The Generation R Study: a review of design, findings to date, and a study of the 5-HTTLPR by environmental interaction from fetal life onward

J Am Acad Child Adolesc Psychiatry. 2012 Nov;51(11):1119-1135.e7. doi: 10.1016/j.jaac.2012.08.021. Epub 2012 Sep 30.


Objective: First, we give an overview of child psychiatric research in the Generation R Study, a population-based cohort from fetal life forward. Second, we examine within Generation R whether the functional polymorphism (5-HTTLPR) in the promoter of the serotonin transporter gene interacts with prenatal maternal chronic difficulties, prenatal maternal anxiety or postnatal maternal anxiety to influence child emotional development.

Method: A total of 2,136 northern European children were genotyped for 5-HTTLPR and rs25531. Mothers reported chronic difficulties and anxiety symptoms at 20 weeks' pregnancy and when the child was 3 years old. Child emotion recognition was observed at 3 years, and child emotional problems were assessed with the CBCL/1½-5 at 5 years.

Results: There were consistent main effects of maternal difficulties and anxiety on child emotional problems, but no main effect of 5-HTTLPR. Moreover, children with the s allele were at increased risk for emotional problems if their mothers reported prenatal anxiety symptoms (β = 2.02, p < .001) or postnatal anxiety symptoms (β = 1.64, p < 0.001). Also, in children of mothers with prenatal anxiety symptoms, the s allele was associated with less accurate emotion-matching (β = -0.11, p = .004).

Conclusions: This population-based study shows that vulnerability due to 5-HTTLPR is not specific for certain adverse exposures or severe events, but suggests that the small effects of gene-environment interaction on emotional development become manifest early in life.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adult
  • Child
  • Child Development / physiology*
  • Female
  • Fetal Development / genetics
  • Fetal Development / physiology*
  • Gene-Environment Interaction*
  • Humans
  • Mothers / psychology
  • Netherlands / epidemiology
  • Population Surveillance
  • Pregnancy
  • Pregnancy Complications / epidemiology
  • Pregnancy Complications / genetics
  • Pregnancy Complications / psychology
  • Research Design / standards*
  • Research Design / trends
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Serotonin Plasma Membrane Transport Proteins / physiology*


  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins