Hostname: page-component-7479d7b7d-qlrfm Total loading time: 0 Render date: 2024-07-11T22:09:18.509Z Has data issue: false hasContentIssue false
  • English
  • Français

Influence of DAT1 and COMT variants on neural activation during response inhibition in adolescents with attention-deficit/hyperactivity disorder and healthy controls

Published online by Cambridge University Press:  15 June 2015

D. van Rooij ,
P. J. Hoekstra ,
J. Bralten ,
M. Hakobjan ,
J. Oosterlaan ,
B. Franke ,
N. Rommelse ,
J. K. Buitelaar  and
C. A. Hartman
D. van Rooij*
Affiliation:
Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Radboud University, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands
P. J. Hoekstra
Affiliation:
Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
J. Bralten
Affiliation:
Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands
M. Hakobjan
Affiliation:
Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands
J. Oosterlaan
Affiliation:
Department of Neuropsychology, VU University Amsterdam, Amsterdam, The Netherlands
B. Franke
Affiliation:
Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands Department of Psychiatry, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands
N. Rommelse
Affiliation:
Department of Psychiatry, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands Karakter Child and Adolescent Psychiatry, Radboud University Center Nijmegen, Nijmegen, The Netherlands
J. K. Buitelaar
Affiliation:
Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands Karakter Child and Adolescent Psychiatry, Radboud University Center Nijmegen, Nijmegen, The Netherlands
C. A. Hartman
Affiliation:
Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
*
*Address for correspondence: D. van Rooij, M.Sc., Department of Psychiatry, University of Groningen, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. (Email: d.vanrooij@fcdonders.ru.nl)
Get access Rights & Permissions [Opens in a new window]

Abstract

Background.

Impairment of response inhibition has been implicated in attention-deficit/hyperactivity disorder (ADHD). Dopamine neurotransmission has been linked to the behavioural and neural correlates of response inhibition. The current study aimed to investigate the relationship of polymorphisms in two dopamine-related genes, the catechol-O-methyltransferase gene (COMT) and the dopamine transporter gene (SLC6A3 or DAT1), with the neural and behavioural correlates of response inhibition.

Method.

Behavioural and neural measures of response inhibition were obtained in 185 adolescents with ADHD, 111 of their unaffected siblings and 124 healthy controls (mean age 16.9 years). We investigated the association of DAT1 and COMT variants on task performance and whole-brain neural activation during response inhibition in a hypothesis-free manner. Additionally, we attempted to explain variance in previously found ADHD effects on neural activation during response inhibition using these DAT1 and COMT polymorphisms.

Results.

The whole-brain analyses demonstrated large-scale neural activation changes in the medial and lateral prefrontal, subcortical and parietal regions of the response inhibition network in relation to DAT1 and COMT polymorphisms. Although these neural activation changes were associated with different task performance measures, no relationship was found between DAT1 or COMT variants and ADHD, nor did variants in these genes explain variance in the effects of ADHD on neural activation.

Conclusions.

These results suggest that dopamine-related genes play a role in the neurobiology of response inhibition. The limited associations between gene polymorphisms and task performance further indicate the added value of neural measures in linking genetic factors and behavioural measures.

