There is increasing evidence to support the theory that gene–environment interactions are involved in shaping the ADHD phenotype. The objective of this study was to investigate the neural correlates of the most prominent dopaminergic candidate genes (DRD4 and DAT1) for ADHD, prenatal exposure to alcohol or smoking, and their interaction during response inhibition (the ability to suppress inappropriate response) in adolescents and young adults with and without ADHD.
Participants were originally enrolled in the NeuroIMAGE study, a follow-up of the Dutch part of the International Multicentre ADHD Genetics (IMAGE) study. ADHD was assessed using the Kiddie Schedule for Affective Disorders and Schizophrenia — Present and Lifetime version and the Conners’ Rating Scales. Prenatal exposure to maternal alcohol use and smoking was obtained retrospectively via a structured questionnaire that was completed by the parents, and standard polymerase chain reaction protocols on DNA extracted from blood samples were used to determine the DRD4 and DAT1 genotype. Response inhibition was measured using the stop-signal task.* Functional magnetic resonance imaging blood-oxygen-level–dependent responses to successful stop, failed stop and successful go trials were also examined.
239 patients were included in the study (mean age 17.1 years; 53.6% male); of these, 53 had been exposed to prenatal smoking and 45 had been exposed to prenatal alcohol. 86 patients were found to be carriers of the DRD4 7-repeat (7R) allele and 34 were DAT1 10/6 homozygotes. No effect was observed between the genotypes or environmental factors and ADHD severity, and there was no evidence that DRD4 or DAT1 genotype moderated the association between alcohol exposure or smoking and ADHD severity.
Results showed that the DRD4 7R allele was associated with lower activation of frontal and parietal brain activity (two brain regions involved in response inhibition) and with greater activity in the frontal medial cortex and lateral occipital cortex. Prenatal exposure to smoking was associated with lower superior frontal gyrus activity, but with greater activity in the parietal lobe. Prenatal exposure to alcohol was associated with greater activity in the lateral orbitofrontal cortex, and the DAT1 7R risk variant was associated with lower cerebellar activity.
The retrospective nature of maternal substance use and the cross-sectional study design were key limitations of this study, which prohibits inferring any causality, and further research is warranted. Results from this study suggest that ADHD severity is not associated with gene–environment interactions between prenatal stressors and dopaminergic genes. However, the risk factors investigated influenced the activity of brain regions associated with response inhibition, which suggests that they may add to problems with inhibiting behaviour.
Read more about gene–environment interactions and response inhibition here
*Participants were asked to respond with a button press as quickly as possible when a stimulus was presented, called the “go” signal. In a subset of trials, the “go” signal was followed after a short interval by a “stop” signal, which indicated that the participant should withhold the response. The delay between the “go” and “stop” signals was either increased or decreased by 50 ms after each stop trial, depending on success or failure to inhibit the button press
van der Meer D, Hartman CA, van Rooij D, et al. Effects of dopaminergic genes, prenatal adversities, and their interaction on attention-deficit/hyperactivity disorder and neural correlates of response inhibition. J Psychiatry Neurosci 2017; 42: 113-121.