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Background: Maternal stress during pregnancy may impact offspring development via changes in the intrauterine environment. However, genetic and environmental factors shared between mothers and children might skew our understanding of this pathway. This study assesses whether prenatal maternal stress has causal links to offspring outcomes: birthweight, gestational age, or emotional and behavioral difficulties, triangulating across methods that account for various measured and unmeasured confounders., Methods: We used data from the Norwegian Mother, Father, and Child Cohort Study (MoBa), including maternal reports on prenatal stress at work, at home, and via stressful life events as exposures. Outcomes were children's birthweight and gestational age, from the Medical Birth Registry of Norway, and maternal reports on early offspring emotional and behavioral difficulties. We assessed associations using four approaches: sibling control analyses, gene-environment interaction analyses, intergenerational Mendelian randomization (MR), and negative control (i.e., postnatal stress) analyses., Results: Maternal prenatal stress was observationally associated with offspring lower birthweight (e.g., β work  = - 0.01 [95%CI: - 0.02, - 0.01]), earlier birth (e.g., β work  = - 0.04 [95%CI: - 0.04, - 0.03])), and more emotional (e.g., β events  = 0.08 [95%CI: 0.07, 0.09]) and behavioral difficulties (e.g., β relationship  = 0.08 [95%CI: 0.07, 0.09]) in the full sample (N = 112,784). However, sibling control analyses (N = 36,511) revealed substantial attenuation of all associations after accounting for familial factors. Gene-environment interaction models (N = 76,288) showed no clear evidence of moderation of associations by mothers' polygenic scores for traits linked to stress sensitivity. Intergenerational MR analyses (N = 29,288) showed no clear evidence of causal effects of maternal plasma cortisol on any offspring outcomes. Negative control exposure analyses revealed similar effect sizes whether exposures were measured prenatally or postnatally., Conclusions: Our results indicate that links between prenatal maternal stress and variation in early offspring outcomes are more likely to be confounded than causal. While no observational study can rule out causality, the consistency of our findings across different approaches is striking. Other sources of prenatal stress or more extreme levels may represent intrauterine causal risk factors for offspring development. Nonetheless, our research contributes to identifying boundary conditions of the fetal programming and developmental origins of health and disease hypotheses, which may not be as universal as sometimes assumed., Competing Interests: Declarations. Ethics approval and consent to participate: The current study was approved by The Regional Committees for Medical and Health Research Ethics (2016/1702). All mothers and fathers provided informed consent at recruitment. Consent for publication: The consent to participate includes consent for publications based on the MoBa study. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Whether emotional problems during childhood and adolescence are longitudinally associated with adult alcohol use behaviors is unclear. This study examined associations between developmental trajectories of emotional problems and early adult alcohol use behaviors, while considering co-occurring conduct problems, developmental change/timing, sex differences, and potential confounds., Methods: Participants were from the Twins Early Development Study (analytic N = 19,908 individuals). Emotional and conduct problems were measured by parent reports at child ages 4, 7, and 9 years and via self-reports at ages 9, 11, and 16 years on the Strengths and Difficulties Questionnaire. Alcohol use behaviors (alcohol consumption and alcohol-related problems) were self-reported by the twins on the Alcohol Use Disorders Identification Test at age 22 years. Piecewise latent growth curve models described nonlinear developmental trajectories of emotional and conduct problems from ages 4 to 16. At age 22, alcohol use was regressed on emotional and conduct problems' intercepts and slopes from piecewise latent growth curve model and sex differences in regression coefficients were tested. Using twin modeling, Cholesky decompositions and direct path models were compared to test whether significant phenotypic associations were best explained by direct phenotypic influences or correlated genetic and environmental influences., Results: Emotional problems had different associations with alcohol-related problems versus alcohol consumption. After accounting for direct influences from conduct problems, emotional problems were not associated with alcohol-related problems, while emotional problems at age 9 were negatively associated with alcohol consumption in males., Conclusions: Overall, findings did not support emotional problems as prospective risk factors for severe alcohol use above and beyond risks associated with conduct problems. Sex- and age-specific links between emotional problems and alcohol consumption in early adulthood may be worthy of further exploration, particularly as twin analyses improved our confidence that such links may be underpinned by causal mechanisms., (© 2024 The Author(s). Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Background: Symptoms related to mood and anxiety disorders (emotional disorders) often present in childhood and adolescence. Some of the genetic liability for mental disorders, and emotional and behavioral difficulties seems to be shared. Yet, it is unclear how genetic liability for emotional disorders and related traits influence trajectories of childhood behavioral and emotional difficulties, and if specific developmental patterns are associated with higher genetic liability for these disorders., Methods: This study uses data from a genotyped sample of children (n = 54,839) from the Norwegian Mother, Father, and Child Cohort Study (MoBa). We use latent growth models (1.5-5 years) and latent profile analyses (1.5-8 years) to quantify childhood trajectories and profiles of emotional and behavioral difficulties and diagnoses. We examine associations between these trajectories and profiles with polygenic scores for bipolar disorder (PGS BD ), anxiety (PGS ANX ), depression (PGS DEP ), and neuroticism (PGS NEUR )., Results: Associations between PGS DEP , PGS ANX , and PGS NEUR , and emotional and behavioral difficulties in childhood were more persistent than age-specific across early childhood (1.5-5 years). Higher PGS ANX and PGS DEP were associated with steeper increases in behavioral difficulties across early childhood. Latent profile analyses identified five profiles with different associations with emotional disorder diagnosis. All PGS were associated with the probability of classification into profiles characterized by some form of difficulties (vs. a normative reference profile), but only PGS BD was uniquely associated with a single developmental profile., Conclusions: Genetic risk for mood disorders and related traits contribute to both a higher baseline level of, and a more rapid increase in, emotional and behavioral difficulties across early and middle childhood, with some indications for disorder-specific profiles. Our findings may inform research on developmental pathways to emotional disorders and the improvement of initiatives for early identification and targeted intervention., (© 2024 The Author(s). Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Lay Abstract: Using questionnaires in research relies on the expectation that they measure the same things across different groups of individuals. If this is not true, then interpretations of results can be misleading when researchers compare responses across different groups of individuals or use in it a group that differs from that in which the questionnaire was developed. For the questionnaire we investigated, the Social Communication Questionnaire (SCQ), we found that parents of boys and girls responded to questionnaire items in largely the same way but that the SCQ measured traits and behaviors slightly differently depending on whether the children had autism. Based on these results, we concluded that researchers using this questionnaire should carefully consider these differences when deciding how to interpret findings. SCQ scores as a reflection of "autism-associated traits" in samples that are mostly or entirely made up of individuals without an autism diagnosis may be misleading and we encourage a more precise interpretation of scores as a broader indication of social-communicative and behavioral traits., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: V.H.B. receives research funding from Western Psychological Services for research related to the Autism Diagnostic Interview–Revised and receives consultant fees from Janssen Research and Development, Inc.

Children born to parents with fewer years of education are more likely to have depression, anxiety, and attention-deficit hyperactivity disorder (ADHD), but it is unclear to what extent these associations are causal. We estimated the effect of parents' educational attainment on children's depressive, anxiety, and ADHD traits at age 8 years, in a sample of 40,879 Norwegian children born in 1998-2009 and their parents. We used within-family Mendelian randomization, which employs genetic variants as instrumental variables, and controlled for direct genetic effects by adjusting for children's polygenic indexes. We found little evidence that mothers' or fathers' educational attainment independently affected children's depressive, anxiety, or ADHD traits. However, children's own polygenic scores for educational attainment were independently and negatively associated with these traits. Results suggest that differences in these traits according to parents' education may reflect direct genetic effects more than genetic nurture. Consequences of social disadvantage for children's mental health may however be more visible in samples with more socioeconomic variation, or contexts with larger socioeconomic disparities than present-day Norway. Further research is required in populations with more educational and economic inequality and in other age groups., (© 2024. The Author(s).)

Importance: Adolescence is a critical developmental phase when mental health disorders, such as anxiety and depression, often emerge. Stringent public health measures and quarantine mandates during the COVID-19 pandemic could threaten adolescent mental health., Objective: To investigate the associations of public health measures and quarantine experiences with mental distress among Norwegian adolescents and to explore if certain vulnerability factors moderate these associations., Design, Setting, and Participants: This longitudinal cohort study used repeated measures to capture variations in mental distress explained by the stringency of public health measures and quarantine experiences. Data from the Norwegian Mother, Father, and Child cohort study were linked to national health registries and a national stringency index from April 1, 2020, to February 17, 2021. Participant included 7787 Norwegian adolescents aged 16 to 18 years. Data were analyzed from October 2022 to October 2023., Exposures: Stringency index of public health measures and quarantine experiences including recent quarantine (within the last 2 weeks) and quarantine frequency (cumulative number of quarantine episodes)., Main Outcome and Measures: Mental distress was measured using the Hopkins Symptom Checklist across 6 data collection waves., Results: In this study, 7787 participants were included in the analysis (4473 female [57%]; mean [SD] age, 17.0 [0.6] years). Stringent public health measures (β = 0.18; SE, 0.02; P < .001), recent quarantine (β = 0.11; SE, 0.02; P < .001), and frequent quarantine (β = 0.08; SE, 0.01; P < .001) were associated with higher levels of mental distress. The associations between public health measures and mental distress were not moderated by sex, age, prepandemic anxiety or depression, or genetic liability for mental health conditions. Frequency of quarantine appeared to be more strongly associated with mental distress among younger adolescents (β = -0.04; SE, 0.01; P = .008), those with parents with lower education (β = -0.04; SE, 0.01; P = .007), and those with lower genetic risk for depression (β = -0.03; SE, 0.01; P = .006)., Conclusions and Relevance: In this study, younger adolescents, those with parents with lower education, or those with low genetic liability for depression appeared more vulnerable when being quarantined several times. These findings emphasize the need for targeted support strategies to better protect adolescent well-being during future crises. Adolescents who experienced increased mental distress during the COVID-19 pandemic may be at risk of continued mental health problems and in need of ongoing support.

