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It is well-known that childhood attention-deficit hyperactivity disorder (ADHD) is associated with later adverse mental health and social outcomes. Patient-based studies suggest that ADHD may be associated with later cardiovascular disease (CVD) but the focus of preventive interventions is unclear. It is unknown whether ADHD leads to established cardiovascular risk factors because so few cohort studies measure ADHD and also follow up to an age where CVD risk is evident.
To examine associations between childhood ADHD problems and directly measured CVD risk factors at ages 44/45 years in a UK population-based cohort study (National Child Development Study) of individuals born in 1958.
Childhood ADHD problems were defined by elevated ratings on both the parent Rutter A scale and a teacher-rated questionnaire at age 7 years. Outcomes were known cardiovascular risk factors (blood pressure, lipid measurements, body mass index and smoking) at the age 44/45 biomedical assessment.
Of the 8016 individuals assessed both during childhood and at the biomedical assessment 3.0% were categorised as having childhood ADHD problems. ADHD problems were associated with higher body mass index (B = 0.92 kg/m2, s.d. = 0.27–1.56), systolic (3.5 mmHg, s.d. = 1.4–5.6) and diastolic (2.2 mmHg, s.d. = 0.8–3.6) blood pressure, triglyceride levels (0.24 mol/l, s.d. = 0.02–0.46) and being a current smoker (odds ratio OR = 1.6, s.d. = 1.2–2.1) but not with LDL cholesterol.
Childhood ADHD problems predicted multiple cardiovascular risk factors by mid-life. These findings, when taken together with previously observed associations with cardiovascular disease in registries, suggest that individuals with ADHD could benefit from cardiovascular risk monitoring, given these risk factors are modifiable with timely intervention.
Current psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic and environmental risk factors are shared across disorders. However, the relationship between shared symptoms and shared genetic liability is still poorly understood.
Well-characterised, cross-disorder samples are needed to investigate this matter, but few currently exist. Our aim is to develop procedures to purposely curate and aggregate genotypic and phenotypic data in psychiatric research.
As part of the Cardiff MRC Mental Health Data Pathfinder initiative, we have curated and harmonised phenotypic and genetic information from 15 studies to create a new data repository, DRAGON-Data. To date, DRAGON-Data includes over 45 000 individuals: adults and children with neurodevelopmental or psychiatric diagnoses, affected probands within collected families and individuals who carry a known neurodevelopmental risk copy number variant.
We have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all data-sets with genotype information have undergone rigorous quality control, imputation, copy number variant calling and polygenic score generation.
DRAGON-Data combines genetic and non-genetic information, and is available as a resource for research across traditional psychiatric diagnostic categories. Algorithms and pipelines used for data harmonisation are currently publicly available for the scientific community, and an appropriate data-sharing protocol will be developed as part of ongoing projects (DATAMIND) in partnership with Health Data Research UK.
The multifactorial nature of psychopathology, whereby both genetic and environmental factors contribute risk, has long been established. In this paper, we provide an update on genetically informative designs that are utilized to disentangle genetic and environmental contributions to psychopathology. We provide a brief reminder of quantitative behavioral genetic research designs that have been used to identify potentially causal environmental processes, accounting for genetic contributions. We also provide an overview of recent molecular genetic approaches that utilize genome-wide association study data which are increasingly being applied to questions relevant to psychopathology research. While genetically informative designs typically have been applied to investigate the origins of psychopathology, we highlight how these approaches can also be used to elucidate potential causal environmental processes that contribute to developmental course and outcomes. We highlight the need to use genetically sensitive designs that align with intervention and prevention science efforts, by considering strengths-based environments to investigate how positive environments can mitigate risk and promote children’s strengths.
To investigate the accuracy of the age-at-onset criterion in those who meet other DSM-5 criteria for attention-deficit hyperactivity disorder, using a prospective population cohort we compared four different approaches to asking those aged 25 years (n = 138) when their symptoms started. Receiver operating characteristic curves showed variation between the approaches (χ(3) = 8.99, P = 0.03); all four showed low discrimination against symptoms that had been assessed when they were children (area under the curve: 0.57–0.68). Asking adults to recall specific symptoms may be preferable to recalling at what age symptoms started. However, limitations to retrospective recall add to debate on the validity of ADHD age-at-onset assessment.
Attention-deficit hyperactivity disorder (ADHD) is associated with later depression and there is considerable genetic overlap between them. This study investigated if ADHD and ADHD genetic liability are causally related to depression using two different methods.
