavior (GO:0007610; FDR=2.22e −4 ) was also found, which could be related to the association of VNTR loci with aggressive behavior (101,102,103).…”

“…disease (39,52,53) and Huntington's disease (36,54), and other psychiatric conditions, such as PTSD (55), ADHD (56,57), depression (58), and addiction (59).…”

A Neurodevelopmental Model of Combined Pyrethroid and Chronic Stress Exposure

“…Several monoaminergic neurotransmitter circuits have been implicated in ADHD. Notably, genetic studies reveal variants in several genes related to the dopamine system are associated with ADHD, including dopaminergic receptors, enzymes, and transporters [4,5,6,7]. Variants in the dopamine receptor 5 gene ( DRD5 ) modulate age of ADHD onset, while variants in the dopamine transporter ( DAT1 ) gene predict severity of hyperactivity and impulsivity symptoms [8,9].…”