Velders, F.P.

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 (Article)

2012-11-01T00:00:00Z

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/1-5 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.

Genes, Parental Psychiatric Symptoms and Child Emotional Problems: Nurture versus Nature: There and Back Again (Doctoral Thesis)

2012-10-31T00:00:00Z

Childhood psychiatric disorders are common, show a high comorbidity and are associated with a long-term vulnerability for mental health problems, which underscores the importance of a better understanding of their etiology. Psychiatric symptoms of the parents place children at risk for the development of emotional and behavioural problems. Previous studies showed that parental depression and hostility often co-occur. The independent contributions of depressive symptoms and symptoms of hostility of a mother or a father to the risk of child emotional and behavioural problems are unclear. Twin studies reported moderate to high heritability estimates for psychiatric disorders. The actual genes accounting for these estimates remain to be determined. In light of the inherent complexity of psychiatric disorders, it seems likely that these disorders are caused by small effects of many genes in interaction with other genes and in interaction with the environment. As described in Chapter 1, the aim of this thesis was to study the effect of common genetic variation, parental psychiatric symptoms and the effect of their interaction during pregnancy and early childhood on the risk of emotional and behavioural problems in preschool children. The studies in this thesis were embedded in The Generation R Study, a large prospective population-based cohort study from fetal life onwards in the city of Rotterdam, the Netherlands. It was designed to identify early biological and environmental determinants of growth, development and health in fetal life and childhood. Between 2002 and 2006, 8,880 pregnant women enrolled in the prenatal part of the study. In total, 7,893 children participated in the postnatal phase of the Generation R Study. The study described in Chapter 3.2 was embedded in the Rotterdam Study, a cohort of elderly people in the city of Rotterdam, the Netherlands. The first part of this thesis focused on the impact of prenatal and postnatal psychiatric symptoms and family function of both mothers and fathers on the risk for child emotional and behavioural problems. In Chapter 2, we showed that postnatal hostility symptoms of mother and father independently contributed to the risk of child emotional problems. Parental hostility accounted for the association between parental depressive symptoms and child emotional problems. These findings suggest that the association between parental depression and child emotional and behavioural problems may be indexed, mediated or confounded by parental hostility. These findings also showed that parental hostility is a strong risk factor for child emotional and behavioural problems, which could already be observed during pregnancy. The second part of this thesis focused on genetic main effects on child emotional and behavioural problems. In Chapter 3.1, we examined the association between a candidate SNP in the FTO gene and child (eating) behaviour. Previously, this FTO gene was found to be associated with increased BMI, increased food intake and eating behaviour. Given the relation between eating behaviour and other behavioural phenotypes in combination with the high expression of FTO in the brain, we hypothesized that this gene may also be associated with child behavioural problems. We showed that the FTO minor allele was already associated with food approach in preschool children, thus before the association with BMI at age 5 becomes apparent. The minor allele was also associated with a decreased risk for symptoms of ADHD and more emotional self-control. This may reflect advanced development of carriers of the minor allele at rs9939609. It may also suggest that the FTO gene has pleiotropic effects on child development. In Chapter 3.2, we sought to identify new genes related to both cortisol secretion and depression using a GWAS approach and a candidate gene approach. Our candidate gene study of cortisolAUC showed that common variation in the FKBP5 gene was associated with a decrease in cortisolAUC. Carriers of the minor alleles of SNPs in the FKBP5 gene were also at increased risk of clinically relevant depressive symptoms. These findings support the relation between HPA-axis regulation and depressive symptoms. To identify new genes related to HPA-axis functioning, we performed a GWAS on cortisolAUC. This GWAS did not identify genome-wide significant SNPs associated with cortisolAUC, which may be due to insufficient power. The negative replication results may indicate that the initial findings were indeed false-positive, but could also be the result of heterogeneity in the cortisol measurements among our study sample and the replication sample. The third part of this thesis focused on the effect of the interaction between HPA-axis related genes and parental psychiatric symptoms on child emotional and behavioural problems. In Chapter 4.1, we evaluated the effect of candidate SNPs located in the GR gene region and the FKBP5 gene region in interaction with child attachment quality on child cortisol reactivity. This study showed that variance in the FKBP5 gene and attachment quality are associated with an increased cortisol reactivity evoked by stress. Resistant infants with the FKBP5-TT genotype showed the largest increases in cortisol reactivity. In Chapter 4.2, we hypothesized that children carrying the minor alleles of SNPs located in the GR gene region and the FKBP5 gene region would be more vulnerable to the effect of maternal psychiatric symptoms during pregnancy, resulting in an increased risk of emotional and behavioural problems. In this study, common variation in the GR gene at rs41423247 (BclI1) significantly moderated the association between prenatal maternal psychological symptoms and child emotional and behavioural problems. This prenatal interaction effect was independent of mother’s genotype and maternal postnatal psychopathology, and not found for prenatal psychological symptoms of the father. In addition to an effect on child behaviour, the minor allele at rs41423247 and prenatal maternal psychological symptoms interacted to influence prenatal GxE interaction influenced child cortisol reactivity, resulting in decreased cortisol levels after exposure to stress. In Chapter 5, we hypothesized that 5-HTTLPR interacts with prenatal and postnatal maternal anxiety symptoms to influence child emotional development. In Chapter 5.1, we showed that 6 month-old infants with the short allele of the 5-HTTLPR were more likely to be negatively emotional when mother reported anxiety symptoms during pregnancy than long allele carriers. This early moderation of 5-HTTLPR was further studied in Chapter 5.2. In this chapter, we showed that 5-HTTLPR moderates the effect of prenatal maternal anxiety symptoms on child emotional problems and child emotion processing. Independent of this prenatal effect, 5-HTTLPR also interacted with postnatal maternal anxiety symptoms to influence the risk for child emotional problems. These results provide initial evidence for early moderation by 5-HTTLPR on the effect of maternal psychiatric symptoms on child emotional development In Chapter 6, the main findings of these studies were reviewed, methodological considerations and clinical implications were discussed and we reflected on future perspectives. In short, we showed that HPA-axis related genes may moderate the effect of prenatal and postnatal maternal psychological symptoms on child emotional and behavioural problems. During pregnancy, the HPA-axis of the fetus is programmed according to the circumstances in the intra-uterine environment in anticipation of life outside the womb. Mothers with psychiatric problems during pregnancy have increased cortisol levels. Despite the barrier function of the placenta, maternal cortisol will reach the fetus. In response, the fetal HPA-axis develops under the influence of increased cortisol levels. This fetal anticipation is highly effective if indeed the circumstances outside the womb match the stress experienced during fetal development. However, the HPA-axis of these children may be too reactive to the environment, also in the absence of true danger, which may result in chronic activation of the HPA-axis and related psychopathology. These early gene-environment effects may at least partly explain why some children of parents with psychiatric symptoms get ill, and others do not. Furthermore, this gene-environment interaction may partly account for the missing heritability in psychiatric genetics. Several investigators have argued that cortisol is a suitable biomarker of anxious or depressed disorders. The challenge is, however, that cortisol is the end product of a complex hormonal axis involved in many other systems than the psychological stress response. Therefore, optimal levels of cortisol that could be used as reference for making clinical decisions cannot be defined. Thus, it will take time before these fundamental findings will be of direct use for the clinical practice. Our findings do suggest that it is important to better consider parental hostility as a risk factor for child emotional and behavioural problems next to depression of parents. Second, our findings support the important role of FKBP5 in depression, and may enhance the development of new antidepressant therapies. Epigenetic processes represent a mechanism by which the environment affects the function of a gene. It would be very interesting to examine the long term effect of early methylation of the GR gene region on child HPA-axis regulation and emotional development. Due to the high rate of non-replication of most initial findings, the validity of GxE interaction studies is under debate. Especially during pregnancy, the empirical evidence remained scarce. We concluded that the concept of GxE should not be the focus of the debate. Rather, the focus should be on the study design including observational assessments, repeated measurements and multiple informants. Importantly, future GxE studies should better assess the environmental risk factors. Only if we measure the environment in more detail, with more precision and over time, will we understand how it influences and interacts with biology. Ultimately, this insight will answer to the question why some children get ill and others do not.