First, a longitudinal population cohort design was used to assess the association between childhood ADHD (age 7 years) and recurrent depression in young-adulthood (age 18–25 years) in N = 8310 individuals in the Avon Longitudinal Study of Parents and Children (ALSPAC). Second, two-sample Mendelian randomization (MR) analyses examined relationships between genetic liability for ADHD and depression utilising published Genome-Wide Association Study (GWAS) data.
Childhood ADHD was associated with an increased risk of recurrent depression in young-adulthood (OR 1.35, 95% CI 1.05–1.73). MR analyses suggested a causal effect of ADHD genetic liability on major depression (OR 1.21, 95% CI 1.12–1.31). MR findings using a broader definition of depression differed, showing a weak influence on depression (OR 1.07, 95% CI 1.02–1.13).
Our findings suggest that ADHD increases the risk of depression later in life and are consistent with a causal effect of ADHD genetic liability on subsequent major depression. However, findings were different for more broadly defined depression.
There is an enormous interest in identifying the causes of psychiatric disorders but there are considerable challenges in identifying which risks are genuinely causal. Traditionally risk factors have been inferred from observational designs. However, association with psychiatric outcome does not equate to causation. There are a number of threats that clinicians and researchers face in making causal inferences from traditional observational designs because adversities or exposures are not randomly allocated to individuals. Natural experiments provide an alternative strategy to randomized controlled trials as they take advantage of situations whereby links between exposure and other variables are separated by naturally occurring events or situations. In this review, we describe a growing range of different types of natural experiment and highlight that there is a greater confidence about findings where there is a convergence of findings across different designs. For example, exposure to hostile parenting is consistently found to be associated with conduct problems using different natural experiment designs providing support for this being a causal risk factor. Different genetically informative designs have repeatedly found that exposure to negative life events and being bullied are linked to later depression. However, for exposure to prenatal cigarette smoking, while findings from natural experiment designs are consistent with a causal effect on offspring lower birth weight, they do not support the hypothesis that intra-uterine cigarette smoking has a causal effect on attention-deficit/hyperactivity disorder and conduct problems and emerging findings highlight caution about inferring causal effects on bipolar disorder and schizophrenia.
Identifying prenatal environmental factors that have genuinely causal effects on psychopathology is an important research priority, but it is crucial to select an appropriate research design. In this review we explain why and what sorts of designs are preferable and focus on genetically informed/sensitive designs. In the field of developmental psychopathology, causal inferences about prenatal risks have not always been based on evidence generated from appropriate designs. We focus on reported links between maternal smoking during pregnancy and offspring attention-deficit/hyperactivity disorder or conduct problems. Undertaking a systematic review of findings from genetically informed designs and “triangulating” evidence from studies with different patterns of bias, we conclude that at present findings suggest it is unlikely that there is a substantial causal effect of maternal smoking in pregnancy on either attention-deficit/hyperactivity disorder or conduct problems. In contrast, for offspring birth weight (which serves as a positive control) findings strongly support a negative causal effect of maternal smoking in pregnancy. For maternal pregnancy stress, too few studies use genetically sensitive designs to draw firm conclusions, but continuity with postnatal stress seems important. We highlight the importance of moving beyond observational designs, for systematic evaluation of the breadth of available evidence and choosing innovative designs. We conclude that a broader set of prenatal risk factors should be examined, including those relevant in low- and middle-income contexts. Future directions include a greater use of molecular genetically informed designs such as Mendelian randomization to test causal hypotheses about prenatal exposure and offspring outcome.
Previous studies find that both schizophrenia and mood disorder risk alleles contribute to adult depression and anxiety. Emotional problems (depression or anxiety) begin in childhood and show strong continuities into adult life; this suggests that symptoms are the manifestation of the same underlying liability across different ages. However, other findings suggest that there are developmental differences in the etiology of emotional problems at different ages. To our knowledge, no study has prospectively examined the impact of psychiatric risk alleles on emotional problems at different ages in the same individuals.
Data were analyzed using regression-based analyses in a prospective, population-based UK cohort (the National Child Development Study). Schizophrenia and major depressive disorder (MDD) polygenic risk scores (PRS) were derived from published Psychiatric Genomics Consortium genome-wide association studies. Emotional problems were assessed prospectively at six time points from age 7 to 42 years.
Schizophrenia PRS were associated with emotional problems from childhood [age 7, OR 1.09 (1.03–1.15), p = 0.003] to mid-life [age 42, OR 1.10 (1.05–1.17), p < 0.001], while MDD PRS were associated with emotional problems only in adulthood [age 42, OR 1.06 (1.00–1.11), p = 0.034; age 7, OR 1.03 (0.98–1.09), p = 0.228].