Keywords

Attention-deficit/hyperactivity disorderCOMTDAT1dopamineresponse inhibition
Type
Original Articles
Information
Psychological Medicine , Volume 45 , Issue 15 , November 2015 , pp. 3159 - 3170
Copyright
Copyright © Cambridge University Press 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Albrecht, DS, Kareken, DA, Christian, BT, Dzemidzic, M, Yoder, KK (2014). Cortical dopamine release during a behavioral response inhibition task. Synapse 68, 266–274.CrossRefGoogle ScholarPubMed
Aron, AR (2011). From reactive to proactive and selective control: developing a richer model for stopping inappropriate responses. Biological Psychiatry 69, 55–68.CrossRefGoogle ScholarPubMed
Asherson, P, Brookes, K, Franke, B, Chen, W, Gill, M, Ebstein, RP, Buitelaar, J, Banaschewski, T, Sonuga-Barke, E, Eisenberg, J, Manor, I, Miranda, A, Oades, RD, Roeyers, H, Rothenberger, A, Sergeant, J, Steinhausen, H-C, Faraone, SV (2007). Confirmation that a specific haplotype of the dopamine transporter gene is associated with combined-type ADHD. American Journal of Psychiatry 164, 674–677.CrossRefGoogle ScholarPubMed
Bertolino, A, Rubino, V, Sambataro, F, Blasi, G, Latorre, V, Fazio, L, Caforio, G, Petruzzella, V, Kolachana, B, Hariri, A, Meyer-Lindenberg, A, Nardini, M, Weinberger, DR, Scarabino, T (2006). Prefrontal–hippocampal coupling during memory processing is modulated by COMT Val158Met genotype. Biological Psychiatry 60, 1250–1258.CrossRefGoogle ScholarPubMed
Braet, W, Johnson, KA, Tobin, CT, Acheson, R, McDonnell, C, Hawi, Z, Barry, E, Mulligan, A, Gill, M, Bellgrove, MA, Robertson, IH, Garavan, H (2011). fMRI activation during response inhibition and error processing: the role of the DAT1 gene in typically developing adolescents and those diagnosed with ADHD. Neuropsychologia 49, 1641–1650.CrossRefGoogle ScholarPubMed
Bralten, J, Franke, B, Waldman, I (2013). Candidate genetic pathways for attention-deficit/hyperactivity disorder (ADHD) show association to hyperactive/impulsive symptoms in children with ADHD. Journal of the American Academy of Child and Adolescent Psychiatry 52, 1204–1212.CrossRefGoogle ScholarPubMed
Brookes, K, Xu, X, Chen, W, Zhou, K, Neale, B, Lowe, N, Anney, R, Aneey, R, Franke, B, Gill, M, Ebstein, R, Buitelaar, J, Sham, P, Campbell, D, Knight, J, Andreou, P, Altink, M, Arnold, R, Boer, F, Buschgens, C, Butler, L, Christiansen, H, Feldman, L, Fleischman, K, Fliers, E, Howe-Forbes, R, Goldfarb, A, Heise, A, Gabriëls, I, Korn-Lubetzki, I, Johansson, L, Marco, R, Medad, S, Minderaa, R, Mulas, F, Müller, U, Mulligan, A, Rabin, K, Rommelse, N, Sethna, V, Sorohan, J, Uebel, H, Psychogiou, L, Weeks, A, Barrett, R, Craig, I, Banaschewski, T, Sonuga-Barke, E, Eisenberg, J, Kuntsi, J, Manor, I, McGuffin, P, Miranda, A, Oades, RD, Plomin, R, Roeyers, H, Rothenberger, A, Sergeant, J, Steinhausen, H-C, Taylor, E, Thompson, M, Faraone, SV, Asherson, P (2006 a). The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Molecular Psychiatry 11, 934–953.CrossRefGoogle ScholarPubMed
Brookes, K-J, Mill, J, Guindalini, C, Curran, S, Xu, X, Knight, J, Chen, C-K, Huang, Y-S, Sethna, V, Taylor, E, Chen, W, Breen, G, Asherson, P (2006 b). A common haplotype of the dopamine transporter gene associated with attention-deficit/hyperactivity disorder and interacting with maternal use of alcohol during pregnancy. Archives of General Psychiatry 63, 74–81.CrossRefGoogle ScholarPubMed
