An association between a dopamine transporter gene (SLC6A3) haplotype and ADHD symptom measures in nonclinical adults

Abstract

Previous genetic studies have postulated that attention deficit hyperactivity disorder (ADHD) should be regarded as the extreme end of a set of behavioural traits that can be continuously measured in the general population. The current study adopted a quantitative trait approach to examine the relationship between dopamine gene variants and self-reported ADHD symptoms in 517 nonclinical adults. Although genetic associations with variants of both the dopamine transporter (DAT1; SLC6A3) and D4 receptor (DRD4) genes have been reliably reported in children, results in adults are less consistent. We probed two potentially functional variable number of tandem repeat (VNTR) polymorphisms in the 3 0 UTR and intron 8 of DAT1, the 10-repeat and 6-repeat alleles of which respectively form a haplotype (10/6 DAT1 haplotype) that is associated with childhood ADHD. We also genotyped the exon 3 VNTR of DRD4, the 7-repeat allele of which is also an established risk factor for childhood ADHD. Permutation analysis showed an influence of the 10/6 DAT1 haplotype on both CAARS-G and CAARS-H (DSM-IV ADHD Symptoms Total and ADHD Index respectively), such that ADHD symptom scores increased with each additional copy of the 10/6 DAT1 haplotype. This result survived corrections for multiple comparisons both at the level of genotype and phenotype. A nominal association with CAARS-G was also found for the 7-repeat allele of the DRD4 VNTR however this did not survive multiple comparison correction. Our results provide further support for the influence of variation in the 10/6 DAT1 haplotype and individual differences in ADHD symptoms in adults.

Maternal high-fat diet programming of the neuroendocrine system and behavior

“…Maternal inflammation has been previously shown to cause offspring deficits in latent and prepulse inhibition, along with decreased social and exploratory behavior (Smith et al, 2007), which are associated with dopamine dysfunction and mental health disorders such as schizophrenia and ASD. The increased inflammation that accompanies maternal HFD consumption likely impacts the dopaminergic system of offspring, causing increased risk of psychopathology as changes in the dopaminergic system are associated with disorders such as ASD(Bowton et al, 2014; Hamilton et al, 2015; Staal, 2014), ADHD (Hasler et al, 2015; Pan et al, 2015; Tong et al, 2015), schizophrenia (Howes et al, 2015; Slifstein et al, 2015; Sumiyoshi et al, 2014), anxiety (Agius et al, 2014; Lee et al, 2015), and depression (Clausius et al, 2009; Dunlop and Nemeroff, 2007). …”

5p deletions: Current knowledge and future directions

“…The dopaminergic system is involved in the pathophysiology of ADHD and DAT has been associated with the condition [Swanson et al, ], with mouse models that homozygously knockout DAT (DAT‐KO) displaying severe hyperactivity [Giros et al, ; Spielewoy et al, ; Pogorelov et al, ]. Because the most severe phenotypes occur when both alleles are deleted, individuals that are hemizygous for SLC6A3 may be uniquely sensitive to the detrimental effects of other ADHD‐susceptibility alleles that have been reported for this gene [Tong et al, ].…”

Enlarged striatal volume in adults with ADHD carrying the 9-6 haplotype of the dopamine transporter gene DAT1

“…More recent studies suggested that the 10-repeat allele might increase ADHD risk in children particularly in the context of a haplotype with the 6-repeat allele of another VNTR in intron 8 of the gene (Asherson et al 2007 ; Brookes et al 2008 ). A recent study also found an association between this 10-6 haplotype and ADHD symptom measures in nonclinical adults (Tong et al 2015 ), but association studies in clinical samples of adults with ADHD could not confirm this relationship (Brüggemann et al 2007 ) and reported an association of the 9-6 haplotype with adult ADHD (Franke et al 2008 , 2010 ). Together, these findings suggest a role for DAT1 in modulating the ADHD phenotype across the lifespan, with different associations depending on age and diagnostic status.…”