Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in children, with a worldwide prevalence of 4–8% in school-matured youngsters and may continue during adulthood in 50–80% of cases (1–3). ADHD is described by symptoms of inattention, hyperactivity, and impulsivity and has a wide range of possible clinical presentations(4&5). Considering the importance of ADHD in children and its impact on their health and the fact that its exact etiology is not yet completely understood, evaluating and researching the possible genetic factors involved in it may help us to comprehend, prevent, and possibly cure this disorder better.
To find better ways to treat and decrease the risks of ADHD, scientists are researching cause(s) and risk factors. Although the etiology and risk factors for ADHD remain unclear, recent evidence suggests that genetics play a key role (6–10). The ADHD patients' genes have been evaluated and statistically, among these genes, DRD4, DRD5, DAT, DBH, SNAP-25, HTR1B, and 5-HTT seem to be involved in the etiology of ADHD (2 & 11–14).
The location of the serotonin transporter gene (SLC6A4; 5HTT) is on chromosome 17q. This gene encodes a carrier protein responsible for retaking serotonin from the synapse and returning it to presynaptic neurons, which has a crucial role in serotonergic activity regulation within the brain. Attention, memory, and voluntary activity are connected to areas of the brain such as the amygdala, hippocampus, thalamus, putamen, and anterior cortex, which are the areas that 5HTT is expressed (12).
Based on the available evidence, the 5HTT gene could play a significant role in ADHD. Studies have observed this gene's role in impulsivity's etiology and stimulus responses in hyperactivity (14).
The serotonin transporter gene (5-HTT/SLC6A4) is amongst the most researched genes in psychiatry and has been linked with a wide variety of diseases (11).
A study reported a significant association of the polymorphism within the promoter region of 5-HTT with scores on the Wender Utah Rating Scale, which is used to assess a history of ADHD-associated symptoms, indicating a higher frequency of the long variant allele in individuals with high scores (15).
One common polymorphism of the SLC6A4 gene is STin2 VNTR (Serotonin Transporter Intronic VNTR Enhancer), a 17-bp variable number of tandem repeats. Two primary alleles (called STin2.10 and STin2.12) and additional low-frequency alleles (called STin2.7 and STin2.9) are involved in this polymorphism (16).
Although some studies have reported the STin2.12 allele (a major allele of STin2 polymorphism) as a transcriptional enhancer, one research showed that STin2.12/STin2.12 homozygotes appear to show fewer serotonin transporters available inside the brain (16–18). In 2002, Zoroğlu et al. noted that the STin2.12/12 variant of VNTR polymorphismappears to be associated with an increased risk of ADHD (19).
In a study that evaluated the association between ADHD and polymorphism of the two regions of the 5-HTT gene [variable number of tandem repeats (VNTR) and 5-HTTLRR] 5-HTTLPR S/S genotype was significantly lower in the ADHD group but Homozygous and heterozygous L variant predominated in it. The VNTR STin2.12/12 genotype was found significantly less in the ADHD group but there was no significant difference between the frequency of the short (S), long(L), 10, and 12 alleles in the two groups. They suggested the lack of an S/S variant of 5-HTTLPR polymorphism or the STin2.12/12 variant of VNTR polymorphism as a risk factor for ADHD (19).
In a study evaluating the serotonin transporter gene in aggressive children with and without ADHD, the 10R allele of the 5HTT VNTR polymorphism was significantly less frequent in the study group and there was a significant link between 5HTTLPR and ADHD. Aggressive children were statistically more likely to have at least one copy of the long allele than were those without ADHD (20).
In a study evaluating the possible role of the 5-HTTLPR polymorphism in childhood disruptive behaviors using the haplotype relative risk design, a significant decrease in the short/short 5‐HTTLPR genotype was observed in the ADHD type III combined group. Comparing the allele frequencies yielded similar results (21).
A review article reports that when the 5-HTTLPR studies are combined, the pooled OR for the long allele is 1.31 (95% CI 1.09–1.59) (3).
Although there are many studies about ADHD, few have focused on the role of STin2 variants. Therefore, we aimed to analyze the molecular analysis of the STin2 variants of the SLC6A4 in children and adolescent with ADHD.