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

FTO at rs9939609, Food Responsiveness, Emotional Control and Symptoms of ADHD in Preschool Children

The FTO minor allele at rs9939609 has been associated with body mass index (BMI: weight (kg)/height (m)2) in children from 5 years onwards, food intake, and eating behaviour. The high expression of FTO in the brain suggests that this gene may also be associated with behavioural phenotypes, such as impulsivity and control. We examined the effect of the FTO minor allele (A) at rs9939609 on eating behaviour, impulsivity and control in young children, thus before the BMI effect becomes apparent. This study was embedded in the Generation R Study, a population-based cohort from fetal life onwards. 1,718 children of European descent were genotyped for FTO at rs9939609. With logistic regression assuming an additive genetic model, we examined the association between the FTO minor allele and eating behaviour, impulsivity and control in preschool children. There was no relation between FTO at rs9939609 and child BMI at this age. The A allele at rs9939609 was associated with increased food responsiveness (OR 1.21, p = 0.03). Also, children with the A allele were less likely to have symptoms of ADHD (OR 0.74, p = 0.01) and showed more emotional control (OR 0.64, p = 0.01) compared to children without the A allele. Our findings suggest that before the association between FTO and BMI becomes apparent, the FTO minor allele at rs9939609 leads to increased food responsiveness, a decreased risk for symptoms of ADHD and better emotional control. Future studies are needed to investigate whether these findings represent one single mechanism or reflect pleiotropic effects of FTO

Everolimus- and sirolimus-eluting stents in patients with and without ST-segment elevation myocardial infarction

Aims Everolimus-eluting stents (EES) were superior to sirolimus-eluting stents (SES) in a dedicated myocardial infarction trial, a finding that was not observed in trials with low percentages of ST-elevation myocardial infarction (STEMI). Therefore, this study sought to investigate the influence of clinical presentation on outcome after EES and SES implantation. Methods A pooled population of 1602 randomised patients was formed from XAMI (acute MI trial) and APPENDIXAMI (all-comer trial). Primary outcome was cardiac mortality, MI and target vessel revascularisation at 2 years. Secondary endpoints included definite/probable stent thrombosis (ST). Adjustment was done using Cox regression. Results In total, 902 EES and 700 SES patientswere included, of which 44%STEMI patients (EES 455; SES 257) and 56% without STEMI (EES 447; SES 443). In the pooled population, EES and SES showed similar outcomes during followup. Moreover, no differences in the endpoints were observed after stratification according to presentation. Although a trend toward reduced early definite/probable ST was observed in EES compared with SES in STEMI patients, long-term ST rates were low and comparable. Conclusions EES and SES showed a similar outcome during 2-year follow-up, regardless of clinical presentation. Longterm safety was excellent for both devices, despite wide inclusion criteria and a large sub-population of STEMI patients

Information extraction from free text for aiding transdiagnostic psychiatry: constructing NLP pipelines tailored to clinicians’ needs

Background: Developing predictive models for precision psychiatry is challenging because of unavailability of the necessary data: extracting useful information from existing electronic health record (EHR) data is not straightforward, and available clinical trial datasets are often not representative for heterogeneous patient groups. The aim of this study was constructing a natural language processing (NLP) pipeline that extracts variables for building predictive models from EHRs. We specifically tailor the pipeline for extracting information on outcomes of psychiatry treatment trajectories, applicable throughout the entire spectrum of mental health disorders (“transdiagnostic”). Methods: A qualitative study into beliefs of clinical staff on measuring treatment outcomes was conducted to construct a candidate list of variables to extract from the EHR. To investigate if the proposed variables are suitable for measuring treatment effects, resulting themes were compared to transdiagnostic outcome measures currently used in psychiatry research and compared to the HDRS (as a gold standard) through systematic review, resulting in an ideal set of variables. To extract these from EHR data, a semi-rule based NLP pipeline was constructed and tailored to the candidate variables using Prodigy. Classification accuracy and F1-scores were calculated and pipeline output was compared to HDRS scores using clinical notes from patients admitted in 2019 and 2020. Results: Analysis of 34 questionnaires answered by clinical staff resulted in four themes defining treatment outcomes: symptom reduction, general well-being, social functioning and personalization. Systematic review revealed 242 different transdiagnostic outcome measures, with the 36-item Short-Form Survey for quality of life (SF36) being used most consistently, showing substantial overlap with the themes from the qualitative study. Comparing SF36 to HDRS scores in 26 studies revealed moderate to good correlations (0.62—0.79) and good positive predictive values (0.75—0.88). The NLP pipeline developed with notes from 22,170 patients reached an accuracy of 95 to 99 percent (F1 scores: 0.38 – 0.86) on detecting these themes, evaluated on data from 361 patients. Conclusions: The NLP pipeline developed in this study extracts outcome measures from the EHR that cater specifically to the needs of clinical staff and align with outcome measures used to detect treatment effects in clinical trials

