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

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.

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