Evidence for a gene-gene interaction in predicting children's behavior problems: association of serotonin transporter short and dopamine receptor D4 long genotypes with internalizing and externalizing behaviors in typically developing 7-year-olds

Dev Psychopathol. Fall 2007;19(4):1105-16. doi: 10.1017/S0954579407000569.


Recent work on the molecular genetics of complex traits in typical and atypical human development has focused primarily on associations of single genes with behavior. Disparate literature suggests that the presence of one or two copies of the short allele of the serotonin transporter (5-HTT) gene and the long allele (7-repeat allele) version of the dopamine receptor D4 (DRD4) gene predicts internalizing- and externalizing-related behaviors, respectively. Apparently for the first time in the extant literature, we report a gene-gene statistical interaction on behavior problems in a group of typically developing children at age 7. DNA was extracted from buccal cells collected from 108 children and genotyped for short and long alleles of the 5-HTT gene and the short (2-5 repeats) versus long (6-8 repeats) allele of the DRD4 gene. Mothers completed the Child Behavior Checklist. As predicted, children with one or two copies of the short allele of the 5-HTT gene and the long allele version of the DRD4 gene exhibited significantly more internalizing and externalizing behaviors at age 7 than children with other combinations of the 5-HTT and DRD4 short and long genotypes. As well, children with the 5-HTT long and DRD4 long genotypes had the lowest reported scores on internalizing and externalizing behaviors at age 7, suggesting that the presence of the 5-HTT long genotype may serve as a protective factor against these behaviors in children with the long DRD4 genotype. Implications of these findings for understanding cumulative biological risk and protective factors in childhood behavior problems and psychopathology are discussed.

Publication types

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

MeSH terms

  • Alleles*
  • Anxiety / genetics
  • Child
  • Child Behavior Disorders / genetics*
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genotype*
  • Humans
  • Internal-External Control
  • Longitudinal Studies
  • Male
  • Object Attachment
  • Personality Assessment
  • Receptors, Dopamine D4 / genetics*
  • Risk Factors
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • Tandem Repeat Sequences / genetics


  • Serotonin Plasma Membrane Transport Proteins
  • Receptors, Dopamine D4