Top

Published in:

Open Access 01-08-2016 | Psychiatry and Preclinical Psychiatric Studies - Original Article

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

Authors: A. Marten H. Onnink, Barbara Franke, Kimm van Hulzen, Marcel P. Zwiers, Jeanette C. Mostert, Aart H. Schene, Dirk J. Heslenfeld, Jaap Oosterlaan, Pieter J. Hoekstra, Catharina A. Hartman, Alejandro Arias Vasquez, Cornelis C. Kan, Jan Buitelaar, Martine Hoogman

Published in: Journal of Neural Transmission | Issue 8/2016

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.

Available only for authorised users

Akutagava-Martins GC, Salatino-Oliveira A, Kieling CC, Rohde LA, Hutz MH (2013) Genetics of attention-deficit/hyperactivity disorder: current findings and future directions. Expert Rev Neurother 13:435–445. doi:10.1586/ern.13.30 CrossRefPubMed

Asherson P et al (2007) Confirmation that a specific haplotype of the dopamine transporter gene is associated with combined-type ADHD:674–677

Almeida Montes LG, Ricardo-Garcell J, Barajas De La Torre LB, Prado Alcántara H, Martínez García RB, Fernández-Bouzas A, Avila Acosta D (2010) Clinical correlations of grey matter reductions in the caudate nucleus of adults with attention deficit hyperactivity disorder. J Psychiatry Neurosci JPN 35:238–246CrossRefPubMed

Biederman J, Mick E, Faraone SV (2000) Age-dependent decline of symptoms of attention deficit hyperactivity disorder: impact of remission definition and symptom type. AJ Psychiatry 157:816–818CrossRef

Bradley RA, Srivastava SS (1979) Correlation in polynomial regression. Am Stat 33:11–14. doi:10.2307/2683059

Brookes KJ et al (2008) Association of ADHD with genetic variants in the 5′-region of the dopamine transporter gene: evidence for allelic heterogeneity. Am J Med Genet Part B, Neuropsychiatr Genet Off Publ Int Soc Psychiatr Genet 147B:1519–1523. doi:10.1002/ajmg.b.30782 CrossRef

Brüggemann D et al (2007) No association between a common haplotype of the 6 and 10-repeat alleles in intron 8 and the 3′UTR of the DAT1 gene and adult attention deficit hyperactivity disorder. Psychiatr Genet 17:121. doi:10.1097/YPG.0b013e32801231d4 CrossRefPubMed

Castellanos FX et al (2002) Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. JAMA 288:1740–1748CrossRefPubMed

Ciliax BJ et al (1999) Immunocytochemical localization of the dopamine transporter in human brain. J Comp Neurol 409:38–56CrossRefPubMed

Conners CK, Sitarenios G, Parker JD, Epstein JN (1998) The revised Conners’ Parent Rating Scale (CPRS-R): factor structure, reliability, and criterion validity. J Abnorm Child Psychol 4:257–268. doi:10.1023/A:1022602400621 CrossRef

Cortese S (2012) The neurobiology and genetics of attention-deficit/hyperactivity disorder (ADHD): what every clinician should know. Eur J Paediatr Neurol EJPN Off J Eur Paediatr Neurol Soc 16:422–433. doi:10.1016/j.ejpn.2012.01.009 CrossRef

Durston S et al (2005) Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls. Mol Psychiatry 10:678–685. doi:10.1038/sj.mp.4001649 CrossRefPubMed

Durston S, de Zeeuw P, Staal WG (2009) Imaging genetics in ADHD: a focus on cognitive control. Neurosci Biobehav Rev 33:674–689. doi:10.1016/j.neubiorev.2008.08.009 CrossRefPubMed

Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, Sklar P (2005) Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 57:1313–1323. doi:10.1016/j.biopsych.2004.11.024 CrossRefPubMed

Faraone SV, Bonvicini C, Scassellati C (2014a) Biomarkers in the diagnosis of ADHD—promising directions. Curr Psychiatry Rep 16:497. doi:10.1007/s11920-014-0497-1 CrossRefPubMed

Faraone SV, Spencer TJ, Madras BK, Zhang-James Y, Biederman J (2014b) Functional effects of dopamine transporter gene genotypes on in vivo dopamine transporter functioning: a meta-analysis. Mol Psychiatry 19:880–889. doi:10.1038/mp.2013.126 CrossRefPubMed

Franke B et al (2008) Association of the dopamine transporter (SLC6A3/DAT1) gene 9-6 haplotype with adult ADHD. Am J Med Genet Part B, Neuropsychiatr Genet Off Publ Int Soc Psychiatr Genet 147B:1576–1579. doi:10.1002/ajmg.b.30861 CrossRef