Chambers, CD, Garavan, H, Bellgrove, MA (2009). Insights into the neural basis of response inhibition from cognitive and clinical neuroscience. Neuroscience and Biobehavioral Reviews 33, 631–646.CrossRefGoogle ScholarPubMed
Congdon, E, Constable, RT, Lesch, KP, Canli, T (2009). Influence of SLC6A3 and COMT variation on neural activation during response inhibition. Biological Psychology 81, 144–152.CrossRefGoogle ScholarPubMed
Congdon, E, Lesch, KP, Canli, T (2008). Analysis of DRD4 and DAT polymorphisms and behavioral inhibition in healthy adults: implications for impulsivity. American Journal of Medical Genetics 147B, 27–32.Google ScholarPubMed
Cornish, KM, Manly, T, Savage, R, Swanson, J, Morisano, D, Butler, N, Grant, C, Cross, G, Bentley, L, Hollis, CP (2005). Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample. Molecular Psychiatry 10, 686–698.CrossRefGoogle Scholar
Costa, A, Riedel, M, Pogarell, O, Menzel-Zelnitschek, F, Schwarz, M, Reiser, M, Möller, H, Rubia, K, Meindl, T, Ettinger, U (2013). Methylphenidate effects on neural activity during response inhibition in healthy humans. Cerebral Cortex 23, 1179–1189.CrossRefGoogle ScholarPubMed
Crosbie, J, Arnold, P, Paterson, A, Swanson, J, Dupuis, A, Li, X, Shan, J, Goodale, T, Tam, C, Strug, LJ, Schachar, RJ (2013). Response inhibition and ADHD traits: correlates and heritability in a community sample. Journal of Abnormal Child Psychology 41, 497–507.CrossRefGoogle Scholar
Cross-Disorder Group of the Psychiatric Genomics Consortium (2013 a). Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nature Genetics 45, 984–994.CrossRefGoogle Scholar
Cross-Disorder Group of the Psychiatric Genomics Consortium (2013 b). Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381, 1371–1379.CrossRefGoogle Scholar
Cubillo, A, Halari, R, Giampietro, V, Taylor, E, Rubia, K (2011). Fronto-striatal underactivation during interference inhibition and attention allocation in grown up children with attention deficit/hyperactivity disorder and persistent symptoms. Psychiatry Research 193, 17–27.CrossRefGoogle ScholarPubMed
Cummins, TDR, Hawi, Z, Hocking, J, Strudwick, M, Hester, R, Garavan, H, Wagner, J (2012). Dopamine transporter genotype predicts behavioural and neural measures of response inhibition. Molecular Psychiatry 11, 1086–1192.CrossRefGoogle Scholar
Dudbridge, F (2013). Power and predictive accuracy of polygenic risk scores. PLoS Genetics 9, e1003348.CrossRefGoogle ScholarPubMed
Durston, S, Fossella, JA, Casey, BJ, Hulshoff Pol, HE, Galvan, A, Schnack, HG, Steenhuis, MP, Minderaa, RB, Buitelaar, JK, Kahn, RS, Van Engeland, H (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. Molecular Psychiatry 10, 678–685.CrossRefGoogle Scholar
Enticott, PG, Ogloff, JRP, Bradshaw, JL (2008). Response inhibition and impulsivity in schizophrenia. Psychiatry Research 157, 251–254.CrossRefGoogle ScholarPubMed
Faraone, S, Khan, S (2005). Candidate gene studies of attention-deficit/hyperactivity disorder. Journal of Clinical Psychiatry 67 (Suppl. 8), 13–20.Google Scholar
Fassbender, C, Murphy, K, Hester, R, Meaney, J, Robertson, IH, Garavan, H (2006). The role of a right fronto-parietal network in cognitive control: common activations for “cues-to-attend” and response inhibition. Journal of Psychophysiology 20, 286–296.CrossRefGoogle Scholar
