Common variation near ROBO2 is associated with expressive vocabulary in infancy.

Twin studies suggest that expressive vocabulary at ~24 months is modestly heritable. However, the genes influencing this early linguistic phenotype are unknown. Here we conduct a genome-wide screen and follow-up study of expressive vocabulary in toddlers of European descent from up to four studies of the EArly Genetics and Lifecourse Epidemiology consortium, analysing an early (15-18 months, 'one-word stage', N(Total) = 8,889) and a later (24-30 months, 'two-word stage', N(Total)=10,819) phase of language acquisition. For the early phase, one single-nucleotide polymorphism (rs7642482) at 3p12.3 near ROBO2, encoding a conserved axon-binding receptor, reaches the genome-wide significance level (P=1.3 × 10(-8)) in the combined sample. This association links language-related common genetic variation in the general population to a potential autism susceptibility locus and a linkage region for dyslexia, speech-sound disorder and reading. The contribution of common genetic influences is, although modest, supported by genome-wide complex trait analysis (meta-GCTA h(2)(15-18-months) = 0.13, meta-GCTA h(2)(24-30-months) = 0.14) and in concordance with additional twin analysis (5,733 pairs of European descent, h(2)(24-months) = 0.20).

Variations in maternal 5-HTTLPR affect observed sensitive parenting.

BACKGROUND: Little is known about the genetic determinants of sensitive parenting. Two earlier studies examined the effect of the serotonin transporter polymorphism (5-HTTLPR) on sensitive parenting, but reported opposite results. In a large cohort we further examined whether 5-HTTLPR is a predictor of observed maternal sensitivity and whether observed child social fearfulness moderates the effect of 5-HTTLPR on maternal sensitivity. METHODS: The population-based cohort consisted of 767 mother-child dyads. Maternal sensitivity was repeatedly observed at the child's age of 14 months, 36 months and 48 months. Sensitivity was coded using the Ainsworth's rating scales for sensitivity and cooperation and the revised Erickson rating scales for Supportive presence and Intrusiveness. Child social fearfulness was observed using the Stranger Approach episode of the Laboratory Temperament Assessment Battery at 36 months. RESULTS: Repeated measurement analyses showed a consistent main effect of maternal 5-HTTLPR on sensitivity; mothers carrying the S-allele were more sensitive toward their children (p = .005). This effect was not explained by the child's 5-HTTLPR genotype. We found no evidence that child social fearfulness moderated the effect of 5-HTTLPR on sensitivity. CONCLUSIONS: This study suggests that variations in maternal 5-HTTLPR genotype appear to be involved in the etiology of parenting behavior. The observed effects of this genetic variation are consistent with the notion that parenting may have a genetic component, but large studies are needed to find the specific small molecular effects.

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.

Maternal smoking during pregnancy and child emotional problems: the relevance of maternal and child 5-HTTLPR genotype.

Serotonin is involved in the development of neural circuits modulating emotional behavior. The short allele (s) of a polymorphism (5-HTTLPR) of the serotonin transporter gene is a risk factor for psychopathology in the presence of environmental stressors. Maternal smoking is associated with growth restriction of the human fetal brain and adverse effects of nicotine on the developing serotonin system have been documented. We hypothesized that maternal smoking interacts with both child and mother 5-HTTLPR genotype as a risk factor for later child emotional problems. In a sample of n = 1,529 mother-child dyads, smoking habits were assessed by questionnaires during pregnancy. Child emotional problems were measured by the Child Behavior Checklist at the child's age of 3 years. Maternal smoking during pregnancy significantly increased the risk for emotional problems in children carrying the s-allele; ß = 0.24, P = 0.03 (mother-report), and ß = 0.46, P = 0.001 (father-report). In children heterozygous at 5-HTTLPR and exposed to maternal prenatal smoking (n = 79) risk of emotional problems increased with each additional s-allele the mother carried. The associations between 5-HTTLPR and child emotional problems were not moderated by paternal prenatal smoking. These findings imply that the vulnerability for emotional problems in s-allele carriers may already originate in fetal life.

Grandparental anxiety and depression predict young children's internalizing and externalizing problems: the generation R study.

BACKGROUND: Family history is a major risk factor for child problem behaviour, yet few studies have examined the association between grandparental psychiatric disorder and child problem behaviour. Results are inconsistent as to whether the effect of grandparental depression on child problem behaviour is independent of parental psychopathology. METHODS: Mothers and their children participated in an ethnically Dutch subcohort of a population-based prospective cohort in the Netherlands. N = 816 (66%) mothers and n = 691 fathers participated in the prenatal interviews. N = 687 (84%) mothers and children and n = 565 (82%) fathers participated three years postpartum. (Grand)parental psychopathology was assessed during pregnancy of the mothers with the Family Informant Schedule and Criteria (FISC), the Composite International Diagnostic Interview (CIDI) and the Brief Symptom Inventory (BSI). Child behaviour was assessed with the Child Behavior Checklist (CBCL) by mother and father when the child was three years old. RESULTS: Grandparental anxiety disorder predicted maternal reports of children's internalizing problems (OR = 1.98, 95% C.I. (1.20, 3.28), p-value<0.01) and externalizing problems (OR = 1.73, 95% C.I. (1.04, 2.87), p-value = 0.03), independent of parental psychopathology. Results were similar for grandparental depression; internalizing OR = 1.75, 95% C.I (1.11, 2.75), p-value = 0.02 and externalizing OR = 1.67, 95% C.I. (1.05, 2.64) p-value = 0.03. However, grandparental psychopathology was not associated with children's problem behaviour as reported by the father. LIMITATIONS: Information on grandparental lifetime psychiatric disorder was assessed through a parental interview which may have led to an underestimation of the prevalence rates. CONCLUSIONS: These results confirm the importance of a family history including not only the parental but also the grandparental generations.