Franke B et al (2010) Multicenter analysis of the SLC6A3/DAT1 VNTR haplotype in persistent ADHD suggests differential involvement of the gene in childhood and persistent ADHD. Neuropsychopharmacology 35:656–664. doi:10.1038/npp.2009.170 CrossRefPubMed

Franke B et al (2012) The genetics of attention deficit/hyperactivity disorder in adults, a review. Mol Psychiatry 17:960–987. doi:10.1038/mp.2011.138 CrossRefPubMed

Frodl T, Skokauskas N (2012) Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects. Acta Psychiatr Scand 125:114–126. doi:10.1111/j.1600-0447.2011.01786.x CrossRefPubMed

Gizer IR, Ficks C, Waldman ID (2009) Candidate gene studies of ADHD: a meta-analytic review. Hum Genet 126:51–90. doi:10.1007/s00439-009-0694-x CrossRefPubMed

Greven CU et al (2015) Developmentally stable whole-brain volume reductions and developmentally sensitive caudate and putamen volume alterations in those with attention-deficit/hyperactivity disorder and their unaffected siblings. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2014.3162

Guadalupe T et al (2014) Measurement and genetics of human subcortical and hippocampal asymmetries in large datasets. Hum Brain Mapp 35:3277–3289. doi:10.1002/hbm.22401 CrossRefPubMed

Hong SB et al (2015) COMT genotype affects brain white matter pathways in attention-deficit/hyperactivity disorder. Hum Brain Mapp 36:367–377. doi:10.1002/hbm.22634 CrossRefPubMed

Hoogman M et al (2012) The dopamine transporter haplotype and reward-related striatal responses in adult ADHD. Eur Neuropsychopharmacol. doi:10.1016/j.euroneuro.2012.05.011

Jovicich J et al (2009) MRI-derived measurements of human subcortical, ventricular and intracranial brain volumes: Reliability effects of scan sessions, acquisition sequences, data analyses, scanner upgrade, scanner vendors and field strengths. Neuroimage 46:177–192. doi:10.1016/j.neuroimage.2009.02.010 CrossRefPubMedPubMedCentral

Kooij JJ, Buitelaar JK, van den Oord EJ, Furer JW, Rijnders CA, Hodiamont PP (2005) Internal and external validity of attention-deficit hyperactivity disorder in a population-based sample of adults. Psychol Med 35:817–827. doi:10.1017/S003329170400337X CrossRefPubMed

Larsson H, Chang Z, D’Onofrio BM, Lichtenstein P (2013) The heritability of clinically diagnosed attention deficit hyperactivity disorder across the lifespan. Psychol Med. doi:10.1017/S0033291713002493

Li D, Sham PC, Owen MJ, He L (2006) Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). Hum Mol Genet 15:2276–2284. doi:10.1093/hmg/ddl152 CrossRefPubMed

Madras BK, Miller GM, Fischman AJ (2005) The dopamine transporter and attention-deficit/hyperactivity disorder. Biol Psychiatry 57:1397–1409. doi:10.1016/j.biopsych.2004.10.011 CrossRefPubMed

Hoogman M et al. (submitted) Subcortical brain volume differences between patients with ADHD and healthy individuals across the lifespan: an ENIGMA collaboration

Maier S et al. (2015) Discrete global but no focal gray matter volume reductions in unmedicated adult patients with attention-deficit/hyperactivity disorder. Biol Psychiatry

Miller GA, Chapman JP (2001) Misunderstanding analysis of covariance. J Abnorm Psychol 110:40–48CrossRefPubMed

Moffitt TE et al (2015) Is adult adhd a childhood-onset neurodevelopmental disorder? Evidence from a four-decade longitudinal cohort study. AJ Psychiatry 172:967–977. doi:10.1176/appi.ajp.2015.14101266 CrossRef

Nakao T, Radua J, Rubia K, Mataix-Cols D (2011) Gray matter volume abnormalities in ADHD: voxel-based meta-analysis exploring the effects of age and stimulant medication. Am J Psychiatry 168:1154–1163. doi:10.1176/appi.ajp.2011.11020281 CrossRefPubMed

Onnink AM, Zwiers MP, Hoogman M, Mostert JC, Kan CC, Buitelaar J, Franke B (2014) Brain alterations in adult ADHD: effects of gender, treatment and comorbid depression. Eur Neuropsychopharmacol 24:397–409. doi:10.1016/j.euroneuro.2013.11.011 CrossRefPubMed

