Effects of dopaminergic genes, prenatal adversities, and their interaction on attention-deficit/hyperactivity disorder and neural correlates of response inhibition

Dennis van der Meer*, Catharina A. Hartman, Daan van Rooij, Barbara Franke, Dirk J. Heslenfeld, Jaap Oosterlaan, Stephen V. Faraone, Jan K. Buitelaar, Pieter J. Hoekstra

*Corresponding author for this work

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Background: Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by impaired response inhibition; both have been associated with aberrant dopamine signalling. Given that prenatal exposure to alcohol or smoking is known to affect dopamine-rich brain regions, we hypothesized that individuals carrying the ADHD risk alleles of the dopamine receptor D4 (DRD4) and dopamine transporter (DAT1) genes may be especially sensitive to their effects. Methods: Functional MRI data, information on prenatal adversities and genetic data were available for 239 adolescents and young adults participating in the multicentre ADHD cohort study NeuroIMAGE (average age 17.3 yr). We analyzed the effects of DRD4 and DAT1, prenatal exposure to alcohol and smoking and their interactions on ADHD severity, response inhibition and neural activity. Results: We found no significant gene × environment interaction effects. We did find that the DRD4 7-repeat allele was associated with less superior frontal and parietal brain activity and with greater activity in the frontal pole and occipital cortex. Prenatal exposure to smoking was also associated with lower superior frontal activity, but with greater activity in the parietal lobe. Further, those exposed to alcohol had more activity in the lateral orbitofrontal cortex, and the DAT1 risk variant was associated with lower cerebellar activity. Limitations: Retrospective reports of maternal substance use and the cross-sectional study design restrict causal inference. Conclusion: While we found no evidence of gene × environment interactions, the risk factors under investigation influenced activity of brain regions associated with response inhibition, suggesting they may add to problems with inhibiting behaviour.

Original languageEnglish
Pages (from-to)113-121
Number of pages9
JournalJournal of Psychiatry and Neuroscience
Issue number2
Early online date24 Jan 2017
Publication statusPublished - 1 Mar 2017


The authors acknowledge the Department of Pediatrics of the VU University Medical Center for having the opportunity to use the mock scanner for preparation of the participants. This work was supported by NIH Grant R01MH62873 (to S.V. Faraone), Large Investment Grant 1750102007010 and NWO Brain & Cognition an Integrative Approach grant (433-09-242) (to J. Buitelaar), and grants from Radboud University Nijmegen Medical Centre, University Medical Center Groningen and Accare, and VU University Amsterdam. The research leading to these results also received funding from the European Community?s Seventh Framework Programme (FP7/2007? 2013) under grant agreement numbers 278948 (TACTICS), 602450 (IMAGEMEND), and n? 602805 (Aggressotype), and from the European Community?s Horizon 2020 Programme (H2020/2014 ? 2020) under grant agreement n? 643051 (MiND). B. Franke is supported by a Vici grant from NWO (grant number 016-130-669). In addition, J. Buitelaar and B. Franke are supported by a grant for the ENIGMA Consortium (grant number U54 EB020403) from the BD2K Initiative of a cross-NIH partnership. S. Faraone is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Community?s Seventh Framework Programme (FP7/2007-2013) under grant agreement n?602805 and NIMH grant R01MH094469.

FundersFunder number
ENIGMA ConsortiumU54 EB020403
European Community’s Horizon 2020 Programme643051
K.G. Jebsen Centre for Research
VU University Medical Center
National Institutes of Health1750102007010, R01MH62873
National Institute of Mental HealthR01MH094469
National Institute of Biomedical Imaging and BioengineeringU54EB020403
Seventh Framework Programme602805, 602450, 278948
Vrije Universiteit Amsterdam
Nederlandse Organisatie voor Wetenschappelijk Onderzoek433-09-242
Radboud Universitair Medisch Centrum


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