Franke, B, Vasquez, AA, Johansson, S, Hoogman, M, Romanos, J, Boreatti-Hümmer, A, Heine, M, Jacob, CP, Lesch, KP, Casas, M, Ribasés, M, Bosch, R, Sánchez-Mora, C, Gómez-Barros, N, Fernàndez-Castillo, N, Bayés, M, Halmøy, A, Halleland, H, Landaas, ET, Fasmer, OB, Knappskog, PM, Heister, AJ, Kiemeney, LA, Kooij, JJ, Boonstra, AM, Kan, CC, Asherson, P, Faraone, SV, Buitelaar, JK, Haavik, J, Cormand, B, Ramos-Quiroga, JA, Reif, A (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.CrossRefGoogle ScholarPubMed
Gizer, IR, Ficks, C, Waldman, ID (2009). Candidate gene studies of ADHD: a meta-analytic review. Human Genetics 126, 51–90.CrossRefGoogle ScholarPubMed
Gottesman, II, Gould, TD (2003). The endophenotype concept in psychiatry: etymology and strategic intentions. American Journal of Psychiatry 160, 636–645.CrossRefGoogle ScholarPubMed
Guan, L, Wang, B, Chen, Y, Yang, L, Li, J, Qian, Q, Wang, Z, Faraone, SV, Wang, Y (2009). A high-density single-nucleotide polymorphism screen of 23 candidate genes in attention deficit hyperactivity disorder: suggesting multiple susceptibility genes among Chinese Han population. Molecular Psychiatry 14, 546–554.CrossRefGoogle ScholarPubMed
Holm, S (1979). A simple sequentially rejective multiple test procedure. Scandinavian Journal of Statistics 6, 65–70.Google Scholar
Hong, J, Shu-Leong, H, Tao, X, Lap-Ping, Y (1998). Distribution of catechol-O-methyltransferase expression in human central nervous system. Neuroreport 9, 2861–2864.CrossRefGoogle ScholarPubMed
Krach, S, Jansen, A, Krug, A, Markov, V, Thimm, M, Sheldrick, AJ, Eggermann, T, Zerres, K, Stöcker, T, Shah, NJ, Kircher, T (2010). COMT genotype and its role on hippocampal–prefrontal regions in declarative memory. NeuroImage 53, 978–984.CrossRefGoogle ScholarPubMed
Lipszyc, J, Schachar, R (2010). Inhibitory control and psychopathology: a meta-analysis of studies using the stop signal task. Journal of the International Neuropsychological Society 16, 1064–1076.CrossRefGoogle ScholarPubMed
Matsumoto, M, Weickert, CS, Akil, M, Lipska, BK, Hyde, TM, Herman, MM, Kleinman, JE, Weinberger, DR (2003). Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function. Neuroscience 116, 127–137.CrossRefGoogle ScholarPubMed
Matthews, N, Vance, A, Cummins, TDR, Wagner, J, Connolly, A, Yamada, J, Lockhart, PJ, Panwar, A, Wallace, RH, Bellgrove, MA (2012). The COMT Val158 allele is associated with impaired delayed-match-to-sample performance in ADHD. Behavioral and Brain Functions 8, 25.CrossRefGoogle ScholarPubMed
Mulligan, CR, Knopik, VS, Sweet, LH, Fisher, MS, Seidenberg, M, Rao, SM (2011). Neural correlates of inhibitory control in adult ADHD: evidence from the Milwaukee longitudinal sample. Psychiatry Research 194, 119–129.CrossRefGoogle ScholarPubMed
Nymberg, C, Jia, T, Lubbe, S, Ruggeri, B, Desrivieres, S, Barker, G, Büchel, C, Fauth-Buehler, M, Cattrell, A, Conrod, P, Flor, H, Gallinat, J, Garavan, H, Heinz, A, Ittermann, B, Lawrence, C, Mann, K, Nees, F, Salatino-Oliveira, A, Paillère Martinot, M-L, Paus, T, Rietschel, M, Robbins, T, Smolka, M, Banaschewski, T, Rubia, K, Loth, E, Schumann, G (2013). Neural mechanisms of attention-deficit/hyperactivity disorder symptoms are stratified by MAOA genotype. Biological Psychiatry 74, 607–614.CrossRefGoogle ScholarPubMed
Passarotti, AM, Sweeney, JA, Pavuluri, MN (2010). Neural correlates of response inhibition in pediatric bipolar disorder and attention deficit hyperactivity disorder. Psychiatry Research 181, 36–43.CrossRefGoogle ScholarPubMed
