Double dissociation between lab measures of inattention and impulsivity and the dopamine transporter gene (DAT1) and dopamine D4 receptor gene (DRD4)
Abstract
Studies examining the biological and neuropsychological processes underlying attention-deficit/hyperactivity disorder (ADHD) suggest that error indices from the A-X Continuous Performance Test (A-X CPT) might represent useful endophenotypes for ADHD. The current study extended such findings by evaluating the utility of these putative endophenotypes in the context of a molecular genetic study. One hundred and forty-eight clinic-referred ADHD probands and 56 siblings were recruited as part of an ongoing study. Between- and within-family tests of association were conducted to test for relations between polymorphisms in two candidate genes, the dopamine transporter gene (DAT1) and the dopamine D4 receptor gene (DRD4), and indices of inattention and impulsivity derived from the A-X CPT. Association analyses of these polymorphisms with the A-X CPT indices suggested a double dissociation such that an index of inattention was associated with DRD4 but not DAT1, and an index of impulsivity was associated with DAT1 but not DRD4. Further analyses suggested that an A-X CPT index of impulsivity partially mediated previously observed associations between hyperactive-impulsive ADHD symptoms and DAT1. Additionally, an A-X CPT index of inattention moderated the relation between inattentive ADHD symptoms and DRD4 such that children with high levels of the endophenotype showed a stronger association between inattentive symptoms and DRD4. The potential utility of endophenotypes derived from the A-X CPT in molecular genetic studies of ADHD is discussed. (PsycINFO Database Record (c) 2012 APA, all rights reserved).
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Evidence on whether DRD4 is more strongly associated with inattentive symptoms than hyperactive-impulsive symptoms of ADHD is inconsistent, with some studies finding a stronger inattentive association and others finding association with both symptom domains.
“Several studies have suggested that DRD4 is more strongly associated with inattentive symptoms than hyperactive-impulsive symptoms of ADHD (McCracken et al., 2000; Gizer and Waldman, 2012), while other studies showed that DRD4 was implicated in both inattentive and hyperactive symptoms (Lasky-Su et al., 2007; Bidwell et al., 2011).”
From A Review of Heterogeneity in Attention Deficit/Hyperactivity Disorder (ADHD) (2019) · cites this paper as Gizer and Waldman, 2012
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Albrecht, B., Brandeis, D., Sandersleben, H. U.-V., Valko, L., Heinrich, H., Xu, X.-H., Drechsler, R., Heise, A., Kuntsi, J., Müller, U., et al. (2014) · Journal of Child Psychology and Psychiatry and Allied Disciplines · doi:10.1111/jcpp.12212 · Cited by 44 · see citing works
“The dopamine D4 receptor (DRD4) gene modulates a receptor, which is mostly present in the frontal lobe, orbitofrontal and anterior cingulate cortex (Gizer & Waldman, 2012; Noain et al., 2006).”
InfluentialADHD History of the Concept: the Case of the Continuous Performance Test
Albrecht, B., Sandersleben, H. U.-V., Wiedmann, K., & Rothenberger, A. (2015) · Current Developmental Disorders Reports · doi:10.1007/s40474-014-0035-1 · Cited by 45 · see citing works
Fernández‐Jaén, A., López‐Martín, S., Albert, J., Fernández-Mayoralas, D. M., Fernández‐Perrone, A. L., de la Peña, M. J., Calleja‐Pérez, B., Rodríguez, M. R., López-Arribas, S., & Jareño, N. M. (2015) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2015.07.005 · Cited by 40 · see citing works
Li, W.-D., Wang, N., Arvey, R., Soong, R., Saw, S., & Song, Z.-L. (2015) · The Leadership Quarterly · doi:10.1016/j.leaqua.2014.12.005 · Cited by 27 · see citing works
Davis, G. L., Stewart, A., Stanwood, G. D., Gowrishankar, R., Hahn, M. K., & Blakely, R. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.09.043 · Cited by 31 · see citing works
“Although initially surprising, these findings may relate to studies in humans reporting a stronger association of DAT polymorphisms with impulsivity versus inattention [45], as well as brain activity linked to inhibitory response control versus attentional orienting [46].”