Variation in the glucocorticoid receptor gene at rs41423247 moderates the effect of prenatal maternal psychological symptoms on child cortisol reactivity and behavior (Article)

2012-10-01T00:00:00Z

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, p0.009). 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.

Variation in the glucocorticoid receptor gene at rs41423247 moderates the effect of prenatal maternal psychological symptoms on child cortisol reactivity and behavior (Article)

2012-10-01T00:00:00Z

Prenatal and postnatal psychological symptoms of parents and family functioning: The impact on child emotional and behavioural problems (Article)

2011-07-01T00:00:00Z

Although relations of various parental psychological problems and family functioning with child development are well documented, it remains unclear whether specific prenatal or specific postnatal risk factors are independently associated with child emotional and behavioural problems, or whether observed associations can be explained by general parental psychopathology. Using a stepwise approach, we examined the effects of prenatal and postnatal parental depressive symptoms, prenatal and postnatal hostility of the parents, as well as prenatal family functioning on the risk of child emotional and behavioural problems. This study was embedded in Generation R: a population-based cohort from foetal life onwards. Mothers and fathers of 2,698 children provided information about depressive symptoms, symptoms of hostility and family functioning during pregnancy and 3 years after birth. Mother and father each reported on child behaviour when the child was 3 years old. Parental depressive symptoms increased the risk of child emotional and behavioural problems, but this increase was explained by postnatal parental hostile behaviour. Postnatal symptoms of hostility of mothers (OR = 1.34, p value <0.001) and postnatal symptoms of hostility of fathers (OR = 1.30, p value <0.001) each contributed independently to the risk of child emotional and behavioural problems. Postnatal parental hostility is associated with an increased risk of child emotional and behavioural problems, independent of parental depressive symptoms. These findings suggest that prevention and intervention strategies should focus on psychological symptoms of both mothers and fathers, in particular on hostile behaviour, in families with young children.

