Objective: Both genetic and environmental factors have been implicated in the etiology of attention deficit/hyperactivity disorder (ADHD), but there is a need for further characterisation of the relevant risk factors. This study presents a comprehensive analysis of the role of dopamine receptor 4 (DRD4) gene polymorphism in childhood ADHD. First, we examine the effect of DRD4 exon 3 genotype on response to methylphenidate (MPH) with a pharmacodynamic design. Second, we explore an interaction between the genotype and exposure to maternal stress during pregnancy and their effect on symptom severity in children with ADHD.

Methods: Children with ADHD (ages 6-13) were recruited from an ongoing 2-week, placebo- controlled, double blind, crossover trial at the Douglas Institute (Montreal, QC). Response to MPH was evaluated by parents and teachers using Conner’s Global Index; information on symptom severity was extracted from Child Behavioral Checklist (CBCL) questionnaire completed by the parents; stress during pregnancy was classified into low (no and mild) and high (moderate, severe and extreme). DNA samples were collected and extracted from 404 subjects. Subject were divided into three genotype groups: homozygotes for short alleles, SS (2-,3- and 4-repeat alleles; n=270), homozygotes for long alleles, LL (n=21; 7-repeat allele), and heterozygotes for both, SL (n=92). Since 7-repeat allele was the only long allele present in our sample, long homozygote group was made of carriers of two 7-repeat alleles. Previous literature has linked 7-repeate allele to personality quality of novelty seeking; the allele has also been implicated in ADHD phenotypes.

Results: (1) There was a significant interaction between DRD4 genotype and treatment course (p=.037, effect size of 0.013). Children with LL genotype had a better response to placebo, and lower symptomatology at both placebo and active medication weeks, as evaluated by the parents. (2) Gene-by-environment analysis revealed a significant interaction (p=.003, effect size of 0.030) on overall CBCL score, as well as internalizing, externalizing and attentional problems sub-scores.

Conclusion: According to the parents, children homozygous for long 7-repeat DRD4 exon 3 alleles showed better response to MPH. An interaction between genotype and exposure to stress during pregnancy resulted in significantly higher CBCL scores in high stress pregnancies. This effect was significant across all three genotypes for externalizing and internalizing scores. However, exposure to high stress pregnancy resulted in more attentional problems only in children with LL genotype (two long 7-repeate alleles). These results suggest that DRD4 genotype could be used to predict the strength of treatment and clinical outcomes in children with ADHD.