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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 (pΔβ = 9.95 × 10−17 for maternal and pΔβ = 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.

BackgroundThe intergenerational transmission of obesity-related traits could propagate an accelerating cycle of obesity, if parental adiposity causally influences offspring adiposity via intrauterine or periconceptional mechanisms. We aimed to establish whether associations between parental peri-pregnancy body mass index (BMI) and offspring birth weight (BW), BMI until 8 years and 8-year eating behaviour are due to genetic confounding.MethodsWe used data from the Norwegian Mother, Father and Child Cohort Study and the Medical Birth Registry of Norway. We compared the strength of the associations of maternal versus paternal BMI with offspring outcomes, and used an extended children of twins structural equation model (SEM) to quantify the extent to which associations were due to genetic confounding (n = 17001 to 85866 children).FindingsMaternal BMI was more strongly associated than paternal BMI with offspring BW, but the maternal-paternal difference decreased for offspring BMI after birth. Greater parental BMI was associated with obesity-related offspring eating behaviours. SEM results indicated that genetic confounding did not explain the association between parental BMI and offspring BW, but explained the majority of the association with offspring BMI from 6 months onwards. For 8-year BMI, genetic confounding explained 79% (95% CI: 62%, 95%) of the covariance with maternal BMI and 94% (95% CI: 72%, 113%) of the covariance with paternal BMI.InterpretationWe found strong evidence that parent-child BMI associations are primarily due to genetic confounding, arguing against a strong causal effect of maternal or paternal adiposity on childhood adiposity via intrauterine or periconceptional mechanisms.

SummaryBackgroundUnderstanding factors associated with mental distress during a pandemic is imperative for planning interventions to reduce the negative mental health impact of future crises. Our aim was to identify factors associated with change in levels of mental distress in the Norwegian adult population at the onset of the Covid-19 pandemic, relative to pre-pandemic levels, and with longitudinal changes in mental distress until vaccination against Covid-19 became widespread in Norway (the first 1.5 years of the pandemic).MethodsThe Norwegian Mother, Father and Child Cohort Study (MoBa) is a prospective longitudinal study with baseline recruitment from 1999-2009. Baseline characteristics and eight waves of data collection during the pandemic (between March 2020 and September 2021) were used for this analysis. Mental distress was measured with the 5-item version of Hopkins Symptoms Checklist (HSCL-5). A piecewise latent growth model was fitted to identify initial change in mental distress (March-early April 2020, adjusting for pre-pandemic mental distress measured during prior years of data collection) and longitudinal changes across the pandemic in three distinct periods.FindingsOur sample consisted of 105 972 adult participants (59.6% females). Mental distress levels peaked at the beginning of the pandemic. Several factors were associated with initial increases in distress: chronic medical conditions, living alone, history of psychiatric disorders, relatively lower educational background, female sex, younger age, and obesity. Several of these factors were also associated with long-term change. Being quarantined or having to isolate was associated with the likelihood of increasing distress during the pandemic. We observed a reduction in distress associated with Covid-19 vaccination status, while being infected with SARS-CoV-2 was associated with increasing distress late in the pandemic.InterpretationPre-pandemic vulnerability factors – like having a chronic disease – as well as Covid-19-related factors – like being quarantined or infected by SARS-CoV-2 – were associated with increased mental distress during the pandemic. This knowledge is important for planning of interventions to support vulnerable individuals during pandemics and other health crises.FundingThe Norwegian Ministry of Health, and Care Services and the Ministry of Education and Research. NordForsk, The Research Council of Norway, The South-Eastern Norway Regional Health Authority.

BackgroundPeople with comorbidities are under-represented 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 ResultsUsing 126 industry-sponsored phase 3/4 trials across 23 index conditions, we performed a two-stage IPD meta-analysis to estimate modification of treatment effect by comorbidity. 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 six commonest comorbid diseases for each index condition, and (iii) using continuous markers of underlying conditions (e.g., estimated glomerular function).Comorbidities were under-represented in trial participants and few had >2 comorbidities. 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 three 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 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).ConclusionFor trials included in this analysis, there was no empirical evidence of treatment effect modification by comorbidity. Our findings support the assumption that estimates of treatment efficacy are constant, at least across modest levels of comorbidity.

Background Attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (autism), and schizophrenia, are highly heritable neurodevelopmental disorders, affecting the lives of many individuals. To improve prevention and treatment, it is important to increase our understanding of how the polygenic risk for neurodevelopmental disorders manifests during childhood in boys and girls.Method Polygenic risk scores (PRS) for ADHD, autism and schizophrenia were calculated in a sub-sample 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 multi-group framework were used to investigate associations between the three PRS and dimensional trait measures in MoBa, and sex was used as a grouping variable. Results Before the age of 2, PRS associations were found with language difficulties, inattention and hyperactivity, mostly increasing in strength up to 8 years. PRS for autism was associated with motor difficulties as early as 6 months. By 8 years, all measured neurodevelopmental traits had shown some association with at least one neurodevelopmental PRS. In general, genetic risk manifested similarly in boys and girls. Associations were, however, stronger in girls for language difficulties and ADHD PRS at 8 years. The association between schizophrenia PRS and inattention was found in girls only at 18 months. For autism PRS, associations with social communication difficulties at 18 months, and motor difficulties at 5 years were observed in boys only. Conclusions Genetic risk for neurodevelopmental disorders manifests early in childhood and broadly across behavioral measures of neurodevelopment. Manifestations may be sex specific in some domains, but these findings need to be replicated.

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.

Background Parental criticism is correlated with internalising symptoms in adolescent offspring. This correlation could in part reflect their genetic relatedness, if the same genes influence behaviours in both parents and offspring. We use a Children-of-Twins design to assess whether parent-reported criticism and offspring internalising symptoms remain associated after controlling for shared genes. To aid interpretation of our results and those of previous Children-of-Twins studies, we examine statistical power for the detection of genetic effects and explore the direction of possible causal effects between generations. Methods Data were drawn from two Swedish twin samples, comprising 876 adult twin pairs with adolescent offspring and 1,030 adolescent twin pairs with parents. Parent reports of criticism towards their offspring were collected concurrently with parent and offspring reports of adolescent internalising symptoms. Children-of-Twins structural equation models were used to control for genetic influence on the intergenerational association between parental criticism and adolescent internalising. Results Parental criticism was associated with adolescent internalising symptoms after controlling for genetic influence. No significant role was found for shared genes influencing phenotypes in both generations, although power analyses suggested that some genetic effects may have gone undetected. Models could not distinguish directionality for nongenetic, causal effects between generations. Conclusions Parental criticism may be involved in psychosocial family processes in the context of adolescent internalising. Future studies should seek to identify these processes and provide clarity on the direction of potential causal effects.

BackgroundShame 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.MethodsThe sample was twin and sibling pairs from the Genesis 1219 Study (Time 1, N = 2,685; males 42.8%, Mage = 14.95, SD = 1.67, age range: 12–21; Time 2, N = 1618; males 39.7%, Mage = 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).ResultsShame 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.ConclusionsThe 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.

Now, more than a decade into the genome-wide association study (GWAS) era, continued progress in genomic discovery for psychiatric traits is easily taken for granted. The winning formula of large-scale collaborative science, uncompromising methodological rigor, and brute force sample size accumulation has become well established, and its regular empirical returns have become progressively less headline-making. However, we should not be complacent. As the results of the systematic review by Akingbuwa et al.1 in this issue of the Journal make clear, accumulating the necessary numbers of genotyped cases to identify the majority of common risk variants remains a daunting and distant prospect for many psychiatric traits relevant to children and adolescents. But more than this, the challenge of providing clinically and societally meaningful returns on the considerable investments of the GWAS era will require a continued and concerted research effort well into the future.

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.

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).

BackgroundMood and anxiety disorders, often emerging during adolescence, account for a large share of the global burden of disability. Prospectively assessed premorbid early signs and trajectories can provide useful insights for early detection and development of these disorders.MethodsUsing the health registry linked Norwegian Mother, Father and Child Cohort Study (MoBa) of 110,367 children, we here examine cross-sectional and longitudinal association between temperamental traits, emotional and behavioral problems in childhood (0.5-8 years) and diagnosis of mood or anxiety (emotional) disorders in adolescence (10-18 years). We included birth year and sex, retrieved from the Medical Birth Registry of Norway, as covariates in all analyses.ResultsLogistic 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) and with similar magnitude of association for the associated traits. 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: 3.73-6.30).ConclusionsWe 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 most predictive of 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 a potential for prevention and early intervention initiatives.

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 non-shared 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 non-shared 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.

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).

BackgroundTiming 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.MethodsWe 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.ResultsWe found that ADHD PGS were associated with earlier walking age (β = −0.033, padj < 0.001) in both males and females. Additionally, autism PGS were associated with later walking (β = 0.039, padj = 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.ConclusionsGenetic 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.

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: 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 enrollment. 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.

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 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.