Background: Autism and different neurodevelopmental conditions frequently co-occur, as do their symptoms at sub-diagnostic threshold levels. Overlapping traits and shared genetic liability are potential explanations., Methods: In the population-based Norwegian Mother, Father, and Child Cohort study (MoBa), we leverage item-level data to explore the phenotypic factor structure and genetic architecture underlying neurodevelopmental traits at age 3 years (N = 41,708-58,630) using maternal reports on 76 items assessing children's motor and language development, social functioning, communication, attention, activity regulation, and flexibility of behaviors and interests., Results: We identified 11 latent factors at the phenotypic level. These factors showed associations with diagnoses of autism and other neurodevelopmental conditions. Most shared genetic liabilities with autism, ADHD, and/or schizophrenia. Item-level GWAS revealed trait-specific genetic correlations with autism (items r g range = - 0.27-0.78), ADHD (items r g range = - 0.40-1), and schizophrenia (items r g range = - 0.24-0.34). We find little evidence of common genetic liability across all neurodevelopmental traits but more so for several genetic factors across more specific areas of neurodevelopment, particularly social and communication traits. Some of these factors, such as one capturing prosocial behavior, overlap with factors found in the phenotypic analyses. Other areas, such as motor development, seemed to have more heterogenous etiology, with specific traits showing a less consistent pattern of genetic correlations with each other., Conclusions: These exploratory findings emphasize the etiological complexity of neurodevelopmental traits at this early age. In particular, diverse associations with neurodevelopmental conditions and genetic heterogeneity could inform follow-up work to identify shared and differentiating factors in the early manifestations of neurodevelopmental traits and their relation to autism and other neurodevelopmental conditions. This in turn could have implications for clinical screening tools and programs., (© 2024. The Author(s).)

Background: The timing of puberty may have an important impact on adolescent mental health. In particular, earlier age at menarche has been associated with elevated rates of depression in adolescents. Previous research suggests that this relationship may be causal, but replication and an investigation of whether this effect extends to other mental health domains is warranted., Methods: In this Registered Report, we triangulated evidence from different causal inference methods using a new wave of data (N = 13,398) from the Norwegian Mother, Father, and Child Cohort Study. We combined multiple regression, one- and two-sample Mendelian randomisation (MR), and negative control analyses (using pre-pubertal symptoms as outcomes) to assess the causal links between age at menarche and different domains of adolescent mental health., Results: Our results supported the hypothesis that earlier age at menarche is associated with elevated depressive symptoms in early adolescence based on multiple regression (β =  - 0.11, 95% CI [- 0.12, - 0.09], p one-tailed  < 0.01). One-sample MR analyses suggested that this relationship may be causal (β =  - 0.07, 95% CI [- 0.13, 0.00], p one-tailed  = 0.03), but the effect was small, corresponding to just a 0.06 standard deviation increase in depressive symptoms with each earlier year of menarche. There was also some evidence of a causal relationship with depression diagnoses during adolescence based on one-sample MR (OR = 0.74, 95% CI [0.54, 1.01], p one-tailed  = 0.03), corresponding to a 29% increase in the odds of receiving a depression diagnosis with each earlier year of menarche. Negative control and two-sample MR sensitivity analyses were broadly consistent with this pattern of results. Multivariable MR analyses accounting for the genetic overlap between age at menarche and childhood body size provided some evidence of confounding. Meanwhile, we found little consistent evidence of effects on other domains of mental health after accounting for co-occurring depression and other confounding., Conclusions: We found evidence that age at menarche affected diagnoses of adolescent depression, but not other domains of mental health. Our findings suggest that earlier age at menarche is linked to problems in specific domains rather than adolescent mental health in general., (© 2024. The Author(s).)

The aetiology of conduct problems involves a combination of genetic and environmental factors, many of which are inherently linked to parental characteristics given parents' central role in children's lives across development. It is important to disentangle to what extent links between parental heritable characteristics and children's behaviour are due to transmission of genetic risk or due to parental indirect genetic influences via the environment (i.e., genetic nurture). We used 31,290 genotyped mother-father-child trios from the Norwegian Mother, Father and Child Cohort Study (MoBa), testing genetic transmission and genetic nurture effects on conduct problems using 13 polygenic scores (PGS) spanning psychiatric conditions, substance use, education-related factors, and other risk factors. Maternal or self-reports of conduct problems at ages 8 and 14 years were available for up to 15,477 children. We found significant genetic transmission effects on conduct problems for 12 out of 13 PGS at age 8 years (strongest association: PGS for smoking, β = 0.07, 95% confidence interval = [0.05, 0.08]) and for 4 out of 13 PGS at age 14 years (strongest association: PGS for externalising problems, β = 0.08, 95% confidence interval = [0.05, 0.11]). Conversely, we did not find genetic nurture effects for conduct problems using our selection of PGS. Our findings provide evidence for genetic transmission in the association between parental characteristics and child conduct problems. Our results may also indicate that genetic nurture via traits indexed by our polygenic scores is of limited aetiological importance for conduct problems-though effects of small magnitude or effects via parental traits not captured by the included PGS remain a possibility., (© 2024. The Author(s).)

Importance: Conventional epidemiological analyses have suggested that lower birth weight is associated with later neurodevelopmental difficulties; however, it is unclear whether this association is causal., Objective: To investigate the relationship between intrauterine growth and offspring neurodevelopmental difficulties., Design, Setting, and Participants: MoBa is a population-based pregnancy cohort that recruited pregnant women from June 1999 to December 2008 included approximately 114 500 children, 95 200 mothers, and 75 200 fathers. Observational associations between birth weight and neurodevelopmental difficulties were assessed with a conventional epidemiological approach. Mendelian randomization analyses were performed to investigate the potential causal association between maternal allele scores for birth weight and offspring neurodevelopmental difficulties conditional on offspring allele scores., Exposures: Birth weight and maternal allele scores for birth weight (derived from genetic variants robustly associated with birth weight) were the exposures in the observational and mendelian randomization analyses, respectively., Main Outcomes and Measures: Clinically relevant maternal ratings of offspring neurodevelopmental difficulties at 6 months, 18 months, 3 years, 5 years, and 8 years of age assessing language and motor difficulties, inattention and hyperactivity-impulsivity, social communication difficulties, and repetitive behaviors., Results: The conventional epidemiological sample included up to 46 970 offspring, whereas the mendelian randomization sample included up to 44 134 offspring (median offspring birth year, 2005 [range, 1999-2009]; mean [SD] maternal age at birth, 30.1 [4.5] years; mean [SD] paternal age at birth, 32.5 [5.1] years). The conventional epidemiological analyses found evidence that birth weight was negatively associated with several domains at multiple offspring ages (outcome of autism-related trait scores: Social Communication Questionnaire [SCQ]-full at 3 years, β = -0.046 [95% CI, -0.057 to -0.034]; SCQ-Restricted and Repetitive Behaviors subscale at 3 years, β = -0.049 [95% CI, -0.060 to -0.038]; attention-deficit/hyperactivity disorder [ADHD] trait scores: Child Behavior Checklist [CBCL]-ADHD subscale at 18 months, β = -0.035 [95% CI, -0.045 to -0.024]; CBCL-ADHD at 3 years, β = -0.032 [95% CI, -0.043 to -0.021]; CBCL-ADHD at 5 years, β = -0.050 [95% CI, -0.064 to -0.037]; Rating Scale for Disruptive Behavior Disorders [RS-DBD]-ADHD at 8 years, β = -0.036 [95% CI, -0.049 to -0.023]; RS-DBD-Inattention at 8 years, β = -0.037 [95% CI, -0.050 to -0.024]; RS-DBD-Hyperactive-Impulsive Behavior at 8 years, β = -0.027 [95% CI, -0.040 to -0.014]; Conners Parent Rating Scale-Revised [Short Form] at 5 years, β = -0.041 [95% CI, -0.054 to -0.028]; motor scores: Ages and Stages Questionnaire-Motor Difficulty [ASQ-MOTOR] at 18 months, β = -0.025 [95% CI, -0.035 to -0.015]; ASQ-MOTOR at 3 years, β = -0.029 [95% CI, -0.040 to -0.018]; and Child Development Inventory-Gross and Fine Motor Skills at 5 years, β = -0.028 [95% CI, -0.042 to -0.015]). Mendelian randomization analyses did not find any evidence for an association between maternal allele scores for birth weight and offspring neurodevelopmental difficulties., Conclusions and Relevance: This study found that the maternal intrauterine environment, as proxied by maternal birth weight genetic variants, is unlikely to be a major determinant of offspring neurodevelopmental outcomes.

