Variation in the glucocorticoid receptor gene at rs41423247 moderates the effect of prenatal maternal psychological symptoms on child cortisol reactivity and behavior.
Prenatal maternal psychopathology affects child development, but some children seem more vulnerable than others. Genetic variance in hypothalamic-pituitary-adrenal axis genes may influence the effect of prenatal maternal psychological symptoms on child emotional and behavioral problems. This hypothesis was tested in the Generation R Study, a population-based cohort from fetal life onward. In total, 1727 children of Northern European descent and their mothers participated in this study and were genotyped for variants in the glucocorticoid receptor (GR) gene (rs6189/rs6190, rs10052957, rs41423247, rs6195, and rs6198) and the FK506-binding protein 5 (FKBP5) gene (rs1360780). Prenatal maternal psychological symptoms were assessed at 20 weeks pregnancy and child behavior was assessed by both parents at 3 years. In a subsample of 331 children, data about cortisol reactivity were available. Based on power calculations, only those genetic variants with sufficient minor allele frequencies (rs41423247, rs10052957, and rs1360780) were included in the interaction analyses. We found that variation in GR at rs41423247 moderates the effect of prenatal maternal psychological symptoms on child emotional and behavioral problems (beta 0.41, SE 0.16, p=0.009). This prenatal interaction effect was independent of mother's genotype and maternal postnatal psychopathology, and not found for prenatal psychological symptoms of the father. Moreover, the interaction between rs41423247 and prenatal psychological symptoms was also associated with decreased child cortisol reactivity (beta -2.30, p-value 0.05). These findings emphasize the potential effect of prenatal gene-environment interaction, and give insight in possible mechanisms accounting for children's individual vulnerability to develop emotional and behavioral problems.
Department of Child and Adolescent Psychiatry, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
Fleur P
FP
Velders
Gwen
G
Dieleman
Rolieke A M
RA
Cents
Marian J
MJ
Bakermans-Kranenburg
Vincent W V
VW
Jaddoe
Albert
A
Hofman
Marinus H
MH
Van Ijzendoorn
Frank C
FC
Verhulst
Henning
H
Tiemeier
D000328:Adult; D002652:Child Behavior / Q000502:physiology; D002653:Child Behavior Disorders / Q000209:etiology* / Q000378:metabolism*; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D005838:Genotype; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D007118:Immunoassay; D016014:Linear Models; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D011569:Psychiatric Status Rating Scales; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D012463:Saliva / Q000378:metabolism; D018709:Statistics, Nonparametric; D013315:Stress, Psychological / Q000235:genetics*; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D000099159:Tacrolimus Binding Protein 5
D006854:Hydrocortisone; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5