ImportanceKnowledge of the mechanisms underlying the intergenerational transmission of risk for attention-deficit/hyperactivity disorder (ADHD) symptoms can inform psychosocial interventions.ObjectiveTo investigate whether parental genetic risk factors associate with their children’s ADHD symptoms due to genetic transmission of risk or due to parental genetic liability that influences offspring ADHD via parenting environments (genetic nurture).Design and participantsThis study is based on the Norwegian Mother, Father and Child Cohort Study and uses data from the Medical Birth Registry of Norway. This prospective cohort study consisted of 5,405 mother-father-offspring trios recruited between 1999 – 2008.ExposuresWe calculated polygenic scores for parental traits previously associated with ADHD, including psychopathology, substance use, neuroticism, educational attainment and intellectual ability.Main outcomes and measuresMothers reported on their 8-year-old children’s ADHD symptoms using the Parent/Teacher Rating Scale for Disruptive Behavior Disorders.ResultsMaternal polygenic scores for ADHD, autism spectrum disorder (ASD), neuroticism and smoking predicted child ADHD symptoms in bivariate analyses. After jointly modelling maternal, paternal and child polygenic scores, ADHD symptoms were predicted by children’s polygenic scores for ADHD (β = 0.10; 95% CI 0.07 to 0.14), smoking (β = 0.07; 95% CI 0.03 to 0.10) and educational attainment (β = −0.09; 95% CI −0.13 to −0.05), indicating direct genetic transmission of risk. Mothers’ polygenic scores for ASD (β = 0.05; 95% CI 0.02 to 0.08) and neuroticism (β = 0.05; 95% CI 0.01 to 0.08) predicted children’s ADHD symptoms conditional on fathers’ and children’s scores, implicating genetic nurture, or effects due to population stratification or assortative mating.ConclusionsThese results suggest that associations between some parental traits and offspring ADHD symptoms likely reflect a nuanced mix of direct genetic transmission (ADHD, smoking and educational attainment) and genetic nurture (ASD and neuroticism). If confirmed, these findings support previous evidence that maternal ASD or neuroticism may be possible targets for intervention to help break the chain of the intergenerational transmission of ADHD risk.

Non-random mating by assortment on heritable traits can have consequences for the genetic resemblance between siblings and in-laws in succeeding generations. We studied polygenic scores and phenotypic data from pairs of partners (26,681), siblings (2,170), siblings-in-law (3,905), and siblings-co-in-law (1,763) in the Norwegian Mother, Father and Child Cohort Study. Using structural equation models, we estimated associations between latent genetic and phenotypic variables without measurement error. We found evidence of genetic similarity between partners for educational attainment (rg=0.37), height (rg=0.13), and depression (rg=0.03). Common genetic variants related to educational attainment correlated between siblings above 0.50 (rg=0.68) and between siblings-in-law (rg=0.25) and siblings-co-in-law (rg=0.09). There was indirect assortment on proxy traits for education and depression but not height. Comparisons between the genetic similarities of partners and siblings indicated that genetic variances were in intergenerational equilibrium. This study shows that assortative mating has influenced the genetic structure of extended families for several generations.

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.

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).

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 four exemplar phenotypes; offspring birth weight, offspring temperament, maternal relationship satisfaction, and paternal body-mass index, using real data from the Norwegian Mother, Father and Child Cohort Study (MoBa).

BackgroundParental criticism is correlated with internalising symptoms in adolescent offspring. This correlation could in part reflect their genetic relatedness, if the same genes influence behaviours in both parents and offspring. We use a Children-of-Twins design to assess whether parent-reported criticism and offspring internalising symptoms remain associated after controlling for shared genes. To aid interpretation of our results and those of previous Children-of-Twins studies, we examine statistical power for the detection of genetic effects and explore the direction of possible causal effects between generations.MethodsData were drawn from two Swedish twin samples, comprising 876 adult twin pairs with adolescent offspring and 1030 adolescent twin pairs with parents. Parent reports of criticism towards their offspring were collected concurrently with parent and offspring reports of adolescent internalising symptoms. Children-of-Twins structural equation models were used to control for genetic influence on the intergenerational association between parental criticism and adolescent internalising.ResultsParental criticism was associated with adolescent internalising symptoms after controlling for genetic influence. No significant role was found for shared genes influencing phenotypes in both generations, although power analyses suggested that some genetic effects may have gone undetected. Models could not distinguish directionality for non-genetic, causal effects between generations.ConclusionsParental criticism may be involved in psychosocial family processes in the context of adolescent internalising. Future studies should seek to identify these processes and provide clarity on the direction of potential causal effects.