Serotonin transporter polymorphism moderates effects of prenatal maternal anxiety on infant negative emotionality (Article)

2011-03-15T00:00:00Z

Background: Consistent with the fetal programming hypothesis, effects of maternal prenatal anxiety have been found to predict various measures of infant temperament in the early postnatal period. In recent years, a polymorphism in the serotonin transporter gene (5-HTTLPR) emerged as a moderator of diverse environmental influences on different outcomes, with individuals carrying the short allele being generally more vulnerable to adversity. Methods: We tested whether the association between self-reported maternal anxiety at 20 weeks gestation (Brief Symptom Inventory) and mother-rated infant negative emotionality at 6 months after birth (Infant Behavior Questionnaire-Revised) would be moderated by the 5-HTTLPR in a large Dutch cohort sample (n = 1513). We hypothesized that infants carrying the 5-HTTLPR short allele would be more susceptible and therefore more affected by both low and high prenatal maternal anxiety vis-à-vis negative emotionality than other genotypes. Results: Findings of a significant gene X environment interaction (B = .65, p = .01) were supportive of a vulnerability model, with infants carrying the short allele being more negatively emotional when mothers reported anxiety during pregnancy, whereas there was no difference between genotypes on negative emotionality when maternal anxiety was low. Conclusions: The association between maternal anxiety during pregnancy and negative emotionality in early infancy was significant in infants carrying one or more copies of the short allele but not in those homozygous for the long allele. The 5-HTTLPR short allele might increase vulnerability to adverse environmental influences as early as the fetal period.

Genetics of cortisol secretion and depressive symptoms: A candidate gene and genome wide association approach (Article)

2011-02-14T00:00:00Z

Background: Depressive patients often have altered cortisol secretion, but few studies have investigated genetic variants in relation to both cortisol secretion and depression. To identify genes related to both these conditions, we: (1) tested the association of single nucleotide polymorphisms (SNPs) in hypothalamic-pituitary-adrenal-axis (HPA-axis) candidate genes with a summary measure of total cortisol secretion during the day (cortisolAUC), (2) performed a genome wide association study (GWAS) of cortisolAUC, and (3) tested the association of identified cortisol-related SNPs with depressive symptoms. Methods: We analyzed data on candidate SNPs for the HPA-axis, genome-wide scans, cortisol secretion (n = 1711) and depressive symptoms (the Centre for Epidemiology Studies Depression Scale, CES-D) (n = 2928) in elderly persons of the Rotterdam Study. We used data from the Whitehall II study (n = 2836) to replicate the GWAS findings. Results: Of the 1456 SNPs in 33 candidate genes, minor alleles of 4 SNPs (rs9470080, rs9394309, rs7748266 and rs1360780) in the FKBP5 gene were associated with a decreased cortisolAUC (p < 1 × 10(-4) after correction for multiple testing using permutations). These SNPs were also associated with an increased risk of depressive symptoms (rs9470080: OR 1.19 (95%CI 1.0; 1.4)). The GWAS for cortisol yielded 2 SNPs with p-values of 1 × 10(-06) (rs8062512, rs2252459), but these associations could not be replicated. Conclusions: These results suggest that variation in the FKBP5 gene is associated with both cortisolAUC and the likelihood of depressive symptoms.

FKBP5 and resistant attachment predict cortisol reactivity in infants: Gene-environment interaction (Article)

2010-11-01T00:00:00Z

Quality of the parent-infant attachment relationship influences physiological stress regulation. Genetic factors also contribute to the stress regulatory HPA-axis. Quality of attachment as an index of the rearing environment (measured with the Strange Situation Procedure, SSP), and HPA-axis related SNPs (BclI, rs41423247; TthIIII, rs10052957; GR-9β, rs6198; N363S, rs6195; ER22/23EK, rs6189 and 6190; and FKBP5, rs1360780) were hypothesized to be related to cortisol reactivity in the stressful SSP. In this large population based sample, FKBP5 rs1360780, but not GR haplotype, was related to cortisol reactivity. Moreover, we found a significant interaction effect for insecure-resistant attachment and FKBP5 rs1360780, indicating a double-risk for heightened cortisol reactivity levels in infants with one or two T-alleles of the FKBP5 SNP and an insecure-resistant attachment relationship with their mother. Findings are discussed from the perspective of gene-environment interaction.