Patenaude B, Smith SM, Kennedy DN, Jenkinson M (2011) A Bayesian model of shape and appearance for subcortical brain segmentation. Neuroimage 56:907–922. doi:10.1016/j.neuroimage.2011.02.046 CrossRefPubMedPubMedCentral

Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA (2007) The worldwide prevalence of ADHD: a systematic review and metaregression analysis. AJ Psychiatry 164:942–948. doi:10.1176/ajp.2007.164.6.942 CrossRef

Proal E et al (2011) Brain gray matter deficits at 33-year follow-up in adults with attention-deficit/hyperactivity disorder established in childhood. Arch Gen Psychiatry 68:1122–1134. doi:10.1001/archgenpsychiatry.2011.117 CrossRefPubMedPubMedCentral

Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA (2002) Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 70:425–434CrossRefPubMed

Seidman LJ et al (2011) Gray matter alterations in adults with attention-deficit/hyperactivity disorder identified by voxel based morphometry. Biol Psychiatry 69:857–866. doi:10.1016/j.biopsych.2010.09.053 CrossRefPubMed

Shaw P et al (2007) Polymorphisms of the dopamine D4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 64:921–931. doi:10.1001/archpsyc.64.8.921 CrossRefPubMed

Shaw P et al (2014) Mapping the development of the basal ganglia in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 53(780–789):e711. doi:10.1016/j.jaac.2014.05.003

Shook D et al (2011) Effect of dopamine transporter genotype on caudate volume in childhood ADHD and controls. Am J Med Genet Part B Neuropsychiatr Genet Off Publ Int Soc Psychiatr Genet 156B:28–35. doi:10.1002/ajmg.b.31132 CrossRef

Shumay E, Chen J, Fowler JS, Volkow ND (2011) Genotype and ancestry modulate brain’s DAT availability in healthy humans. PloS One 6:e22754. doi:10.1371/journal.pone.0022754 CrossRefPubMedPubMedCentral

Simon V, Czobor P, Bálint S, Mészáros A, Bitter I (2009) Prevalence and correlates of adult attention-deficit hyperactivity disorder: meta-analysis. Br J Psychiatry J Mental Sci 194:204–211. doi:10.1192/bjp.bp.107.048827 CrossRef

Spencer TJ et al (2013) Functional genomics of attention-deficit/hyperactivity disorder (ADHD) risk alleles on dopamine transporter binding in ADHD and healthy control subjects. Biol Psychiatry 74:84–89. doi:10.1016/j.biopsych.2012.11.010 CrossRefPubMed

Tong JH et al (2015) An association between a dopamine transporter gene (SLC6A3) haplotype and ADHD symptom measures in nonclinical adults. Am J Med Genet Part B Neuropsychiatr Genet Off Publ Int Soc Psychiatr Genet 168:89–96. doi:10.1002/ajmg.b.32283 CrossRef

von Rhein D et al (2015) The NeuroIMAGE study: a prospective phenotypic, cognitive, genetic and MRI study in children with attention-deficit/hyperactivity disorder. Design and descriptives. Eur Child Adolesc Psychiatry 24:265–281. doi:10.1007/s00787-014-0573-4 CrossRef

Walhovd KB et al (2005) Effects of age on volumes of cortex, white matter and subcortical structures. Neurobiol Aging 26:1261–1270. doi:10.1016/j.neurobiolaging.2005.05.020 CrossRefPubMed

Title: Enlarged striatal volume in adults with ADHD carrying the 9-6 haplotype of the dopamine transporter gene DAT1
Authors: A. Marten H. Onnink
Barbara Franke
Kimm van Hulzen
Marcel P. Zwiers
Jeanette C. Mostert
Aart H. Schene
Dirk J. Heslenfeld
Jaap Oosterlaan
Pieter J. Hoekstra
Catharina A. Hartman
Alejandro Arias Vasquez
Cornelis C. Kan
Jan Buitelaar
Martine Hoogman
Publication date: 01-08-2016
Publisher: Springer Vienna
Published in: Journal of Neural Transmission / Issue 8/2016
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-016-1521-x

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

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

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 8/2016

Relationship between clozapine dose, serum concentration, and clinical outcome in children and adolescents in clinical practice

Interacting effect of MAOA genotype and maternal prenatal smoking on aggressive behavior in young adulthood

Emotion perception in adult attention-deficit hyperactivity disorder

Reduced functional connectivity to the frontal cortex during processing of social cues in autism spectrum disorder

Developing excellence in developmental psychiatry

Influence of 5-HTT variation, childhood trauma and self-efficacy on anxiety traits: a gene-environment-coping interaction study