title: 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.
authors.affiliation: Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands. martenonnink@gmail.com.|Department of Human Genetics (855), Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. martenonnink@gmail.com.
authors.forename: A Marten H
authors.identifier: 0000-0002-6181-9509
authors.initials: AM
authors.lastname: Onnink
authors.affiliation: Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Human Genetics (855), Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.affiliation: Department of Human Genetics (855), Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Kimm
authors.initials: K
authors.lastname: van Hulzen
authors.affiliation: Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
authors.forename: Marcel P
authors.initials: MP
authors.lastname: Zwiers
authors.affiliation: Department of Human Genetics (855), Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
authors.forename: Jeanette C
authors.initials: JC
authors.lastname: Mostert
authors.affiliation: Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
authors.forename: Aart H
authors.initials: AH
authors.lastname: Schene
authors.affiliation: Clinical Neuropsychology Section, Department of Clinical Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Heslenfeld
authors.affiliation: Clinical Neuropsychology Section, Department of Clinical Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Oosterlaan
authors.affiliation: Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Hoekstra
authors.affiliation: Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Catharina A
authors.initials: CA
authors.lastname: Hartman
authors.affiliation: Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Human Genetics (855), Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.|Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Alejandro Arias
authors.initials: AA
authors.lastname: Vasquez
authors.affiliation: Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Cornelis C
authors.initials: CC
authors.lastname: Kan
authors.affiliation: Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.|Karakter Child and Adolescent Psychiatric University Centre, Nijmegen, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Buitelaar
authors.affiliation: Department of Human Genetics (855), Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Martine
authors.initials: M
authors.lastname: Hoogman
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001289:Attention Deficit Disorder with Hyperactivity / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D015331:Cohort Studies; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000473:pathology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012044:Regression Analysis; D055815:Young Adult
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human
keywords: ADHD; DAT1 gene; Striatum; Volumetry