Background: While maternal at-risk drinking is associated with children's emotional and behavioral problems, there is a paucity of research that properly accounts for genetic confounding and gene-environment interplay. Therefore, it remains uncertain what mechanisms underlie these associations. We assess the moderation of associations between maternal at-risk drinking and childhood emotional and behavioral problems by common genetic variants linked to environmental sensitivity (genotype-by-environment [G × E] interaction) while accounting for shared genetic risk between mothers and offspring (GE correlation)., Methods: We use data from 109 727 children born to 90 873 mothers enrolled in the Norwegian Mother, Father, and Child Cohort Study. Women self-reported alcohol consumption and reported emotional and behavioral problems when children were 1.5/3/5 years old. We included child polygenic scores (PGSs) for traits linked to environmental sensitivity as moderators., Results: Associations between maternal drinking and child emotional ( β 1 = 0.04 [95% confidence interval (CI) 0.03-0.05]) and behavioral ( β 1 = 0.07 [0.06-0.08]) outcomes attenuated after controlling for measured confounders and were almost zero when we accounted for unmeasured confounding (emotional: β 1 = 0.01 [0.00-0.02]; behavioral: β 1 = 0.01 [0.00-0.02]). We observed no moderation of these adjusted exposure effects by any of the PGS., Conclusions: The lack of strong evidence for G × E interaction may indicate that the mechanism is not implicated in this kind of intergenerational association. It may also reflect insufficient power or the relatively benign nature of the exposure in this sample.

Background: People with comorbidities are under-represented in randomised controlled trials, and it is unknown whether patterns of comorbidity are similar in trials and the community., Methods: Individual-level participant data were obtained for 83 clinical trials (54,688 participants) for 16 index conditions from two trial repositories: Yale University Open Data Access (YODA) and the Centre for Global Clinical Research Data (Vivli). Community data (860,177 individuals) were extracted from the Secure Anonymised Information Linkage (SAIL) databank for the same index conditions. Comorbidities were defined using concomitant medications. For each index condition, we estimated correlations between comorbidities separately in trials and community data. For the six commonest comorbidities we estimated all pairwise correlations using Bayesian multivariate probit models, conditioning on age and sex. Correlation estimates from trials with the same index condition were combined into a single estimate. We then compared the trial and community estimates for each index condition., Results: Despite a higher prevalence of comorbidities in the community than in trials, the correlations between comorbidities were mostly similar in both settings. On comparing correlations between the community and trials, 21% of correlations were stronger in the community, 10% were stronger in the trials and 68% were similar in both. In the community, 5% of correlations were negative, 21% were null, 56% were weakly positive and 18% were strongly positive. Equivalent results for the trials were 11%, 33%, 45% and 10% respectively., Conclusions: Comorbidity correlations are generally similar in both the trials and community, providing some evidence for the reporting of comorbidity-specific findings from clinical trials., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Frances S Mair has funding from the Wellcome Trust for a Multimorbidity PhD Programme – 223499/Z/21/Z., (© The Author(s) 2023.)

Objectives: To identify factors associated with change in mental distress at the onset of the COVID-19 pandemic, relative to pre-pandemic levels, and with changes during the following 1.5 years. Methods: The prospective Norwegian Mother, Father and Child Cohort Study collected eight waves of data during the pandemic (March 2020-September 2021) in 105,972 adult participants used for this analyses. A piecewise latent growth model was fitted to identify initial level and longitudinal changes in mental distress. Results: Mental distress peaked at the beginning of the pandemic. Factors associated with initial increases were: medical conditions, living alone, history of psychiatric disorders, lower education, female sex, younger age, and obesity. Being quarantined or infected with SARS-CoV-2 were associated with increasing distress while being vaccinated was associated with reduced mental distress. Conclusion: Having a chronic disease and being quarantined or infected by the SARS-CoV-2 virus were associated with more mental distress during the pandemic. This knowledge is important for planning interventions to support individuals during future pandemics and other societal crises., Competing Interests: Author OA was consultant to the company HealthLytix. The remaining authors declare that they do not have any conflicts of interest., (Copyright © 2023 Lu, Hannigan, Brandlistuen, Nesvåg, Trogstad, Magnus, Unnarsdóttir, Valdimarsdóttir, Andreassen and Ask.)

Background: Several longitudinal studies have cast doubt on the aetiological overlap between child and adult attention-deficit hyperactivity disorder (ADHD). However, a lack of genetically sensitive data following children across adulthood precludes direct evaluation of aetiological overlap between child and adult ADHD., Aims: We circumvent the existing gap in longitudinal data by exploring genetic overlap between maternal (adult) and offspring (child) ADHD and comorbid symptoms in an extended family cohort., Method: Data were drawn from the Norwegian Mother, Father and Child Cohort Study, a Norwegian birth registry cohort of 114 500 children and their parents. Medical Birth Registry of Norway data were used to link extended families. Mothers self-reported their own ADHD symptoms when children were aged 3 years; reported children's ADHD symptoms at age 5 years; and children's ADHD, oppositional defiant disorder (ODD), conduct disorder, anxiety and depression symptoms at age 8 years. Genetic correlations were derived from Multiple-Children-of-Twins-and-Siblings and extended bivariate twin models., Results: Phenotypic correlations between adult ADHD symptoms and child ADHD, ODD, conduct disorder, anxiety and depression symptoms at age 8 years were underpinned by medium-to-large genetic correlations (child ADHD: r G = 0.55, 95% CI 0.43-0.93; ODD: r G = 0.80, 95% CI 0.46-1; conduct disorder: r G = 0.44, 95% CI 0.28-1; anxiety: r G = 0.72, 95% CI 0.48-1; depression: r G = 1, 95% CI 0.66-1). These cross-generational adult-child genetic correlations were of a comparable magnitude to equivalent child-child genetic correlations with ADHD symptoms at age 5 years., Conclusions: Our findings provide genetically sensitive evidence that ADHD symptoms in adulthood share a common genetic architecture with symptoms of ADHD and four comorbid disorders at age 8 years. These findings suggest that in the majority of cases, ADHD symptoms in adulthood are not aetiologically distinct from in childhood.

Background: An individual's overall burden of behavioural and emotional problems across childhood is associated with increased likelihood of later mental health conditions. However, the relative extent of behavioural versus emotional problems - that is, the extent to which the domains are differentiated from one another - may provide additional information about who is at risk of developing a mental health condition. Here, we seek to validate differentiation as an independent predictor of later mental health conditions, and to explore its aetiology., Methods: We analysed data from ~79,000 children in the population-based Norwegian Mother, Father, and Child Cohort Study, and linked health-care registries. In preregistered analyses, we modelled the extent and rate of differentiation of behavioural and emotional problems between ages 1.5-5 years, and estimated associations with later symptoms (age 8) and diagnoses (after age 8). We also explored the aetiology of differentiation by estimating associations with early life exposures and, in a subset of 23,945 full siblings, assessing the impact of accounting for unobserved familial confounding., Results: Differentiation of behavioural and emotional problems was associated with later symptoms and diagnoses of mental health conditions, independent of total problems. Maternal at-risk drinking ( β  = 0.04 [0.02, 0.06]) and parental relationship problems ( β  = 0.04 [0.02, 0.05]) were associated with higher behavioural relative to emotional problems at age 5. Maternal prenatal distress (|β| = 0.04 [0.03, 0.06]), concurrent distress (|β| = 0.04 [0.02, 0.06]) and parental education (|β| = 0.05 [0.04, 0.07]) predicted higher emotional relative to behavioural problems at age 5. Estimates for maternal prenatal distress and at-risk drinking were consistent across both unadjusted and adjusted analyses accounting for unobserved familial risk., Conclusions: Differentiation of behavioural and emotional problems in early childhood represents a valid source of inter-individual variability linked to the later emergence of psychopathology and may be relevant for early detection and prevention strategies for mental health., Competing Interests: Eivind Ystrom is a Joint Editor for JCPP Advances. The remaining authors have declared that they have no competing or potential conflicts on interest., (© 2023 The Authors. JCPP Advances published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Knowledge on how genetic risk for bipolar disorder manifests in developmental, emotional or behavioral traits during childhood is lacking. This issue is important to address to inform early detection and intervention efforts. We investigated whether polygenic risk for bipolar disorder is associated with developmental outcomes during early to middle childhood in the general population, and if associations differ between boys and girls. Our sample consisted of 28 001 children from the Norwegian Mother, Father and Child Cohort study, a prospective pregnancy cohort with available genotype and developmental data. Mothers reported on a range of developmental outcomes in their children at 6 and 18 months, 3, 5 and 8 years. Polygenic risk scores reflecting common variant liability to bipolar disorder were calculated. Linear regression models were used in a multi-group framework to investigate associations between polygenic risk score and developmental outcomes, using sex as a grouping variable. We found robust evidence for an association between polygenic risk scores for bipolar disorder and conduct difficulties (β = 0.041, CI = 0.020-0.062) and oppositional defiant difficulties (β = 0.032, CI = 0.014-0.051) at 8 years. Associations with most other outcomes were estimated within the region of practical equivalence to zero (equivalence range D = -0.1 to 0.1), with the exceptions of negative association for activity levels (β = -0.028, CI = -0.047- -0.010) at age 5 and benevolence (β = -0.025, CI = -0.043 to -0.008) at age 8, and positive association for motor difficulties (β = 0.025, CI = 0.008-0.043) at age 3, inattention (β = 0.021, CI = 0.003-0.041) and hyperactivity (β = 0.025, CI = 0.006-0.044) at age 8. Our results suggest that genetic risk for bipolar disorder manifests as disruptive behaviors like oppositional defiant and conduct difficulties in childhood in the general population., (© 2023. The Author(s).)

Background: Child temperament traits and mothers' emotional symptoms relating to anxiety and depression may drive changes in one another, leading to their 'co-development' across time. Alternatively, links between mother and child traits may be attributable to shared genetic propensities. We explored longitudinal associations between mothers' emotional symptoms and child temperament traits and adjusted for genetic effects shared across generations., Methods: This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa). Mothers ( n  = 34,060) reported on their symptoms of anxiety and depression, and temperament among offspring ( n  = 42,526), at child ages 1.5, 3 and 5 years. Structural equation models parameterised developmental change in traits, and an extended family design adjusted for genetic effects., Results: We found individual differences in stable trait scores and rate of change for all study variables. Longitudinal stability in mothers' emotional symptoms was associated with longitudinal stability in offspring emotionality ( r  = 0.143), shyness ( r  = 0.031), and sociability ( r  = -0.015). Longitudinal change in mothers' symptoms showed very small or negligible correlations with longitudinal change in child temperament. Both genetic and environmental influences explained the stable longitudinal association between mothers' symptoms and child emotionality., Conclusions: The studied associations between mother and child traits across time appeared to be due to stable, trait-like factors, involving genetic and environmental influence, rather than their co-development. Findings contribute knowledge on how emotional symptoms develop in families across time, and the methods with which we can explore such development., Competing Interests: Eivind Ystrom is a Joint Editor for JCPP Advances. Tom McAdams serves on the JCPP Advances Editorial Advisory Board. The remaining authors have declared that they have no competing or potential conflicts of interest., (© 2023 The Authors. JCPP Advances published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Background: People with comorbidities are underrepresented in clinical trials. Empirical estimates of treatment effect modification by comorbidity are lacking, leading to uncertainty in treatment recommendations. We aimed to produce estimates of treatment effect modification by comorbidity using individual participant data (IPD)., Methods and Findings: We obtained IPD for 120 industry-sponsored phase 3/4 trials across 22 index conditions (n = 128,331). Trials had to be registered between 1990 and 2017 and have recruited ≥300 people. Included trials were multicentre and international. For each index condition, we analysed the outcome most frequently reported in the included trials. We performed a two-stage IPD meta-analysis to estimate modification of treatment effect by comorbidity. First, for each trial, we modelled the interaction between comorbidity and treatment arm adjusted for age and sex. Second, for each treatment within each index condition, we meta-analysed the comorbidity-treatment interaction terms from each trial. We estimated the effect of comorbidity measured in 3 ways: (i) the number of comorbidities (in addition to the index condition); (ii) presence or absence of the 6 commonest comorbid diseases for each index condition; and (iii) using continuous markers of underlying conditions (e.g., estimated glomerular filtration rate (eGFR)). Treatment effects were modelled on the usual scale for the type of outcome (absolute scale for numerical outcomes, relative scale for binary outcomes). Mean age in the trials ranged from 37.1 (allergic rhinitis trials) to 73.0 (dementia trials) and percentage of male participants range from 4.4% (osteoporosis trials) to 100% (benign prostatic hypertrophy trials). The percentage of participants with 3 or more comorbidities ranged from 2.3% (allergic rhinitis trials) to 57% (systemic lupus erythematosus trials). We found no evidence of modification of treatment efficacy by comorbidity, for any of the 3 measures of comorbidity. This was the case for 20 conditions for which the outcome variable was continuous (e.g., change in glycosylated haemoglobin in diabetes) and for 3 conditions in which the outcomes were discrete events (e.g., number of headaches in migraine). Although all were null, estimates of treatment effect modification were more precise in some cases (e.g., sodium-glucose co-transporter-2 (SGLT2) inhibitors for type 2 diabetes-interaction term for comorbidity count 0.004, 95% CI -0.01 to 0.02) while for others credible intervals were wide (e.g., corticosteroids for asthma-interaction term -0.22, 95% CI -1.07 to 0.54). The main limitation is that these trials were not designed or powered to assess variation in treatment effect by comorbidity, and relatively few trial participants had >3 comorbidities., Conclusions: Assessments of treatment effect modification rarely consider comorbidity. Our findings demonstrate that for trials included in this analysis, there was no empirical evidence of treatment effect modification by comorbidity. The standard assumption used in evidence syntheses is that efficacy is constant across subgroups, although this is often criticised. Our findings suggest that for modest levels of comorbidities, this assumption is reasonable. Thus, trial efficacy findings can be combined with data on natural history and competing risks to assess the likely overall benefit of treatments in the context of comorbidity., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: SD received fees from the Association of the British Pharmaceutical Industry (ABPI) for delivery of a Masterclass (unrelated to this work). The other authors have declared that no competing interests exist., (Copyright: © 2023 Hanlon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Timing of developmental milestones, such as age at first walking, is associated with later diagnoses of neurodevelopmental disorders. However, its relationship to genetic risk for neurodevelopmental disorders in the general population is unknown. Here, we investigate associations between attainment of early-life language and motor development milestones and genetic liability to autism, attention deficit hyperactivity disorder (ADHD), and schizophrenia., Methods: We use data from a genotyped sub-set ( N = 25699) of children in the Norwegian Mother, Father and Child Cohort Study (MoBa). We calculate polygenic scores (PGS) for autism, ADHD, and schizophrenia and predict maternal reports of children's age at first walking, first words, and first sentences, motor delays (18 months), and language delays and a generalised measure of concerns about development (3 years). We use linear and probit regression models in a multi-group framework to test for sex differences., Results: We found that ADHD PGS were associated with earlier walking age ( β = -0.033, p adj < 0.001) in both males and females. Additionally, autism PGS were associated with later walking ( β = 0.039, p adj = 0.006) in females only. No robust associations were observed for schizophrenia PGS or between any neurodevelopmental PGS and measures of language developmental milestone attainment., Conclusions: Genetic liabilities for neurodevelopmental disorders show some specific associations with the age at which children first walk unsupported. Associations are small but robust and, in the case of autism PGS, differentiated by sex. These findings suggest that early-life motor developmental milestone attainment is associated with genetic liability to ADHD and autism in the general population.

Identifying mechanisms underlying the intergenerational transmission of risk for attention-deficit/hyperactivity disorder (ADHD) traits can inform interventions and provide insights into the role of parents in shaping their children's outcomes. We investigated whether genetic transmission and genetic nurture (environmentally mediated effects) underlie associations between polygenic scores indexing parental risk and protective factors and their offspring's ADHD traits. This birth cohort study included 19,506 genotyped mother-father-offspring trios from the Norwegian Mother, Father and Child Cohort Study. Polygenic scores were calculated for parental factors previously associated with ADHD, including psychopathology, substance use, neuroticism, educational attainment, and cognitive performance. Mothers reported on their 8-year-old children's ADHD traits (n = 9,454 children) using the Parent/Teacher Rating Scale for Disruptive Behaviour Disorders. We found that associations between ADHD maternal and paternal polygenic scores and child ADHD traits decreased significantly when adjusting for the child polygenic score (p Δβ  = 9.95 × 10 -17 for maternal and p Δβ  = 1.48 × 10 -14 for paternal estimates), suggesting genetic transmission of ADHD risk. Similar patterns suggesting genetic transmission of risk were observed for smoking, educational attainment, and cognition. The maternal polygenic score for neuroticism remained associated with children's ADHD ratings even after adjusting for the child polygenic score, indicating genetic nurture. There was no robust evidence of genetic nurture for other parental factors. Our findings indicate that the intergenerational transmission of risk for ADHD traits is largely explained by the transmission of genetic variants from parents to offspring rather than by genetic nurture. Observational associations between parental factors and childhood ADHD outcomes should not be interpreted as evidence for predominantly environmentally mediated effects., (© 2022. The Author(s).)

