Oxytocin and vasopressin hormone genes in children's externalizing problems: A cognitive endophenotype approach

• Genes encoding the oxytocin (OXT) and vasopressin (AVP) hormones are associated with externalizing problems in childhood.
• OXT and AVP are also associated with children’s theory of mind (ToM) and executive functioning (EF).
• The effects of OXT and AVP on externalizing problems are partially mediated by ToM and EF.
• Overall, these results underscore a genotype-endophenotype-phenotype model of externalizing problems in children.

Externalizing problems are among the most common mental health problems of children. Research suggests that these problems are heritable, yet little is known about the specific genes involved in their pathophysiology. The current study examined a genotype-endophenotype-phenotype model of externalizing problems in 320 preschool-aged children. Markers of the oxytocin (OXT) and arginine vasopressin (AVP) hormone genes were selected as candidates owing to their known association with psychopathology in other domains. We tested whether OXT and AVP variants were related to children's externalizing problems, as well as two cognitive endophenotypes presumed to underlie these problems: theory of mind (ToM) and executive functioning (EF). Externalizing problems were assessed at age 4.5 using a previously-validated rating scale. ToM and EF were measured with age-appropriate tasks. Using a family-based association design and controlling for non-genomic confounds, support was found for an association between a two-marker OXT haplotype (rs2740210–rs2770378) and a two-marker AVP haplotype (rs1887854–rs3761249) and externalizing problems. Specific associations of these haplotypes with ToM and EF were also observed. Further, ToM and EF were shown to independently and jointly predict externalizing problems, and to partially mediate the effects of OXT and AVP on externalizing problems. This study provides the first evidence that genetic variation in OXT and AVP may contribute to individual differences in childhood externalizing problems, and that these effects may operate through emerging neurocognitive abilities in the preschool period.