BackgroundGenetic 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.MethodsUsing genotype and questionnaire data on children (N = 15,105) from the Norwegian Mother, Father, and Child Cohort Study (MoBa), we tested associations between schizophrenia polygenic risk scores and measures of childhood emotional and behavioural problems for developmental stability and domain specificity. We then sought to identify symptom profiles – across development and domains – associated with elevated schizophrenia polygenic liability.OutcomesWe found evidence for developmental stability in associations between schizophrenia polygenic risk scores and emotional and behavioural problems, with the latter being mediated via the rate of change in symptoms between 18 months and 5 years specifically (βslope = 0.032; 95% CI 0.007 – 0.057). At age 8, associations with emotional and behavioural psychopathology were found to be better explained by a model of symptom-specific polygenic risk score effects, rather than effects mediated via a general “p” 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 increasing behavioural and emotional symptoms in early childhood, followed by relatively elevated symptoms of conduct disorder, oppositional defiant disorder, hyperactivity and inattention in middle childhood.InterpretationSchizophrenia-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.FundingLaurie Hannigan, Ziada Ayorech, and Alexandra Havdahl were supported by grants from the South-Eastern Norway Regional Health Authority (2018059, 2019097 and 2018058, respectively). Ragna Bugge Askeland and Elizabeth Corfield were supported by a grant from the Norwegian Research Council (274611). Ted Reichborn-Kjennerud was supported by a grant from the Research Council of Norway (274611). Pål Rasmus Njølstad was funded by the ERC AdG SELECTionPREDISPOSED (#293574), the Stiftelsen Kristian Gerhard Jebsen, the Trond Mohn Foundation, the Norwegian Research Council (#240413/F20), the Novo Nordisk Foundation (#54741), the University of Bergen, and the Western Norway health Authorities (Helse Vest; PERSON-MED-DIA and #911745). Ole A. Andreassen was supported the Research Council of Norway (229129; 213837; 248778; 223273; 249711); the South-East Norway Regional Health Authority (2017-112); KG Jebsen Stiftelsen (SKGJ) and H2020 grant # 847776 CoMorMent. George Davey Smith works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1). This work was partly supported by the Research Council of Norway through its Centre of Excellence funding scheme, project number 262700.Research in contextEvidence before this studyGenetic liability to schizophrenia, conferred incrementally by many genetic variants of small effect, is associated with various forms of psychopathology – both symptoms and diagnoses – in the general population during adulthood. To get an overview of the relevant evidence for how genetic liability to schizophrenia manifests in psychopathology in childhood, we performed a systematic search of the published literature using the Ovid MEDLINE and PsychINFO databases, for English-language peer-reviewed journal articles published prior to 28 January 2020. We found 7 studies of core relevance (i.e., containing assessment of symptoms or diagnoses of psychopathology in pre-adolescent children), with a further 9 studies examining outcomes potentially related to psychopathology (such as brain structure, cognitive performance, and social functioning). Of the 7 core studies, 3 used clinical samples to demonstrate that polygenic risk scores for schizophrenia are higher among children with ADHD diagnoses than controls, and among cases of the rare child-onset form of schizophrenia than their healthy siblings. The remainder of studies all examined symptoms of psychopathology among children in the general population, finding modest but robust associations of schizophrenia polygenic risk scores with emotional and behavioural problems measured from 3 years of age, as well as with symptoms of depression, ADHD, anxiety, oppositional defiant disorder and conduct disorder in middle childhood.Added value of this studyIn this study, we present a set of analyses designed to improve our understanding of the nature of associations between schizophrenia risk alleles and childhood psychopathology. Specifically, we employ an approach that aims not just to quantify, but also to explore how the effects of schizophrenia risk manifest across childhood, and across different domains of psychopathology. We find evidence that effects of schizophrenia polygenic risk scores on symptoms of emotional and behavioural problems in early childhood are stable, influencing the overall level and rates of change in symptoms, rather than age-specific (i.e., transient or developmental). We also find evidence of specificity in the effects of schizophrenia polygenic risk scores on different domains of psychopathology in 8-year-old children. Overall, we find that higher schizophrenia polygenic risk scores are associated with a developmental symptom profile comprising elevated and increasing symptoms of behavioural problems and increasing levels of emotional problems in early childhood, as well as particularly elevated symptoms of conduct disorder, inattention, hyperactivity, and oppositional defiant disorder in middle childhood.Implications of all the available evidenceFindings of our study align with a growing body of evidence that the effects of schizophrenia risk alleles on psychopathology begin early in life, and influence the likelihood of children experiencing difficulties across development. While previous work has largely found similar effects of schizophrenia polygenic risk scores across different domains of childhood psychopathology, indicating that such effects may be mediated by a hypothetical latent ‘general psychopathology’ or ‘p’ factor, our results suggest that domain- and even symptom-level specificity may emerge by middle childhood. We may be able to improve our understanding of processes underpinning the emergence of schizophrenia later in life by paying attention to nuances in the ways that genetic risk for schizophrenia manifests across childhood and into adolescence.