Our prospective investigation suggests that early (childhood) emotional problems in the general population share genetic risk with schizophrenia, while later (adult) emotional problems also share genetic risk with MDD. The results suggest that the genetic architecture of depression/anxiety is not static across development.
Objectives: Previous studies have found that oxytocin (OXT) can improve the recognition of emotional facial expressions; it has been proposed that this effect is mediated by an increase in attention to the eye-region of faces. Nevertheless, evidence in support of this claim is inconsistent, and few studies have directly tested the effect of oxytocin on emotion recognition via altered eye-gaze Methods: In a double-blind, within-subjects, randomized control experiment, 40 healthy male participants received 24 IU intranasal OXT and placebo in two identical experimental sessions separated by a 2-week interval. Visual attention to the eye-region was assessed on both occasions while participants completed a static facial emotion recognition task using medium intensity facial expressions. Results: Although OXT had no effect on emotion recognition accuracy, recognition performance was improved because face processing was faster across emotions under the influence of OXT. This effect was marginally significant (p<.06). Consistent with a previous study using dynamic stimuli, OXT had no effect on eye-gaze patterns when viewing static emotional faces and this was not related to recognition accuracy or face processing time. Conclusions: These findings suggest that OXT-induced enhanced facial emotion recognition is not necessarily mediated by an increase in attention to the eye-region of faces, as previously assumed. We discuss several methodological issues which may explain discrepant findings and suggest the effect of OXT on visual attention may differ depending on task requirements. (JINS, 2017, 23, 23–33)
Past research has identified maternal depression and family of origin maltreatment as precursors to adolescent depression and antisocial behavior. Caregiving experiences have been identified as a factor that may ameliorate or accentuate adolescent psychopathology trajectories. Using a multilevel approach that pools the unique attributes of two geographically diverse, yet complementary, longitudinal research designs, the present study examined the role of maternal caregiver involvement as a factor that promotes resilience-based trajectories related to depressive symptoms and antisocial behaviors among adolescent girls. The first sample comprises a group of US-based adolescent girls in foster care (n = 100; mean age = 11.50 years), each of whom had a history of childhood maltreatment and removal from their biological parent(s). The second sample comprises a group of UK-based adolescent girls at high familial risk for depression (n = 145; mean age = 11.70 years), with all girls having biological mothers who experienced recurrent depression. Analyses examined the role of maternal caregiving on girls' trajectories of depression and antisocial behavior, while controlling for levels of co-occurring psychopathology at each time point. Results suggest increasing levels of depressive symptoms for girls at familial risk for depression but decreasing levels of depression for girls in foster care. Foster girls' antisocial behavior also decreased over time. Maternal caregiver involvement was differentially related to intercept and slope parameters in both samples. Results are discussed with respect to the benefits of applying multilevel (multisample, multiple outcome) approaches to identifying family-level factors that can reduce negative developmental outcomes in high-risk youth.
To determine rates of parent-reported child awareness of parental depression, examine characteristics of parents, children and families according to child awareness, and explore whether child awareness is associated with child psychopathology. Data were available from 271 families participating in the Early Prediction of Adolescent Depression (EPAD) study, a longitudinal study of offspring of parents with recurrent depression.
Seventy-three per cent of participating children were perceived as being aware of their parent's depression. Older children, and children of parents who experienced more severe depression, were more likely to be aware. Awareness was not associated with child psychopathology.
Considering children in the context of parental depression is important. Child awareness may influence their access to early intervention and prevention programmes. Further research is needed to understand the impact of awareness on the child.
Children with 22q11.2 deletion syndrome (22q11.2DS) have been reported to have high rates of cognitive and psychiatric problems.
To establish the nature and prevalence of psychiatric disorder and neurocognitive impairment in children with 22q11.2DS and test whether risk of psychopathology is mediated by the children's intellectual impairment.
Neurocognition and psychopathology were assessed in 80 children with 22q11.2DS (mean age 10.2 years, s.d. = 2.1) and 39 sibling controls (mean age 10.9 years, s.d. = 2.0).
More than half (54%) of children with 22q11.2DS met diagnostic criteria for one or more DSM-IV-TR psychiatric disorder. These children had lower IQ (mean 76.8, s.d. = 13.0) than controls (mean 108.6, s.d. = 15.2) (P<0.001) and showed a range of neurocognitive impairments. Increased risk of psychopathology was not mediated by intellectual impairment.
