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

Abstract

The dopamine transporter gene, DAT1 (SLC6A3), has been studied extensively as a candidate gene for attention-deficit/hyperactivity disorder (ADHD). Different alleles of variable number of tandem repeats (VNTRs) in this gene have been associated with childhood ADHD (10/10 genotype and haplotype 10-6) and adult ADHD (haplotype 9-6). This suggests a differential association depending on age, and a role of DAT1 in modulating the ADHD phenotype over the lifespan. The DAT1 gene may mediate susceptibility to ADHD through effects on striatal volumes, where it is most highly expressed. In an attempt to clarify its mode of action, we examined the effect of three DAT1 alleles (10/10 genotype, and the haplotypes 10-6 and 9-6) on bilateral striatal volumes (nucleus accumbens, caudate nucleus, and putamen) derived from structural magnetic resonance imaging scans using automated tissue segmentation. Analyses were performed separately in three cohorts with cross-sectional MRI data, a childhood/adolescent sample (NeuroIMAGE, 301 patients with ADHD and 186 healthy participants) and two adult samples (IMpACT, 118 patients with ADHD and 111 healthy participants; BIG, 1718 healthy participants). Regression analyses revealed that in the IMpACT cohort, and not in the other cohorts, carriers of the DAT1 adult ADHD risk haplotype 9-6 had 5.9 % larger striatum volume relative to participants not carrying this haplotype. This effect varied by diagnostic status, with the risk haplotype affecting striatal volumes only in patients with ADHD. An explorative analysis in the cohorts combined (N = 2434) showed a significant gene-by-diagnosis-by-age interaction suggesting that carriership of the 9-6 haplotype predisposes to a slower age-related decay of striatal volume specific to the patient group. This study emphasizes the need of a lifespan approach in genetic studies of ADHD.Electronic supplementary materialThe online version of this article (doi:10.1007/s00702-016-1521-x) contains supplementary material, which is available to authorized users.

Recent developments in the genetics of attention‐deficit hyperactivity disorder

“…There is some evidence that cortical thickness is a better trait for capturing the heritability of the brain's morphology . In children and adolescents with ADHD, thickness of the lateral prefrontal cortex and the cingulated cortex was increased in 98 cases with the 10R‐allele . Interestingly, homozygotes for the SLC6 A3 10R allele showed increased thickness in the right cingulated gyrus, but decreased cortical thickness in the lateral prefrontal cortex.…”

“…As studies most often use younger aged samples, it is nevertheless interesting to consider whether imaging genetics effects persist into adulthood or whether they change as a function of brain maturation, medication, or further psychiatric comorbidity. In a cross‐sectional structural magnetic resonance imaging (sMRI) study with childhood/adolescent ADHD, an adult ADHD case–control sample, and an adult population‐based sample, only the adult ADHD risk haplotype 9‐6 of SLC6A3 had a 5.9% larger striatum volume . While there are not yet studies sufficiently powered to look at the longitudinal course of striatal volume as a function of an interaction between medication and genotype, a recent study in an adolescent cohort revealed that the left striatal volume was reduced in participants with ADHD carrying one SLC6A3 10‐6 haplotype independent of medication status …”

Imaging genetics in neurodevelopmental psychopathology

“…A total of 76 records were retrieved for the ADHD search term, and a total of 16 research articles describing case-control studies were eligible for review according to our criteria. To those, we added three more recent papers from our own group ([Onnink et al, 2016;Sokolova et al, 2015;van der Meer et al, 2015]; Figure 1). Most of the studies investigated a single gene (all in Caucasians), and three studies investigated multiple genes (2 in Caucasians, 1 in Asians).…”

<b>Efeitos da sibutramina e do metilfenidato em modelo animal do Transtorno do Déficit de Atenção e Hiperatividade (TDAH) induzido em camundongos por etanol no período pós-natal</b>

“…(MADRAS et al, 2005;FRANKE et al, 2012). Além disso, a presença do haplótipo 9-6 já tem sido associada ao aumento no volume estriatal em indivíduos com TDAH (ONNINK et al, 2016).…”

“…O estriado tem participação na hiperatividade (FULTON, 1951;KELLY;MOORE, 1976;YOSHIDA et al, 1991) e pode ser divido em duas regiões, o núcleo caudado e o putâmen. Apesar de já se ter observado aumento da região pré-frontal e maior volume do núcleo caudado em indivíduos com TDAH (SEMRUD-CLIKEMAN et al, 2014;ONNINK et al, 2016), a maior parte dos estudos apontam diminuição dessa região (CASTELANOS et al, 1996;FILIPEK et al, 1997;HILL et al, 2003), e provavelmente isso se deve às diferentes metodologias empregas para quantificar os desvios volumétricos (IANNACCONE et al, 2015). Além destas diferenças anatômicas, disfunções no funcionamento do DAT estão envolvidas na hiperatividade (SPENCER et al, 2005;MADRAS et al, 2005).…”