The dopamine receptor D4 7-repeat allele and prenatal smoking in ADHD-affected children and their unaffected siblings: no gene–environment interaction


  • Conflict of interest statement: No conflicts declared.

Jan K. Buitelaar, Department of Psychiatry, HP 966, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, The Netherlands; Tel: +31 (0)24-3613490; Fax: +31 (0)24-3540561; Email:


Background:  The dopamine receptor D4 (DRD4) 7-repeat allele and maternal smoking during pregnancy are both considered as risk factors in the aetiology of attention deficit hyperactivity disorder (ADHD), but few studies have been conducted on their interactive effects in causing ADHD. The purpose of this study is to examine the gene by environment (G×E) interaction of the DRD4 7-repeat allele and smoking during pregnancy on ADHD and oppositional behavior in families from the International Multicenter ADHD Genetics project; and further, to test the hypothesis that the direction of effect of the DRD4 7-repeat allele differs between ADHD affected and unaffected children.

Methods:  Linear mixed models were used to assess main and interactive effects of the DRD4 7-repeat allele and smoking during pregnancy in 539 ADHD-affected children and their 407 unaffected siblings, aged 6–17 years.

Results:  There was some evidence pointing to differential effects of the DRD4 7-repeat allele on ADHD and oppositional symptoms in the affected (fewer symptoms) and unaffected children (increasing ADHD symptoms of teacher ratings). Affected children were more often exposed to prenatal smoking than unaffected children. There were limited main effects of prenatal smoking on severity of symptoms. Given the number of tests performed, no indication was found for G×E interactions.

Conclusion:  Despite the large sample size, no G×E interactions were found. The impact of the DRD4 7-repeat allele might differ, depending on affected status and rater. This finding is discussed in terms of differences in the activity of the dopaminergic system and of different genes involved in rater-specific behaviors.