Pliszka, SR, Glahn, DC, Semrud-Clikeman, M, Franklin, C, Perez, R III, Xiong, J, Liotti, M (2006). Neuroimaging of inhibitory control areas in children with attention deficit/hyperactivity disorder who were treatment naive or in long-term treatment. American Journal of Psychiatry 163, 1052–1060.CrossRefGoogle ScholarPubMed
Ridderinkhof, KR, Van den Wildenberg, WPM, Segalowitz, SJ, Carter, CS (2004). Neurocognitive mechanisms of cognitive control: the role of prefrontal cortex in action selection, response inhibition, performance monitoring, and reward-based learning. Brain and Cognition 56, 129–140.CrossRefGoogle ScholarPubMed
Rubia, K, Halari, R, Cubillo, A, Mohammad, A-M, Brammer, M, Taylor, E (2009). Methylphenidate normalises activation and functional connectivity deficits in attention and motivation networks in medication-naïve children with ADHD during a rewarded continuous performance task. Neuropharmacology 57, 640–652.CrossRefGoogle ScholarPubMed
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427.CrossRefGoogle Scholar
Schwartz, S, Correll, CU (2014). Efficacy and safety of atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder: results from a comprehensive meta-analysis and metaregression. Journal of the American Academy of Child and Adolescent Psychiatry 53, 174–187.CrossRefGoogle ScholarPubMed
Slaats-Willemse, D, Swaab-Barneveld, H, Sonneville, L, Van der Meulen, E, Buitelaar, JK (2003). Deficient response inhibition as a cognitive endophenotype of ADHD. Journal of the American Academy of Child and Adolescent Psychiatry 42, 1242–1248.CrossRefGoogle ScholarPubMed
Van Meel, CS, Heslenfeld, DJ, Oosterlaan, J, Sergeant, JA (2007). Adaptive control deficits in attention-deficit/hyperactivity disorder (ADHD): the role of error processing. Psychiatry Research 151, 211–220.CrossRefGoogle ScholarPubMed
Van Rooij, D, Hartman, CA, Mennes, M, Oosterlaan, J, Franke, B, Rommelse, N, Heslenfeld, D, Faraone, SV, Buitelaar, JK, Hoekstra, PJ (2015). Distinguishing adolescents with ADHD from their unaffected siblings and healthy comparison subjects by neural activation patterns during response inhibition. American Journal of Psychiatry. Published online 25 January 2015. doi:10.1176/appi.ajp.2014.13121635.CrossRefGoogle ScholarPubMed
Von Rhein, D, Mennes, M, Van Ewijk, H, Groenman, AP, Zwiers, M, Oosterlaan, J, Heslenfeld, D, Franke, B, Hoekstra, PJ, Faraone, SV, Hartman, C, Buitelaar, J (2015). The NeuroIMAGE study: a prospective phenotypic, cognitive, genetic and MRI study in children with attention-deficit/hyperactivity disorder. Design and descriptives. European Child and Adolescent Psychiatry 24, 265–281.CrossRefGoogle ScholarPubMed
White, TP, Loth, E, Rubia, K, Krabbendam, L, Whelan, R, Banaschewski, T, Barker, GJ, Bokde, ALW, Büchel, C, Conrod, P, Fauth-Bühler, M, Flor, H, Frouin, V, Gallinat, J, Garavan, H, Gowland, P, Heinz, A, Ittermann, B, Lawrence, C, Mann, K, Paillère, M-L, Nees, F, Paus, T, Pausova, Z, Rietschel, M, Robbins, T, Smolka, MN, Shergill, SS, Schumann, G (2014). Sex differences in COMT polymorphism effects on prefrontal inhibitory control in adolescence. Neuropsychopharmacology 39, 2560–2569.CrossRefGoogle ScholarPubMed
Woo, C-W, Krishnan, A, Wager, TD (2014). Cluster-extent based thresholding in fMRI analyses: pitfalls and recommendations. NeuroImage 91, 412–419.CrossRefGoogle ScholarPubMed
Supplementary material: File

van Rooij supplementary material

van Rooij supplementary material 1

Download van Rooij supplementary material(File)
File 551.9 KB