title: Beyond main effects of gene-sets: harsh parenting moderates the association between a dopamine gene-set and child externalizing behavior.
abstract: In a longitudinal cohort study, we investigated the interplay of harsh parenting and genetic variation across a set of functionally related dopamine genes, in association with children's externalizing behavior. This is one of the first studies to employ gene-based and gene-set approaches in tests of Gene by Environment (G × E) effects on complex behavior. This approach can offer an important alternative or complement to candidate gene and genome-wide environmental interaction (GWEI) studies in the search for genetic variation underlying individual differences in behavior.
  
  
  
  Genetic variants in 12 autosomal dopaminergic genes were available in an ethnically homogenous part of a population-based cohort. Harsh parenting was assessed with maternal (n = 1881) and paternal (n = 1710) reports at age 3. Externalizing behavior was assessed with the Child Behavior Checklist (CBCL) at age 5 (71 ± 3.7 months). We conducted gene-set analyses of the association between variation in dopaminergic genes and externalizing behavior, stratified for harsh parenting.
  
  
  
  The association was statistically significant or approached significance for children without harsh parenting experiences, but was absent in the group with harsh parenting. Similarly, significant associations between single genes and externalizing behavior were only found in the group without harsh parenting. Effect sizes in the groups with and without harsh parenting did not differ significantly. Gene-environment interaction tests were conducted for individual genetic variants, resulting in two significant interaction effects (rs1497023 and rs4922132) after correction for multiple testing.
  
  
  
  Our findings are suggestive of G × E interplay, with associations between dopamine genes and externalizing behavior present in children without harsh parenting, but not in children with harsh parenting experiences. Harsh parenting may overrule the role of genetic factors in externalizing behavior. Gene-based and gene-set analyses offer promising new alternatives to analyses focusing on single candidate polymorphisms when examining the interplay between genetic and environmental factors.
authors.affiliation: Centre for Child and Family Studies Leiden University Leiden The Netherlands; The Generation R Study Group Erasmus University Medical Center Rotterdam The Netherlands; Department of Child and Adolescent Psychiatry Erasmus University Medical Center-Sophia Children's Hospital Rotterdam The Netherlands.
authors.forename: Dafna A
authors.initials: DA
authors.lastname: Windhorst
authors.affiliation: Centre for Child and Family Studies Leiden University Leiden The Netherlands; The Generation R Study Group Erasmus University Medical Center Rotterdam The Netherlands; Department of Child and Adolescent Psychiatry Erasmus University Medical Center-Sophia Children's Hospital Rotterdam The Netherlands.
authors.forename: Viara R
authors.initials: VR
authors.lastname: Mileva-Seitz
authors.affiliation: Centre for Child and Family Studies Leiden University Leiden The Netherlands.
authors.forename: Ralph C A
authors.initials: RC
authors.lastname: Rippe
authors.affiliation: Department of Child and Adolescent Psychiatry Erasmus University Medical Center-Sophia Children's Hospital Rotterdam The Netherlands; Department of Epidemiology Erasmus University Medical Center Rotterdam The Netherlands; Department of Psychiatry Erasmus University Medical Center Rotterdam The Netherlands.
authors.forename: Henning
authors.initials: H
authors.lastname: Tiemeier
authors.affiliation: The Generation R Study Group Erasmus University Medical Center Rotterdam The Netherlands; Department of Epidemiology Erasmus University Medical Center Rotterdam The Netherlands; Department of Pediatrics Erasmus University Medical Center Rotterdam The Netherlands.
authors.forename: Vincent W V
authors.initials: VW
authors.lastname: Jaddoe
authors.affiliation: Department of Child and Adolescent Psychiatry Erasmus University Medical Center-Sophia Children's Hospital Rotterdam The Netherlands.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Verhulst
authors.affiliation: Centre for Child and Family Studies Leiden University Leiden The Netherlands; School of Pedagogical and Educational Sciences Erasmus University Rotterdam The Netherlands.
authors.forename: Marinus H
authors.initials: MH
authors.lastname: van IJzendoorn
authors.affiliation: Centre for Child and Family Studies Leiden University Leiden The Netherlands.
authors.forename: Marian J
authors.initials: MJ
authors.lastname: Bakermans-Kranenburg
mesh_terms: D002652:Child Behavior / Q000502:physiology*; D002675:Child, Preschool; D004298:Dopamine / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009426:Netherlands; D016487:Parenting; D000066553:Problem Behavior
chemical_list: D004298:Dopamine
keywords: Behavior problems dopaminergic system; child development; dopamine; externalizing behavior; gene‐environment interaction; gene‐set; harsh parenting; parenting; preschoolers