Prenatal smoking exposure and dopaminergic genotypes interact to cause a severe ADHD subtype

Biol Psychiatry. 2007 Jun 15;61(12):1320-8. doi: 10.1016/j.biopsych.2006.08.049. Epub 2006 Dec 6.


Background: In utero exposure to smoking and alcohol are common risk factors that have been associated with attention-deficit/hyperactivity disorder (ADHD) in human beings and animal models. Furthermore, molecular studies have focused on the association between ADHD and DNA polymorphisms in dopamine pathway-related genes. We examined the joint effects of genetic and prenatal substance exposures on DSM-IV and population-defined subtypes of ADHD.

Methods: Logistic regression was used to assess the relationship between ADHD subtypes, DAT1 and DRD4 polymorphisms, and prenatal substance exposures in a birth-record sample of male and female twin pairs, aged 7-19 years.

Results: Interactions between prenatal exposure to smoking and variations in the DAT1 and DRD4 loci were observed in children with either the DSM-IV or population-defined ADHD combined subtypes. The odds of a diagnosis of DSM-IV combined subtype was 2.9 times greater in twins who had inherited the DAT1 440 allele and who were exposed, than in unexposed twins without the risk allele. The OR was 2.6 in the population-defined subtype. Odds ratios for the DRD4 seven-repeat allele were 3.0 (2.8) in the population-defined (DSM-IV) combined ADHD subtypes. The OR for exposed children with both alleles was 9.0 (95% confidence interval=2.0-41.5) for the population-defined combined subtypes.

Conclusions: Results indicate that smoking during pregnancy is associated with specific subtypes of ADHD in genetically susceptible children.

Publication types

  • Research Support, N.I.H., Extramural
  • Twin Study

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Attention Deficit Disorder with Hyperactivity / diagnosis
  • Attention Deficit Disorder with Hyperactivity / epidemiology*
  • Attention Deficit Disorder with Hyperactivity / genetics
  • Child
  • Diagnostic and Statistical Manual of Mental Disorders
  • Dopamine / genetics*
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Female
  • Genetic Variation / genetics
  • Genotype
  • Humans
  • Male
  • Neural Pathways / physiology
  • Observer Variation
  • Polymorphism, Genetic / genetics
  • Pregnancy
  • Prenatal Exposure Delayed Effects / epidemiology*
  • Receptors, Dopamine D4 / genetics
  • Severity of Illness Index
  • Smoking / adverse effects*
  • Surveys and Questionnaires
  • Twins / genetics


  • DRD4 protein, human
  • Dopamine Plasma Membrane Transport Proteins
  • SLC6A3 protein, human
  • Receptors, Dopamine D4
  • Dopamine