ResultThe SLC6A3 gene polymorphism is related to the development of attentional functions but not to ADHD
Kuć, K., Bielecki, M., Racicka, E., Czerwinski, M. B., & Cybulska-Kłosowicz, A. (2020) · Scientific Reports · doi:10.1038/s41598-020-63296-x · Cited by 23 · see citing works
Kamradt, J. M., Nigg, J. T., Friderici, K. H., & Nikolas, M. A. (2017) · Development and Psychopathology · doi:10.1017/s0954579416000195 · Cited by 19 · see citing works
“DRD4 is heavily expressed in brain areas thought to underpin the cognitive deficits that are involved in many cases of ADHD (i.e., frontal lobe, orbitofrontal cortex, and anterior cingulate cortex; Gizer & Waldman, 2012; Noaı́n et al., 2006).”
BackgroundInfluentialInfluence of the COMT val108/158met polymorphism on continuous performance task indices
Park, Y., & Waldman, I. D. (2014) · Neuropsychologia · doi:10.1016/j.neuropsychologia.2014.06.008 · Cited by 15 · see citing works
Self-citationHigh impulsive choice is accompanied by an increase in dopamine release in rat dorsolateral striatum
Moreno, M., Azocar, V. H., Verges, A. J., & Fuentealba, J. A. (2021) · Behavioural Brain Research · doi:10.1016/j.bbr.2021.113199 · Cited by 15 · see citing works
Kasparbauer, A., Merten, N., Aichert, D. S., Wöstmann, N. M., Meindl, T., Rujescu, D., & Ettinger, U. (2015) · Cortex · doi:10.1016/j.cortex.2015.07.002 · Cited by 14 · see citing works
Xie, Z., Maddox, W. T., Knopik, V. S., McGeary, J. E., & Chandrasekaran, B. (2014) · Neuropsychologia · doi:10.1016/j.neuropsychologia.2014.12.013 · Cited by 13 · see citing works
“Interestingly, DRD4 long carriers have demonstrated disrupted or enhanced executive attention (Gizer and Waldman, 2012; Kieling et al., 2006; Swanson et al., 2000), inhibitory control (Congdon et al., 2008; Krämer et al., 2009; Langley et al., 2004; Loo et al., 2008), and short-term memory or…”
Yin, P., Cao, A., Yu, L., Guo, L.-J., Sun, R., & Lei, G.-F. (2014) · Neuroscience Letters · doi:10.1016/j.neulet.2014.08.008 · Cited by 12 · see citing works
Gorlick, M. A., Worthy, D. A., Knopik, V. S., McGeary, J. E., Beevers, C. G., & Maddox, W. T. (2014) · Journal of Cognitive Neuroscience · doi:10.1162/jocn_a_00724 · Cited by 12 · see citing works
Enge, S., Sach, M., Reif, A., Lesch, K., Miller, R. E., & Fleischhauer, M. (2019) · Cognitive Affective & Behavioral Neuroscience · doi:10.3758/s13415-019-00752-w · Cited by 11 · see citing works
Bacanlı, A., Ünsel‐Bolat, G., Süren, S., Yazıcı, K. U., Çallı, C., Jafari, D. A., Kosova, B., Rohde, L. A., & Ercan, E. S. (2021) · Brain Imaging and Behavior · doi:10.1007/s11682-020-00437-w · Cited by 9 · see citing works
Chung, T. A., Ferrell, R. E., & Clark, D. B. (2015) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2015.01.021 · Cited by 8 · see citing works
“Research on the DAT1 genotype indicates that 10R homozygotes (10/10 genotype), relative to 9R carriers, demonstrated greater impulsive responding (Gizer and Waldman, 2012).”