Background: Mood and anxiety disorders account for a large share of the global burden of disability. Some studies suggest that early signs may emerge already in childhood. However, there is a lack of well-powered, prospective studies investigating how and when childhood mental traits and trajectories relate to adolescent mood and anxiety disorders., Methods: We here examine cross-sectional and longitudinal association between maternally reported temperamental traits, emotional and behavioral problems in childhood (0.5-8 years) and clinical diagnosis of mood or anxiety ("emotional") disorders in adolescence (10-18 years), using the prospective Norwegian Mother, Father and Child Cohort Study (MoBa) of 110,367 children., Results: Logistic regression analyses showed consistent and increasing associations between childhood negative emotionality, behavioral and emotional problems and adolescent diagnosis of emotional disorders, present from 6 months of age (negative emotionality). Latent profile analysis incorporating latent growth models identified five developmental profiles of emotional and behavioral problems. A profile of early increasing behavioral and emotional problems with combined symptoms at 8 years (1.3% of sample) was the profile most strongly associated with emotional disorders in adolescence (OR vs. reference: 5.00, 95% CI: 3.70-6.30)., Conclusions: We found a consistent and increasing association between negative emotionality, behavioral and emotional problems in early to middle childhood and mood and anxiety disorders in adolescence. A developmental profile coherent with early and increasing disruptive mood dysregulation across childhood was the profile strongest associated with adolescent emotional disorders. Our results highlight the importance of early emotional dysregulation and childhood as a formative period in the development of adolescent mood and anxiety disorders, supporting potential for prevention and early intervention initiatives., (© 2022 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Background: Health-related quality of life metrics evaluate treatments in ways that matter to patients, so are often included in randomised clinical trials (hereafter trials). Multimorbidity, where individuals have 2 or more conditions, is negatively associated with quality of life. However, whether multimorbidity predicts change over time or modifies treatment effects for quality of life is unknown. Therefore, clinicians and guideline developers are uncertain about the applicability of trial findings to people with multimorbidity. We examined whether comorbidity count (higher counts indicating greater multimorbidity) (i) is associated with quality of life at baseline; (ii) predicts change in quality of life over time; and/or (iii) modifies treatment effects on quality of life., Methods and Findings: Included trials were registered on the United States trials registry for selected index medical conditions and drug classes, phase 2/3, 3 or 4, had ≥300 participants, a nonrestrictive upper age limit, and were available on 1 of 2 trial repositories on 21 November 2016 and 18 May 2018, respectively. Of 124 meeting these criteria, 56 trials (33,421 participants, 16 index conditions, and 23 drug classes) collected a generic quality of life outcome measure (35 EuroQol-5 dimension (EQ-5D), 31 36-item short form survey (SF-36) with 10 collecting both). Blinding and completeness of follow up were examined for each trial. Using trials where individual participant data (IPD) was available from 2 repositories, a comorbidity count was calculated from medical history and/or prescriptions data. Linear regressions were fitted for the association between comorbidity count and (i) quality of life at baseline; (ii) change in quality of life during trial follow up; and (iii) treatment effects on quality of life. These results were then combined in Bayesian linear models. Posterior samples were summarised via the mean, 2.5th and 97.5th percentiles as credible intervals (95% CI) and via the proportion with values less than 0 as the probability (PBayes) of a negative association. All results are in standardised units (obtained by dividing the EQ-5D/SF-36 estimates by published population standard deviations). Per additional comorbidity, adjusting for age and sex, across all index conditions and treatment comparisons, comorbidity count was associated with lower quality of life at baseline and with a decline in quality of life over time (EQ-5D -0.02 [95% CI -0.03 to -0.01], PBayes > 0.999). Associations were similar, but with wider 95% CIs crossing the null for SF-36-PCS and SF-36-MCS (-0.05 [-0.10 to 0.01], PBayes = 0.956 and -0.05 [-0.10 to 0.01], PBayes = 0.966, respectively). Importantly, there was no evidence of any interaction between comorbidity count and treatment efficacy for either EQ-5D or SF-36 (EQ-5D -0.0035 [95% CI -0.0153 to -0.0065], PBayes = 0.746; SF-36-MCS (-0.0111 [95% CI -0.0647 to 0.0416], PBayes = 0.70 and SF-36-PCS -0.0092 [95% CI -0.0758 to 0.0476], PBayes = 0.631., Conclusions: Treatment effects on quality of life did not differ by multimorbidity (measured via a comorbidity count) at baseline-for the medical conditions studied, types and severity of comorbidities and level of quality of life at baseline, suggesting that evidence from clinical trials is likely to be applicable to settings with (at least modestly) higher levels of comorbidity., Trial Registration: A prespecified protocol was registered on PROSPERO (CRD42018048202)., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests. NJW has received honoraria for training and masterclasses from: Association of British Pharmaceutical Industries, Campbell Ireland, Centre for Global Development, NICE International and NICE Scientific Advice, All Wales Therapeutics and Toxicology Centre, University of Leuven. NJW has delivered training for Takeda, ICON plc, and University of Galway for which payment was made to her institution. DM has received funding for this work from the Wellcome Trust., (Copyright: © 2023 Butterly et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The applicability of randomised controlled trials of pharmacological agents to older people with frailty/multimorbidity is often uncertain, due to concerns that trials are not representative. However, assessing trial representativeness is challenging and complex. We explore an approach assessing trial representativeness by comparing rates of trial serious adverse events (SAE) to rates of hospitalisation/death in routine care., Methods: This was an observational analysis of individual (125 trials, n=122,069) and aggregate-level drug trial data (483 trials, n=636,267) for 21 index conditions compared to population-based routine healthcare data (routine care). Trials were identified from ClinicalTrials.gov . Routine care comparison from linked primary care and hospital data from Wales, UK (n=2.3M). Our outcome of interest was SAEs (routinely reported in trials). In routine care, SAEs were based on hospitalisations and deaths (which are SAEs by definition). We compared trial SAEs in trials to expected SAEs based on age/sex standardised routine care populations with the same index condition. Using IPD, we assessed the relationship between multimorbidity count and SAEs in both trials and routine care and assessed the impact on the observed/expected SAE ratio additionally accounting for multimorbidity., Results: For 12/21 index conditions, the pooled observed/expected SAE ratio was <1, indicating fewer SAEs in trial participants than in routine care. A further 6/21 had point estimates <1 but the 95% CI included the null. The median pooled estimate of observed/expected SAE ratio was 0.60 (95% CI 0.55-0.64; COPD) and the interquartile range was 0.44 (0.34-0.55; Parkinson's disease) to 0.87 (0.58-1.29; inflammatory bowel disease). Higher multimorbidity count was associated with SAEs across all index conditions in both routine care and trials. For most trials, the observed/expected SAE ratio moved closer to 1 after additionally accounting for multimorbidity count, but it nonetheless remained below 1 for most., Conclusions: Trial participants experience fewer SAEs than expected based on age/sex/condition hospitalisation and death rates in routine care, confirming the predicted lack of representativeness. This difference is only partially explained by differences in multimorbidity. Assessing observed/expected SAE may help assess the applicability of trial findings to older populations in whom multimorbidity and frailty are common., (© 2022. The Author(s).)

Importance: Several maternal exposures during pregnancy are considered predisposing factors for offspring neurodevelopmental conditions. However, many of these exposures may be noncausal and biased by maternal genetic liability., Objective: To assess whether pregnancy-related predisposing factors for offspring neurodevelopmental conditions are associated with maternal genetic liability for attention-deficit/hyperactivity disorder (ADHD), autism, and schizophrenia and to compare associations for maternal genetic liability with those for paternal genetic liability, which could indicate that paternal exposures are not suitable negative controls for maternal exposures., Design, Setting, and Participants: The Norwegian Mother, Father and Child Cohort Study (MoBa) is a population-based pregnancy cohort that recruited parents from June 1999 to December 2008. Polygenic scores (PGS) for ADHD, autism, and schizophrenia were derived in mothers and fathers. The associations between maternal PGS and 37 pregnancy-related measures were estimated, and these results were compared with those from paternal PGS predicting paternal measures during the mother's pregnancy. Analysis took place between March 2021 and March 2022., Exposures: PGS for ADHD, autism, and schizophrenia, calculated (using discovery effect size estimates and threshold of P < .05) from the largest available genome-wide association studies., Main Outcomes and Measures: Self-reported pregnancy-related measures capturing lifestyle behaviors, metabolism, infectious and autoimmune diseases, other physical health conditions, and medication use., Results: Data were available for up to 14 539 mothers (mean [SD] age, 30.00 [4.45] years) and 14 897 fathers (mean [SD] age, 32.46 [5.13] years) of European ancestry. Modest but robust associations were observed between specific pregnancy-related measures and maternal PGS, including ADHD PGS with asthma (odds ratio [OR], 1.15 [95% CI, 1.06-1.25]), smoking (OR, 1.26 [95% CI, 1.19-1.33]), prepregnancy body mass index (β, 0.25 [95% CI, 0.18-0.31]), pregnancy weight gain (β, 0.20 [95% CI, 0.10-0.30]), taking folate (OR, 0.92 [95% CI, 0.88-0.96]), and not taking supplements (OR, 1.09 [95% CI, 1.04-1.14]). Schizophrenia PGS was associated with coffee consumption (OR, 1.09 [95% CI, 1.05-1.12]), smoking (OR, 1.12 [95% CI, 1.06-1.19]), prepregnancy body mass index (β, -0.18 [95% CI, -0.25 to -0.11]), and pregnancy weight gain (β, 0.17 [95% CI, 0.07-0.27]). All 3 PGSs associated with symptoms of depression/anxiety (ADHD: OR, 1.15 [95% CI, 1.09-1.22]; autism: OR, 1.13 [95% CI, 1.06-1.19]; schizophrenia: OR, 1.13 [95% CI, 1.07-1.20]). Associations were largely consistent for maternal and paternal PGS, except ADHD PGS and smoking (fathers: OR, 1.13 [95% CI, 1.09-1.17])., Conclusions and Relevance: In this study, genetic liability to neurodevelopmental conditions that is passed from mothers to children was associated with several pregnancy-related factors and may therefore confound associations between these pregnancy-related factors and offspring neurodevelopment that have previously been thought to be causal. It is crucial that future study designs account for genetic confounding to obtain valid causal inferences so that accurate advice can be given to pregnant individuals.