22q11.2DS is not related to a specific psychiatric phenotype in children. Moreover, the deletion has largely independent effects on IQ and risk of psychopathology, indicating that psychopathology in 22q11.2DS is not a non-specific consequence of generalised cognitive impairment.
There is recent evidence of some degree of shared genetic susceptibility between adult schizophrenia and childhood attention-deficit hyperactivity disorder (ADHD) for rare chromosomal variants.
To determine whether there is overlap between common alleles conferring risk of schizophrenia in adults with those that do so for ADHD in children.
We used recently published Psychiatric Genome-wide Association Study (GWAS) Consortium (PGC) adult schizophrenia data to define alleles over-represented in people with schizophrenia and tested whether those alleles were more common in 727 children with ADHD than in 2067 controls.
Schizophrenia risk alleles discriminated ADHD cases from controls (P = 1.04 × 104, R2 = 0.45%); stronger discrimination was given by alleles that were risk alleles for both adult schizophrenia and adult bipolar disorder (also derived from a PGC data-set) (P = 9.98 ×10−6, R2 × 0.59%).
This increasing evidence for a small, but significant, shared genetic susceptibility between adult schizophrenia and childhood ADHD highlights the importance of research work across traditional diagnostic boundaries.
Parental depression is associated with disruptions in the parent–child relationship, exposure to stressful family life events, and offspring depressive symptoms. Evidence suggests that intergenerational transmission of depression involves environmental and inherited contributions. We sought to evaluate the role of passive gene–environment correlation (rGE) in relation to depression, family life events that were due to parental behavior, and parental positivity in a sample where children varied in genetic relatedness to their rearing parents. Our study included 865 families with children born through assisted conception (444 related to both parents, 210 related to the mother only, 175 related to the father only, and 36 related to neither parent). Consistent with previous studies, the intergenerational transmission of depressive symptoms was largely due to environmental factors, although parent and child gender influenced results. Maternal and paternal depressive symptoms were associated with reduced positivity and increased parentally imposed life events regardless of parent–child relatedness. Results of path analysis were consistent with passive rGE for both maternal and paternal positivity in that positivity partially mediated the link between maternal/paternal depression and child depression only in genetically related parent–child pairs. Results also suggested passive rGE involving parentally imposed life events for mothers and fathers although passive rGE effects were smaller than for positivity.
Offspring of mothers with depression are at heightened risk of psychiatric disorder. Many mothers with depression have comorbid psychopathology. How these co-occurring problems affect child outcomes has rarely been considered.
To consider whether the overall burden of co-occurring psychopathology in mothers with recurrent depression predicts new-onset psychopathology in offspring.
Mothers with recurrent depression and their adolescent offspring (9–17 years at baseline) were assessed in 2007 and on two further occasions up to 2011. Mothers completed questionnaires assessing depression severity, anxiety, alcohol problems and antisocial behaviour. Psychiatric disorder in offspring was assessed using the Child and Adolescent Psychiatric Assessment.
The number of co-occurring problems in mothers (0, 1 or 2+) predicted new-onset offspring disorder (odds ratio (OR) = 1.80, 95% CI 1.17–2.77, P = 0.007). Rates varied from 15.7 to 34.8% depending on the number of co-occurring clinical problems. This remained significant after controlling for maternal depression severity (OR = 1.73, 95% CI 1.03–2.89, P = 0.040).
The burden of co-occurring psychopathology among mothers with recurrent depression indexes increased risk of future onset of psychiatric disorder for offspring. This knowledge can be used in targeting preventive measures in children at high risk of psychiatric disorder.
Past research has linked interparental conflict, parent psychopathology, hostile parenting, and externalizing behavior problems in childhood. However, few studies have examined these relationships while simultaneously allowing the contribution of common genetic factors underlying associations between family- and parent-level variables on child psychopathology to be controlled. Using the attributes of a genetically sensitive in vitro fertilization research design, the present study examined associations among interparental conflict, parents' antisocial behavior problems, parents' anxiety symptoms, and hostile parenting on children's antisocial behavior problems among genetically related and genetically unrelated mother–child and father–child groupings. Path analyses revealed that for genetically related mothers, interparental conflict and maternal antisocial behavior indirectly influenced child antisocial behavior through mother-to-child hostility. For genetically unrelated mothers, effects were apparent only for maternal antisocial behavior on child antisocial behavior through mother-to-child hostility. For both genetically related and genetically unrelated fathers and children, interparental conflict and paternal antisocial behavior influenced child antisocial behavior through father-to-child hostility. Effects of parental anxiety symptoms on child antisocial behavior were apparent only for genetically related mothers and children. Results are discussed with respect to the relative role of passive genotype–environment correlation as a possible confounding factor underlying family process influences on childhood psychopathology.