BackgroundLi, J. J. (2017) · Development and Psychopathology · doi:10.1017/s0954579417001511 · Cited by 8 · see citing works
“Third, findings have been mixed with regard to whether genetic risk scores computed in this way are predictive of ASB and ASB-related traits (Gizer & Waldman, 2012; Thibodeau et al., 2015).”
BackgroundInteraction between serotonin and dopamine and impulsivity: A gene × gene - interaction approach
Hennig, J., Netter, P., & Munk, A. J. L. (2020) · Personality and Individual Differences · doi:10.1016/j.paid.2020.110014 · Cited by 6 · see citing works
Akay, A. P., Yazıcıoğlu, Ç. E., Güney, S. A., Erkuran, H. Ö., Kızıldağ, S., Baykara, B., Özyurt, G., Kadıçeşme, Ş. Y., Miral, S., & Emiroğlu, N. İ. (2018) · Psychiatry and Clinical Psychopharmacology · doi:10.1080/24750573.2017.1418134 · Cited by 4 · see citing works
“DRD4 is mostly situated in the frontal lobe, orbitofrontal, and anterior cingulate cortex [8,9], and it is crucial because of the acceptance of this receptor’s”
BackgroundInfluentialSLC6A3 Is Associated With Relational Aggression in Children
Lundwall, R. A., Sgro, J., & Wade, T. (2017) · Journal of Individual Differences · doi:10.1027/1614-0001/a000239 · Cited by 5 · see citing works
“Ullsperger, 2010), decision making (Rogers, 2011; Zhong et al., 2009), working memory (Shang & Gau, 2014), and impulsivity (Gizer & Waldman, 2012; Oades et al., 2008).”
A genetic marker of risk in HIV-infected individuals with a history of hazardous drinking
Barker, D., Nugent, N. R., Delgado, J. R., Knopik, V. S., Brown, L. K., Lally, M., & McGeary, J. E. (2017) · AIDS Care · doi:10.1080/09540121.2017.1291898 · Cited by 4 · see citing works
“…number of tandem repeat polymorphism (DAT1*9R & DAT1*10R), and have associated DAT1*10R versus DAT1*9R with greater impulsivity, sensation seeking, and risk-taking (Blum et al., 2011; Gizer & Waldman, 2012; Guo, Cai, Guo, Wang, & Harris, 2010; Mata, Hau, Papassotiropoulos, & Hertwig, 2012).”
Gene-Environment Interplay and Prosocial Behavior An Analysis of Parent-Child Relationships
Meek, S. E. (2013) · Cited by 1 · see citing works
Patte, K. A. (2015) · YorkSpace (York University)
Exploring the aetiology of ADHD : rater effects, co-occurring traits and polygenic scores
Merwood, A. (2013) · Research Portal (King's College London)
- Authors
- Gizer, I. R., & Waldman, I. D.
- Affiliations
- University of Missouri (US)
- Venue
- Journal of Abnormal Psychology
- Published
- 2012-11
- Volume
- 121
- Issue
- 4
- Pages
- 1011-1023
- ISSN
- 0021-843X (ISSN-L)
- 1939-1846
- OpenAlex
- W2054288964
- Cited by
- 36
- References
- 89
- Citations by year
- 2021: 2 · 2020: 4 · 2019: 2 · 2018: 1 · 2017: 6 · 2016: 3 · 2015: 7 · 2014: 6 · 2013: 4 · 2012: 1
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Abnormal Psychology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (F31-MH072083-01, K01-MH01818)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- attention deficit hyperactivity disorder, endophenotypes, inattention, impulsivity, dopamine transporter gene, DAT1, dopamine D4 receptor gene, DRD4, candidate gene polymorphisms, family-based association, mediation, moderation, children
- MeSH terms
- Adolescent, Attention, Attention Deficit Disorder with Hyperactivity, Child, Female, Humans, Impulsive Behavior, Male, Neuropsychological Tests, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Siblings, Dopamine Plasma Membrane Transport Proteins, Receptors, Dopamine D4
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