Background: Attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (autism) and schizophrenia are highly heritable neurodevelopmental disorders, affecting the lives of many individuals. It is important to increase our understanding of how the polygenic risk for neurodevelopmental disorders manifests during childhood in boys and girls., Methods: Polygenic risk scores (PRS) for ADHD, autism and schizophrenia were calculated in a subsample of 15 205 children from the Norwegian Mother, Father and Child Cohort Study (MoBa). Mother-reported traits of repetitive behavior, social communication, language and motor difficulties, hyperactivity and inattention were measured in children at 6 and 18 months, 3, 5 and 8 years. Linear regression models in a multigroup framework were used to investigate associations between the three PRS and dimensional trait measures in MoBa, using sex as a grouping variable., Results: Before the age of 2, the ADHD PRS was robustly associated with hyperactivity and inattention, with increasing strength up to 8 years, and with language difficulties at age 5 and 8. The autism PRS was robustly associated with language difficulties at 18 months, motor difficulties at 36 months, and hyperactivity and inattention at 8 years. We did not identify robust associations for the schizophrenia PRS. In general, the PRS associations were similar in boys and girls. The association between ADHD PRS and hyperactivity at 18 months was, however, stronger in boys., Conclusions: Polygenic risk for autism and ADHD in the general population manifests early in childhood and broadly across behavioral measures of neurodevelopmental traits., (© 2021 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Assortative mating on heritable traits can have implications for the genetic resemblance between siblings and in-laws in succeeding generations. We studied polygenic scores and phenotypic data from pairs of partners (n = 26,681), siblings (n = 2,170), siblings-in-law (n = 3,905), and co-siblings-in-law (n = 1,763) in the Norwegian Mother, Father and Child Cohort Study. Using structural equation models, we estimated associations between measurement error-free latent genetic and phenotypic variables. We found evidence of genetic similarity between partners for educational attainment (r g  = 0.37), height (r g  = 0.13), and depression (r g  = 0.08). Common genetic variants associated with educational attainment correlated between siblings above 0.50 (r g  = 0.68) and between siblings-in-law (r g  = 0.25) and co-siblings-in-law (r g  = 0.09). Indirect assortment on secondary traits accounted for partner similarity in education and depression, but not in height. Comparisons between the genetic similarities of partners and siblings indicated that genetic variances were in intergenerational equilibrium. This study shows genetic similarities between extended family members and that assortative mating has taken place for several generations., (© 2022. The Author(s).)

Background: There is limited guidance for using common drug therapies in the context of multimorbidity. In part, this is because their effectiveness for patients with specific comorbidities cannot easily be established using subgroup analyses in clinical trials. Here, we use simulations to explore the feasibility and implications of concurrently estimating effects of related drug treatments in patients with multimorbidity by partially pooling subgroup efficacy estimates across trials., Methods: We performed simulations based on the characteristics of 161 real clinical trials of noninsulin glucose-lowering drugs for diabetes, estimating subgroup effects for patients with a hypothetical comorbidity across related trials in different scenarios using Bayesian hierarchical generalized linear models. We structured models according to an established ontology-the World Health Organization Anatomic Chemical Therapeutic Classifications-allowing us to nest all trials within drugs and all drugs within anatomic chemical therapeutic classes, with effects partially pooled at each level of the hierarchy. In a range of scenarios, we compared the performance of this model to random effects meta-analyses of all drugs individually., Results: Hierarchical, ontology-based Bayesian models were unbiased and accurately recovered simulated comorbidity-drug interactions. Compared with single-drug meta-analyses, they offered a relative increase in precision of up to 250% in some scenarios because of information sharing across the hierarchy. Because of the relative precision of the approaches, a large proportion of small subgroup effects was detectable only using the hierarchical model., Conclusions: By assuming that similar drugs may have similar subgroup effects, Bayesian hierarchical models based on structures defined by existing ontologies can be used to improve the precision of treatment efficacy estimates in patients with multimorbidity, with potential implications for clinical decision making.

Background: Shame is considered a maladaptive self-conscious emotion that commonly co-occurs alongside depression and anxiety. Little is known, however, about the aetiology of shame and its associations with depression and anxiety. We estimated, for the first time, genetic and environmental influences on shame and on its associations with depression and anxiety in adolescence., Methods: The sample was twin and sibling pairs from the Genesis 1219 Study (Time 1, N = 2,685; males 42.8%, M age  = 14.95, SD = 1.67, age range: 12-21; Time 2, N = 1618; males 39.7%, M age  = 16.97, SD = 1.64, age range: 14-23). Participants completed validated questionnaires to measure shame (at Time 1), depression and anxiety (at Times 1 and 2)., Results: Shame was moderately to strongly associated with concurrent depression and anxiety. Prospectively, shame was significantly associated with an increase in depression, but not anxiety. Genetic analyses revealed that shame was moderately heritable with substantial nonshared environmental influence. The associations between shame and concurrent depression and anxiety were primarily accounted for by overlapping genetic influences. Prospectively, the association between shame and later depression was primarily accounted for by genetic and nonshared environmental influences shared with earlier depression. The unique association between shame and later depression was mostly explained by common nonshared environmental influences., Conclusions: The findings offer novel evidence regarding aetiology of shame-although moderately heritable, shame in adolescents may also result from nonshared environmental factors. Genetic and nonshared environmental influences contribute to the co-occurrence of shame with depression and anxiety., (© 2021 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Background: Children of parents with high levels of neuroticism tend to have high neuroticism themselves as well as increased risk of experiencing symptoms of anxiety and depression. It is not yet clear how much of this link is attributable to a potential effect of parent on child (e.g., via a socializing effect) versus to shared genetic risk. We aimed to determine whether there is an intergenerational association after accounting for genetic transmission and assortative mating., Methods: We used data from the Norwegian Mother, Father and Child Cohort Study including 11,088 sibling pairs in the parental generation, their partners ( N  = 22,176) and their offspring ( N  = 26,091). Exposures were maternal and paternal neuroticism (self-reported), and the outcomes were neuroticism, symptoms of depression, and symptoms of anxiety in 8-year-old children (mother-reported)., Results: After accounting for assortative mating in parents (phenotypic r  = 0.26) and genetic transmission (explaining 0%-18% of the mother-offspring correlations), potential maternal effects explained 80% (95% CI = 47-95) of the association with offspring neuroticism (mother-child r  = 0.31), 78% (95% CI = 66-89) of the association with offspring depressive symptoms ( r  = 0.31), and 98% (95% CI = 45-112) of the association with offspring anxiety symptoms ( r  = 0.16). Intergenerational transmission of genetic variants associated with paternal neuroticism accounted for ∼40% (CI = 22%-58%) of the father-offspring correlations with neuroticism and symptoms of depression ( r  = 0.13 and 0.13, respectively) but none with offspring symptoms of anxiety ( r  = 0.05). The remaining father-offspring correlations were explained by maternal influences through assortative mating., Conclusions: These results are consistent with direct effects between maternal and offspring neuroticism and between maternal neuroticism and offspring symptoms of anxiety and depression. Further understanding of these intergenerational processes will require an adequate model of how these constructs (neuroticism, anxiety and depression) relate to each other within generations., Competing Interests: Eivind Ystrom is a Joint Editor of JCPP Advances. The remaining authors have declared that they have no competing or potential conflicts of interest. Tom A. McAdams is a member of the JCPP Advances Editorial Advisory Board. [Corrections made on 22 June 2022, after first online publication: This Conflict of Interests statement has been updated in this version.], (© 2021 The Authors. JCPP Advances published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Objective: The primary aim of the present study was to separate the direct effect of maternal prenatal depression on offspring ADHD from the passive transmission of genetic liability. Method: A children-of-twins and siblings design including 17,070 extended-family units participating in the Norwegian Mother and Child Cohort Study was used. Self-ratings were obtained from parents using the Symptom Checklist during pregnancy. Maternal ratings using Conner's Parent Rating Scale were obtained when the children were 5 years of age. Results: Genetic influences were important for explaining similarity between parents and offspring. There was also evidence for a maternal effect after accounting for genetic transmission ( m = 0.06, 95% confidence interval [CI] = [0.02, 0.09]). Conclusion: Our results were consistent with hypotheses suggesting that maternal prenatal depression influences symptoms of ADHD in offspring. However, the effect was weak and a substantial portion of the association could be accounted for by shared genetic influences.

Children with attention deficit hyperactivity disorder (ADHD) often experience co-occurring emotional problems. ADHD with this comorbidity is associated with poorer outcomes than ADHD without comorbidity. Better understanding of the etiology of comorbidity could improve prevention of negative outcomes for children with ADHD. The sample consisted of 567 twin pairs, 3,632 sibling pairs, and 2,340 cousin pairs from the Norwegian Mother, Father and Child Cohort Study. Mothers rated offspring symptoms of ADHD, anxiety, and depression at 8 years of age. Biometric modeling was performed to examine genetic and environmental contributions to co-occurring symptoms of ADHD and emotional problems in the children. We fitted four variable (inattention, hyperactivity/impulsivity, anxiety, and depression) covariance matrices of additive genetic, common environmental, twin- and individual-specific environmental effects. Genetic, shared environmental, and individual-specific environmental factors contributed to the correlation between ADHD and depression. The pattern was similar for both inattention and hyperactivity/impulsivity. Familial risk factors (genetic and shared environment), but not individual-specific environmental factors contributed to the positive correlations between each of the two ADHD subdomains and anxiety. The genetic contributions to ADHD-depression comorbidity only partly overlapped with genetic contributions to ADHD-anxiety comorbidity. Our findings indicate that shared risk factors for ADHD and comorbid depression were familial as well as individual-specific, while shared risk factors for ADHD and comorbid anxiety were primarily familial. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Genetic liability for schizophrenia is associated with psychopathology in early life. It is not clear if these associations are time dependent during childhood, nor if they are specific across different forms of psychopathology. Using genotype and questionnaire data on children (N = 15 105) from the Norwegian Mother, Father and Child Cohort Study, we used schizophrenia polygenic risk scores to test developmental stability in associations with measures of emotional and behavioral problems between 18 months and 5 years, and domain specificity in associations with symptoms of depression, anxiety, conduct problems, oppositionality, inattention, and hyperactivity at 8 years. We then sought to identify symptom profiles-across development and domains-associated with schizophrenia polygenic liability. We found evidence for developmental stability in associations between schizophrenia polygenic risk scores and emotional and behavioral problems, with the latter being mediated specifically via the rate of change in symptoms (β slope = 0.032; 95% CI: 0.007-0.057). At age 8, associations were better explained by a model of symptom-specific polygenic effects rather than effects mediated via a general psychopathology factor or by domain-specific factors. Overall, individuals with higher schizophrenia polygenic risk scores were more likely (OR = 1.310 [95% CIs: 1.122-1.528]) to have a profile of increasing behavioral and emotional symptoms in early childhood, followed by elevated symptoms of conduct disorder, oppositionality, hyperactivity, and inattention by age 8. Schizophrenia-associated alleles are linked to specific patterns of early-life psychopathology. The associations are small, but findings of this nature can help us better understand the developmental emergence of schizophrenia., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Neurodevelopmental disorders are widely acknowledged to be complex and multifactorial in origin, but this is rarely reflected in the approaches used to study them. We reflect on the 2021 Annual Research review and its introduction of a new conceptual framework designed to make the complexity of early neurodevelopment more empirically tractable. We evaluate the review authors' justification, explanation, and guidance for implementation of their framework in the context of their stated goals and highlight key assumptions that support its conceptual validity. Finally, we offer a genetic epidemiological perspective on potential applications, suggesting ways in which genomic data can be used to elucidate causal mechanistic processes within the AMEND framework., (© 2021 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Indirect genetic effects from relatives may result in misleading quantifications of heritability, but can also be of interest in their own right. In this paper we propose Trio-GCTA, a model for separating direct and indirect genetic effects when genome-wide single nucleotide polymorphism data have been collected from parent-offspring trios. The model is applicable to phenotypes obtained from any of the family members. We discuss appropriate parameter interpretations and apply the method to three exemplar phenotypes: offspring birth weight, maternal relationship satisfaction, and paternal body-mass index, using real data from the Norwegian Mother, Father and Child Cohort Study (MoBa).