Medical comorbidities in children and adolescents with autism spectrum disorders and attention deficit hyperactivity disorders: a systematic review

Item does not contain fulltextSomatic disorders occur more often in adult psychiatric patients than in the general adult population. However, in child and adolescent psychiatry this association is unclear, mainly due to a lack of integration of existing data. To address this issue, we here present a systematic review on medical comorbidity in the two major developmental disorders autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) and formulate clinical recommendations. The literature was searched using the PubMed and PsycINFO databases (2000-1 May 2016) with the keywords "[((child and adolescent) AND (Autism OR Attention Deficit Hyperactivity Disorder* OR ADHD)) AND ("Cardiovascular Diseases" [Mesh] OR "Endocrine System Diseases" [Mesh] OR "Immune System Diseases" [Mesh] OR "Neurobehavioral Manifestations" [Mesh] OR "Gastrointestinal Disorders" [Mesh] OR Somatic OR Autoimmune disease OR Nervous system disease OR Infection OR Infectious disease)]. Two raters independently assessed the quality of the eligible studies. The initial search identified 5278 articles. Based on inclusion and exclusion criteria 104 papers were selected and subsequently subjected to a quality control. This quality was assessed according to a standardized and validated set of criteria and yielded 29 studies for inclusion. This thorough literature search provides an overview of relevant articles on medical comorbidity in ADHD and/or ASD, and shows that medical disorders in these children and adolescents appear to be widespread. Those who work with children with ASD and/or ADHD should be well aware of this and actively promote routine medical assessment. Additionally, case-control studies and population-based studies are needed to provide reliable prevalence estimates. Future studies should furthermore focus on a broader evaluation of medical disorders in children and adolescents with ADHD and/or ASD to improve treatment algorithm in this vulnerable group

Information extraction from free text for aiding transdiagnostic psychiatry: constructing NLP pipelines tailored to clinicians’ needs

Background Developing predictive models for precision psychiatry is challenging because of unavailability of the necessary data: extracting useful information from existing electronic health record (EHR) data is not straightforward, and available clinical trial datasets are often not representative for heterogeneous patient groups. The aim of this study was constructing a natural language processing (NLP) pipeline that extracts variables for building predictive models from EHRs. We specifically tailor the pipeline for extracting information on outcomes of psychiatry treatment trajectories, applicable throughout the entire spectrum of mental health disorders ("transdiagnostic"). Methods A qualitative study into beliefs of clinical staff on measuring treatment outcomes was conducted to construct a candidate list of variables to extract from the EHR. To investigate if the proposed variables are suitable for measuring treatment effects, resulting themes were compared to transdiagnostic outcome measures currently used in psychiatry research and compared to the HDRS (as a gold standard) through systematic review, resulting in an ideal set of variables. To extract these from EHR data, a semi-rule based NLP pipeline was constructed and tailored to the candidate variables using Prodigy. Classification accuracy and F1-scores were calculated and pipeline output was compared to HDRS scores using clinical notes from patients admitted in 2019 and 2020. Results Analysis of 34 questionnaires answered by clinical staff resulted in four themes defining treatment outcomes: symptom reduction, general well-being, social functioning and personalization. Systematic review revealed 242 different transdiagnostic outcome measures, with the 36-item Short-Form Survey for quality of life (SF36) being used most consistently, showing substantial overlap with the themes from the qualitative study. Comparing SF36 to HDRS scores in 26 studies revealed moderate to good correlations (0.62-0.79) and good positive predictive values (0.75-0.88). The NLP pipeline developed with notes from 22,170 patients reached an accuracy of 95 to 99 percent (F1 scores: 0.38 - 0.86) on detecting these themes, evaluated on data from 361 patients. Conclusions The NLP pipeline developed in this study extracts outcome measures from the EHR that cater specifically to the needs of clinical staff and align with outcome measures used to detect treatment effects in clinical trials

Information extraction from free text for aiding transdiagnostic psychiatry: constructing NLP pipelines tailored to clinicians’ needs