The rate of multiple births is substantially elevated in women who have had assisted reproduction treatment (ART; ˜26%) compared to the general population (˜1%), and these offspring are usually included in twin studies. Several studies have attempted to identify possible consequences of undergoing ART on the subsequent offspring. However, most studies have only included singleton births. We first examined whether twins born by ART differed from other twins on measures of childhood psychopathology, putative risk factors and correlates, and secondly tested for differences in the degree of twin similarity for available outcome measures. From a population-based twin sample, 101 families with dizygotic (DZ) twins conceived via ART were identified and compared with 1073 naturally conceived (NC) control DZ twin pairs. Analyses performed were (1) univariate and multivariate comparisons of between-group mean differences; and (2) comparison of twin 1–twin 2 correlations between the groups. The groups differed significantly on demographic factors (parental age, family size and social class) and pregnancy variables (smoking during pregnancy and birthweight) but did not differ on family conflict scores or in the frequency of obstetric complications. Family cohesion was higher in the ART group but this was accounted for by demographic factors. For child psychopathology there was a difference between the groups only for teacher-rated ADHD (Attention Deficit Hyperactivity Disorder). Differences were also found between groups for twin correlations. The differences found between ART and NC twins on group means and twin correlations suggest that researchers should be aware that including ART twins may influence results from twin studies.
The study of twins and their families provides a highly useful tool for disentangling the genetic and environmental origins of traits. The Cardiff Study of All Wales and North West of England Twins (CaStANET) has followed children and adolescents over time into early adulthood, assessing a wide range of aspects of behavior and psychopathology using self-, parent and teacher reports. Four main waves of data collection have taken place to date, which have provided a wealth of information on the contributions of genetic and environmental risk factors to the psychological health of young people. This article first describes the CaStANET register and subsequently presents some of the findings that have emerged from this resource, with a focus on depression and anxiety, chronic fatigue, attention-deficit/hyperactivity disorder, conduct problems and prosocial behavior. We describe in somewhat more detail the 4th wave of data collection, which has recently been completed and has provided us with extensive information on substance use and problem use as well as associated risk factors in the twins and their families, including longitudinal data on conduct problems and the relations between family members. Because of the wealth of data already collected and the opportunity for genetically informative analyses over time, CaStANET provides a valuable resource for understanding the complexities of the psychological development of young people.
Submicroscopic, rare chromosomal copy number variants (CNVs) contribute to neurodevelopmental disorders but it is not known whether they define atypical clinical cases.
To identify whether large, rare CNVs in attention-deficit hyperactivity disorder (ADHD) are confined to a distinct clinical subgroup.
A total of 567 children with ADHD aged 5–17 years were recruited from community clinics. Psychopathology was assessed using the Child and Adolescent Psychiatric Assessment. Large, rare CNVs (>500 kb, <1% frequency) were defined from single nucleotide polymorphism data.
Copy number variant carriers (13.6%) showed no differences from non-carriers in ADHD symptom severity, symptom type, comorbidity, developmental features, family history or pre-/ perinatal markers. The only significant difference was a higher rate of intellectual disability (24% v. 9%, χ2 = 15.5, P = 0.001). Most CNV carriers did not have intellectual disability.
Large, rare CNVs are not restricted to an atypical form of ADHD but may be more highly enriched in children with cognitive problems.
Some research suggests that children with attention-deficit hyperactivity
disorder (ADHD) have a higher than expected risk of bipolar affective
disorder. No study has examined the prevalence of bipolar disorder in a
UK sample of children with ADHD.
To examine the prevalence of bipolar disorder in children diagnosed with
ADHD or hyperkinetic disorder.
Psychopathology symptoms and diagnoses of bipolar disorder were assessed
in 200 young people with ADHD (170 male, 30 female; age 6–18 years, mean
11.15, s.d. = 2.95). Rates of current bipolar disorder symptoms and
diagnoses are reported. A family history of bipolar disorder in parents
and siblings was also recorded.
Only one child, a 9-year-old boy, met diagnostic criteria for both ICD–10
hypomania and DSM–IV bipolar disorder not otherwise specified.
In a UK sample of children with ADHD a current diagnosis of bipolar
disorder was uncommon.