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.

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) vs. to shared genetic risk. Methods: This study is based on data from the Norwegian Mother, Father and Child Cohort Study. We used data from 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). Outcomes: After accounting for assortative mating in parents (phenotypic r=0.26), genetic transmission of maternal neuroticism accounted for 16% of the correlation with offspring neuroticism (mother-child r=0.31), 18% of the association with offspring depressive symptoms (r=0.31), and 0% of the association with offspring anxiety symptoms (r=0.16). Intergenerational transmission of genes associated with paternal neuroticism accounted for ~40% 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 was explained by maternal influences through assortative mating. Interpretations: These results are consistent with direct effects between maternal and offspring neuroticism and between maternal neuroticism and offspring symptoms of anxiety and depression, suggesting that interventions targeted at family functioning could benefit the children. Funding Statement: This work was supported by the Research Council of Norway (RCN) (262177). E.M.E. and L.C.G. were funded by the RCN (262177). E.Y. was funded by the RCN (288083 and 262177). A.H. was supported by the South-Eastern Norway Regional Health Authority (2018059 and 2020022). T.A.McA. was supported by a Sir Henry Dale Fellowship, jointly funded by the Wellcome Trust and the Royal Society (107706/Z/15/Z) and the RCN (288083). L.J.H. was supported by funding from the SouthEastern Norway Regional Health Authority (2018058). F.A.T. was supported by the RCN (300668). This work was partly supported by the RCN through its Centres of Excellence funding scheme, project number 262700. Declaration of Interests: The authors have declared that they have no competing or potential conflicts of interest. Ethics Approval Statement: The establishment of MoBa and initial data collection was based on a license from the Norwegian Data protection agency and approval from The Regional Committees for Medical and Health Research Ethics. The MoBa cohort is based on regulations based on the Norwegian Health Registry Act. The current study was approved by The Regional Committees for Medical and Health Research Ethics.

Background Clinicians are less likely to prescribe guideline-recommended treatments to people with multimorbidity than to people with a single condition. Doubts as to the applicability of clinical trials of drug treatments (the gold standard for evidence-based medicine) when people have co-existing diseases (comorbidity) may underlie this apparent reluctance. Therefore, for a range of index conditions, we measured the comorbidity among participants in clinical trials of novel drug therapies and compared this to the comorbidity among patients in the community. Methods Data from industry-sponsored phase 3/4 multicentre trials of novel drug therapies for chronic medical conditions were identified from two repositories: Clinical Study Data Request and the Yale University Open Data Access project. We identified 116 trials (n = 122,969 participants) for 22 index conditions. Community patients were identified from a nationally representative sample of 2.3 million patients in Wales, UK. Twenty-one comorbidities were identified from medication use based on pre-specified definitions. We assessed the prevalence of each comorbidity and the total number of comorbidities (level of multimorbidity), for each trial and in community patients. Results In the trials, the commonest comorbidities in order of declining prevalence were chronic pain, cardiovascular disease, arthritis, affective disorders, acid-related disorders, asthma/COPD and diabetes. These conditions were also common in community-based patients. Mean comorbidity count for trial participants was approximately half that seen in community-based patients. Nonetheless, a substantial proportion of trial participants had a high degree of multimorbidity. For example, in asthma and psoriasis trials, 10–15% of participants had ≥ 3 conditions overall, while in osteoporosis and chronic obstructive pulmonary disease trials 40–60% of participants had ≥ 3 conditions overall. Conclusions Comorbidity and multimorbidity are less common in trials than in community populations with the same index condition. Comorbidity and multimorbidity are, nevertheless, common in trials. This suggests that standard, industry-funded clinical trials are an underused resource for investigating treatment effects in people with comorbidity and multimorbidity.

BackgroundAlthough 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.MethodsBiometric 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.ResultsAssociations 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.ConclusionsAssociations 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.

Common genetic influences offer a partial explanation for comorbidity between different psychiatric disorders1,2,3. 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.