Background Developing predictive models for precision psychiatry is challenging because of unavailability of the necessary data: extracting useful information from existing electronic health record (EHR) data is not straightforward, and available clinical trial datasets are often not representative for heterogeneous patient groups. The aim of this study was constructing a natural language processing (NLP) pipeline that extracts variables for building predictive models from EHRs. We specifically tailor the pipeline for extracting information on outcomes of psychiatry treatment trajectories, applicable throughout the entire spectrum of mental health disorders ("transdiagnostic"). Methods A qualitative study into beliefs of clinical staff on measuring treatment outcomes was conducted to construct a candidate list of variables to extract from the EHR. To investigate if the proposed variables are suitable for measuring treatment effects, resulting themes were compared to transdiagnostic outcome measures currently used in psychiatry research and compared to the HDRS (as a gold standard) through systematic review, resulting in an ideal set of variables. To extract these from EHR data, a semi-rule based NLP pipeline was constructed and tailored to the candidate variables using Prodigy. Classification accuracy and F1-scores were calculated and pipeline output was compared to HDRS scores using clinical notes from patients admitted in 2019 and 2020. Results Analysis of 34 questionnaires answered by clinical staff resulted in four themes defining treatment outcomes: symptom reduction, general well-being, social functioning and personalization. Systematic review revealed 242 different transdiagnostic outcome measures, with the 36-item Short-Form Survey for quality of life (SF36) being used most consistently, showing substantial overlap with the themes from the qualitative study. Comparing SF36 to HDRS scores in 26 studies revealed moderate to good correlations (0.62-0.79) and good positive predictive values (0.75-0.88). The NLP pipeline developed with notes from 22,170 patients reached an accuracy of 95 to 99 percent (F1 scores: 0.38 - 0.86) on detecting these themes, evaluated on data from 361 patients. Conclusions The NLP pipeline developed in this study extracts outcome measures from the EHR that cater specifically to the needs of clinical staff and align with outcome measures used to detect treatment effects in clinical trials.Analysis and Stochastic

Media violence and children’s ADHD-related behaviors: a genetic susceptibility perspective

This study examined the relationship between media violence exposure and Attention-deficit/hyperactivity disorder (ADHD)-related behaviors. Using survey (parent-reported) and genetic data of 1,612 Dutch children (aged 5 to 9 years), we examined genetic disposition as a possible cause of individual differences in children's use of and susceptibility to media violence. The gene variant of interest was the 5-HTTLPR polymorphism, which has been associated with ADHD-related behaviors in previous research. Results showed that the "long" variant of the gene polymorphism was related to greater violent media use, which in turn was related to more ADHD-related behaviors. The 5-HTTLPR genotype did not moderate the effect of media violence on ADHD-related behaviors. This study provides insight into the role of genetic factors in media effects

The longitudinal association of the diurnal cortisol rhythm with internalizing and externalizing problems in pre-schoolers. The Generation R Study

Background: Studies investigating the association between diurnal cortisol rhythm and behavioural problems in young children have yielded inconsistent results. We tested the hypothesis that variations in diurnal cortisol rhythm in pre-schoolers are already related to problem behaviour early in life with a cross-sectional and longitudinal design. Methods: This study was embedded in Generation R, a population-based cohort from foetal life onwards. Parents collected saliva samples from their infant at 5 moments during 1 day. In 322 infants aged 12-20 months, we determined the diurnal cortisol rhythm by calculating the area under the curve (AUC), the cortisol awakening response (CAR), and the diurnal slope. Problem behaviour was assessed at ages 1.5 and 3 years with the Child Behavior Checklist/1.5-5 years. Results: No cross-sectional associations between the cortisol composite measures and problem behaviour were found at 1.5 years. However, cortisol predicted change in internalizing problems as assessed from 1.5 to 3 years, but not change in externalizing problems. Children with higher AUC levels, flatter slopes and a more positive CAR at baseline were more likely to score higher on the Internalizing Problems scale (β per nmol/L AUC: 0.08, 95% CI: 0.00; 0.17, p=. 0.04; β per nmol/L/h slope: 0.57, 95% CI: 0.17; 0.98, p=. 0.006; β per nmol/L CAR: 0.04, 95% CI: 0.01; 0.08, p=. 0.02) at follow-up. Conclusions: Variations in diurnal cortisol rhythm are associated with change in internalizing problems in pre-schoolers. The results suggest that variations in diurnal cortisol patterns early in life precede internalizing problems

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

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.|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.|Findings of a significant gene × 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.|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