Background: Although maternal depressive symptoms are robustly associated with offspring early-life psychopathology symptoms, it is not clear which potential mechanisms are at play. We aimed to estimate the relative importance of genetic transmission and direct environmental exposure in these associations on three occasions in early childhood., Methods: Biometric modeling of maternal sisters and their offspring from the Norwegian Mother and Child Cohort Study. The analyzed sample comprised 22 316 mothers and 35 589 offspring. Mothers reported their own depressive symptoms using the Symptom checklist, and offspring's concurrent symptoms of psychopathology using the Child Behavior Checklist at 1.5, 3, and 5 years postpartum., Results: Associations between maternal symptoms of depression and offspring emotional problems were predominantly explained by passive genetic transmission at 1.5 and 3 years postpartum. At age 5, associations were more due to direct environmental exposure. For offspring behavioral problems, there was no net increase in the importance of direct environmental exposure across occasions., Conclusions: Associations between maternal depressive symptoms and offspring psychopathology symptoms remained after accounting for shared genes, consistent with a small, causal effect. For offspring emotional problems, this effect appeared to increase in importance over time. Our findings imply that treatment of maternal depressive symptoms could also benefit the offspring, and that genetic confounding should be considered in future studies of such mother-offspring associations.

Background: Many studies detect associations between parent behaviour and child symptoms of anxiety and depression. Despite knowledge that anxiety and depression are influenced by a complex interplay of genetic and environmental risk factors, most studies do not account for shared familial genetic risk. Quantitative genetic designs provide a means of controlling for shared genetics, but rely on observed putative exposure variables, and require data from highly specific family structures., Methods: The intergenerational genomic method, Relatedness Disequilibrium Regression (RDR), indexes environmental effects of parents on child traits using measured genotypes. RDR estimates how much the parent genome influences the child indirectly via the environment, over and above effects of genetic factors acting directly in the child. This 'genetic nurture' effect is agnostic to parent phenotype and captures unmeasured heritable parent behaviours. We applied RDR in a sample of 11,598 parent-offspring trios from the Norwegian Mother, Father and Child Cohort Study (MoBa) to estimate parental genetic nurture separately from direct child genetic effects on anxiety and depression symptoms at age 8. We tested for mediation of genetic nurture via maternal anxiety and depression symptoms. Results were compared to a complementary non-genomic pedigree model., Results: Parental genetic nurture explained 14% of the variance in depression symptoms at age 8. Subsequent analyses suggested that maternal anxiety and depression partially mediated this effect. The genetic nurture effect was mirrored by the finding of family environmental influence in our pedigree model. In contrast, variance in anxiety symptoms was not significantly influenced by common genetic variation in children or parents, despite a moderate pedigree heritability., Conclusions: Genomic methods like RDR represent new opportunities for genetically sensitive family research on complex human traits, which until now has been largely confined to adoption, twin and other pedigree designs. Our results are relevant to debates about the role of parents in the development of anxiety and depression in children, and possibly where to intervene to reduce problems.

Background: Anxiety sensitivity, the tendency to fear the symptoms of anxiety, is a key risk factor for the development anxiety disorders. Although obsessive-compulsive disorder was previously classified as an anxiety disorder, the prospective relationship between anxiety sensitivity and obsessive-compulsive symptoms (OCS) has been largely overlooked. Furthermore, a lack of genetically informative studies means the aetiology of the link between anxiety sensitivity and OCS remains unclear., Methods: Adolescent twins and siblings (N = 1,579) from the G1219 study completed self-report questionnaires two years apart assessing anxiety sensitivity, OCS, anxiety and depression. Linear regression models tested prospective associations between anxiety sensitivity and OCS, with and without adjustment for anxiety and depressive symptoms. A phenotypic cross-lagged model assessed bidirectional influences between anxiety sensitivity and OCS over time, and a genetic version of this model examined the aetiology of these associations., Results: Anxiety sensitivity was prospectively associated with changes in OCS, even after controlling for comorbid anxiety and depressive symptoms. The longitudinal relationship between anxiety sensitivity and OCS was bidirectional, and these associations were predominantly accounted for by nonshared environmental influences., Conclusions: Our findings are consistent with the notion that anxiety sensitivity is a risk factor for OCS during adolescence, but also suggest that experiencing OCS confers risk for heightened anxiety sensitivity. The reciprocal links between OCS and anxiety sensitivity over time are likely to be largely mediated by nonshared environmental experiences, as opposed to common genes. Our findings raise the possibility that interventions aimed at ameliorating anxiety sensitivity could reduce risk for OCS, and vice versa., (© 2020 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Background: Children in the UK go through rigorous teacher assessments and standardized exams throughout compulsory (elementary and secondary) education, culminating with the GCSE exams (General Certificate of Secondary Education) at the age of 16 and A-level exams (Advanced Certificate of Secondary Education) at the age of 18. These exams are a major tipping point directing young individuals towards different lifelong trajectories. However, little is known about the associations between teacher assessments and exam performance or how well these two measurement approaches predict educational outcomes at the end of compulsory education and beyond., Methods: The current investigation used the UK-representative Twins Early Development Study (TEDS) sample of over 5,000 twin pairs studied longitudinally from childhood to young adulthood (age 7-18). We used teacher assessment and exam performance across development to investigate, using genetically sensitive designs, the associations between teacher assessment and standardized exam scores, as well as teacher assessments' prediction of exam scores at ages 16 and 18, and university enrolment., Results: Teacher assessments of achievement are as reliable, stable and heritable (~60%) as test scores at every stage of the educational experience. Teacher and test scores correlate strongly phenotypically (r ~ .70) and genetically (genetic correlation ~.80) both contemporaneously and over time. Earlier exam performance accounts for additional variance in standardized exam results (~10%) at age 16, when controlling for teacher assessments. However, exam performance explains less additional variance in later academic success, ~5% for exam grades at 18, and ~3% for university entry, when controlling for teacher assessments. Teacher assessments also predict additional variance in later exam performance and university enrolment, when controlling for previous exam scores., Conclusions: Teachers can reliably and validly monitor students' progress, abilities and inclinations. High-stakes exams may shift educational experience away from learning towards exam performance. For these reasons, we suggest that teacher assessments could replace some, or all, high-stakes exams., (© 2019 Association for Child and Adolescent Mental Health.)

