TY - JOUR
T1 - Enlarged striatal volume in adults with ADHD carrying the 9-6 haplotype of the dopamine transporter gene DAT1
AU - Onnink, A. Marten H.
AU - Franke, Barbara
AU - van Hulzen, Kimm
AU - Zwiers, Marcel P.
AU - Mostert, Jeanette C.
AU - Schene, Aart H.
AU - Heslenfeld, Dirk J.
AU - Oosterlaan, Jaap
AU - Hoekstra, Pieter J.
AU - Hartman, Catharina A.
AU - Vasquez, Alejandro Arias
AU - Kan, Cornelis C.
AU - Buitelaar, Jan
AU - Hoogman, Martine
PY - 2016/8
Y1 - 2016/8
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Age Factors
KW - Attention Deficit Disorder with Hyperactivity/diagnostic imaging
KW - Cohort Studies
KW - Corpus Striatum/diagnostic imaging
KW - Dopamine Plasma Membrane Transport Proteins/genetics
KW - Female
KW - Humans
KW - Image Processing, Computer-Assisted
KW - Magnetic Resonance Imaging
KW - Male
KW - Middle Aged
KW - Phenotype
KW - Regression Analysis
KW - Young Adult
U2 - 10.1007/s00702-016-1521-x
DO - 10.1007/s00702-016-1521-x
M3 - Article
C2 - 26935821
SN - 0300-9564
VL - 123
SP - 905
EP - 915
JO - Journal of Neural Transmission
JF - Journal of Neural Transmission
IS - 8
ER -