Background: Punitive parenting and stressful life events are associated with obsessive-compulsive symptoms (OCS). However, the lack of longitudinal, genetically-informative studies means it remains unclear whether these factors represent environmentally-mediated risks for the development of OCS., Methods: Twins and siblings from the Genesis1219 study completed self-report questionnaires two years apart (Time 1: N = 2616, mean age = 15.0; Time 2: N = 1579, mean age = 17.0 years) assessing OCS, maternal and paternal punitive parenting, and dependent stressful life events. Multiple regression models tested cross-sectional and longitudinal associations between the putative environmental risk factors and obsessive-compulsive symptoms using: (a) individual scores; and (b) monozygotic twin difference scores. The aetiologies of significant phenotypic associations between putative risk factors and OCS were further examined using multivariate genetic models., Results: At a phenotypic level, maternal and paternal punitive parenting and stressful life events were all associated with OCS both cross-sectionally and longitudinally. However, only stressful life events predicted the subsequent development of OCS, after controlling for earlier symptoms. Genetic models indicated that the association between life events and change in OCS symptoms was due to both genetic (48%) and environmental (52%) influences. Overall, life events associated with change in OCS accounted for 1.2% of variation in OCS at Time 2., Conclusions: Stressful life events, but not punitive parenting, predict OCS change during adolescence at a phenotypic level. This association exists above and beyond genetic confounding, consistent with the hypothesis that stressful life events play a causal role in the development of obsessive-compulsive symptoms., (Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Maternal prenatal depression is a known risk factor for early-life psychopathology among offspring; however, potential risk transmission mechanisms need to be distinguished. We aimed to test the relative importance of passive genetic transmission, direct exposure, and indirect exposure in the association between maternal prenatal depressive symptoms and early-life internalising and externalising psychopathology in offspring., Methods: We used structural equation modelling of phenotypic data and genetically informative relationships from the families of participants in the Norwegian Mother and Child Birth Cohort Study (MoBa). The analytic subsample of MoBa used in the current study comprises 22 195 mothers and 35 299 children. We used mothers' self-reported depressive symptoms during pregnancy, as captured by the Symptom Checklist, and their reports of symptoms of psychopathology in their offspring during the first few years of life (measured at 18, 36, and 60 months using the Child Behavior Checklist)., Findings: Maternal prenatal depressive symptoms were found to be associated with early-life psychopathology primarily via intergenerationally shared genetic factors, which explained 41% (95% CI 36-46) of variance in children's internalising problems and 37% (30-44) of variance in children's externalising problems. For internalising problems, phenotypic transmission also contributed significantly, accounting for 14% (95% CI 5-19) of the association, but this contribution was found to be explained by exposure to concurrent maternal depressive symptoms, rather than by direct exposure in utero., Interpretation: Associations between maternal prenatal depressive symptoms and offspring behavioural outcomes in early childhood are likely to be at least partially explained by shared genes. This genetic confounding should be considered when attempting to quantify risks posed by in-utero exposure to maternal depressive symptoms., Funding: UK Economic and Social Research Council, Norwegian Research Council, Norwegian Ministries of Health and Care Services, and Education & Research, Wellcome Trust, Royal Society, and National Institute for Health Research., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Little is known about the etiology of developmental change and continuity in educational achievement. Here, we study achievement from primary school to the end of compulsory education for 6000 twin pairs in the UK-representative Twins Early Development Study sample. Results showed that educational achievement is highly heritable across school years and across subjects studied at school (twin heritability ~60%; SNP heritability ~30%); achievement is highly stable (phenotypic correlations ~0.70 from ages 7 to 16). Twin analyses, applying simplex and common pathway models, showed that genetic factors accounted for most of this stability (70%), even after controlling for intelligence (60%). Shared environmental factors also contributed to the stability, while change was mostly accounted for by individual-specific environmental factors. Polygenic scores, derived from a genome-wide association analysis of adult years of education, also showed stable effects on school achievement. We conclude that the remarkable stability of achievement is largely driven genetically even after accounting for intelligence., Competing Interests: The authors declare no competing interests.

Datasets comprising twins and their children can be a useful tool for understanding the nature of intergenerational associations between parent and offspring phenotypes. In the present article we explore structural equation models previously used to analyse Children-of-Twins data, highlighting some limitations and considerations. We then present new variants of these models, showing that extending the models to include multiple offspring per parent addresses several of the limitations discussed. Accompanying the updated models, we provide power calculations and demonstrate with application to simulated data. We then apply to intergenerational analyses of height and weight, using a sub-study of the Norwegian Mother and Child Cohort (MoBa); the Intergenerational Transmission of Risk (IToR) project, wherein all kinships in the MoBa data have been identified (a children-of-twins-and-siblings study). Finally, we consider how to interpret the findings of these models and discuss future directions.

Common genetic influences offer a partial explanation for comorbidity between different psychiatric disorders 1-3 . However, the genetics underlying co-development-the cross-domain co-occurrence of patterns of change over time-of psychiatric symptoms during childhood and adolescence has not been well explored. Here, we show genetic influence on joint symptom trajectories of parent-reported conduct and emotional problems (overall N = 15,082) across development (4-16 years) using both twin- and genome-wide polygenic score analyses (genotyped N = 2,610). Specifically, we found seven joint symptom trajectories, including two characterized by jointly stable and jointly increasing symptoms of conduct and emotional problems, respectively (7.3% of the sample, collectively). Twin modelling analyses revealed substantial genetic influence on trajectories (heritability estimates range of 0.41-0.78). Furthermore, individuals' risk of being classified in the most symptomatic trajectory classes was significantly predicted by polygenic scores for years-of-education-associated alleles and depressive symptoms-associated alleles. Complementary analyses of child self-reported symptoms across late childhood and early adolescence yielded broadly similar results. Taken together, our results indicate that genetic factors are involved in the co-development of conduct and emotional problems across childhood and adolescence, and that individuals with co-developing symptoms across multiple domains may represent a clinical subgroup characterized by increased levels of genetic risk.

Background: Associations between parenting and child outcomes are often interpreted as reflecting causal, social influences. However, such associations may be confounded by genes common to children and their biological parents. To the extent that these shared genes influence behaviours in both generations, a passive genetic mechanism may explain links between them. Here we aim to quantify the relative importance of passive genetic v. social mechanisms in the intergenerational association between parent-offspring relationship quality and offspring internalizing problems in adolescence., Methods: We used a Children-of-Twins (CoT) design with data from the parent-based Twin and Offspring Study of Sweden (TOSS) sample [909 adult twin pairs and their offspring; offspring mean age 15.75 (2.42) years], and the child-based Swedish Twin Study of CHild and Adolescent Development (TCHAD) sample [1120 adolescent twin pairs; mean age 13.67 (0.47) years]. A composite of parent-report measures (closeness, conflict, disagreements, expressions of affection) indexed parent-offspring relationship quality in TOSS, and offspring self-reported internalizing symptoms were assessed using the Child Behavior Checklist (CBCL) in both samples., Results: A social transmission mechanism explained the intergenerational association [r = 0.21 (0.16-0.25)] in our best-fitting model. A passive genetic transmission pathway was not found to be significant, indicating that parental genetic influences on parent-offspring relationship quality and offspring genetic influences on their internalizing problems were non-overlapping., Conclusion: These results indicate that this intergenerational association is a product of social interactions between children and parents, within which bidirectional effects are highly plausible. Results from genetically informative studies of parenting-related effects should be used to help refine early parenting interventions aimed at reducing risk for psychopathology.

Although gene-environment correlation is recognized and investigated by family studies and recently by SNP-heritability studies, the possibility that genetic effects on traits capture environmental risk factors or protective factors has been neglected by polygenic prediction models. We investigated covariation between trait-associated polygenic variation identified by genome-wide association studies (GWASs) and specific environmental exposures, controlling for overall genetic relatedness using a genomic relatedness matrix restricted maximum-likelihood model. In a UK-representative sample ( n = 6,710), we find widespread covariation between offspring trait-associated polygenic variation and parental behavior and characteristics relevant to children's developmental outcomes-independently of population stratification. For instance, offspring genetic risk for schizophrenia was associated with paternal age ( R 2 = 0.002; P = 1e-04), and offspring education-associated variation was associated with variance in breastfeeding ( R 2 = 0.021; P = 7e-30), maternal smoking during pregnancy ( R 2 = 0.008; P = 5e-13), parental smacking ( R 2 = 0.01; P = 4e-15), household income ( R 2 = 0.032; P = 1e-22), watching television ( R 2 = 0.034; P = 5e-47), and maternal education ( R 2 = 0.065; P = 3e-96). Education-associated polygenic variation also captured covariation between environmental exposures and children's inattention/hyperactivity, conduct problems, and educational achievement. The finding that genetic variation identified by trait GWASs partially captures environmental risk factors or protective factors has direct implications for risk prediction models and the interpretation of GWAS findings., Competing Interests: The authors declare no conflict of interest.

Theoretical models of child development typically consider the home environment as a product of bidirectional effects, with parent- and child-driven processes operating interdependently. However, the developmental structure of these processes during the transition from childhood to adolescence has not been well studied. In this study we used longitudinal genetic analyses of data from 6646 UK-representative twin pairs (aged 9-16 years) to investigate stability and change in parenting and household chaos in the context of parent-child bidirectional effects. Stability in the home environment was modest, arising mainly from parent-driven processes and family-wide influences. In contrast, change over time was more influenced by child-driven processes, indicated by significant age-specific genetic influences. Interpretations of these results and their implications for researchers are discussed., (© 2016 The Authors. Developmental Science Published by John Wiley & Sons Ltd.)

Background: Depression is already highly prevalent by late adolescence, indicating that research into its developmental emergence should consider earlier risk factors and environmental contexts. The home environment is a key context for children and adolescents throughout development. However, the nature of relationships that exist between aspects of the home environment and the development of depressive symptoms cannot be assumed. Genetically informative studies have been used to provide insights about the aetiology of such relationships, often finding them to be partly confounded by the influence of children's genes. Here, we investigate developmental change in the aetiology of the association between aspects of the home environment and depressive symptoms at the onset of adolescence., Methods: We used longitudinal child- and parent-report data from >5,000 twin pairs enrolled in the UK-representative Twins Early Development Study. Multivariate, genetically sensitive structural equation models were used to decompose latent variance and covariance in depressive symptoms (measured at 12 and 16 years) and aspects of the home environment (at 9 and 14 years) into genetic and environmental influences., Results: Going from childhood to adolescence, genetic influences accounted for an increasing proportion of the association [30% (16-42) of r = .44 in childhood; 40% (25-61) of r = .43 in adolescence], at the expense of shared environmental influences, which decreased from 70% (58-83) to 48% (29-62). Unique environmental influences accounted for a significant proportion of the association in adolescence only [12% (06-18)]. Developmental changes could largely be attributed to subtle shifts in the relative importance of stable aetiological factors, rather than the emergence of influences unique to adolescence., Conclusions: These findings emphasise the importance of developmental and aetiological context in interpreting associations between aspects of the home environment and child emotional outcomes., (© 2017 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)