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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.

BackgroundPersistence of physical symptoms after SARS-CoV-2 infection is a major public health concern, although evidence from large observational studies remain scarce. We aimed to assess the prevalence of physical symptoms in relation to acute illness severity up to more than 2-years after diagnosis of COVID-19.MethodsThis multinational study included 64 880 adult participants from Iceland, Sweden, Denmark, and Norway with self-reported data on COVID-19 and physical symptoms from April 2020 to August 2022. We compared the prevalence of 15 physical symptoms, measured by the Patient Health Questionnaire (PHQ-15), among individuals with or without a confirmed COVID-19 diagnosis, by acute illness severity, and by time since diagnosis. We additionally assessed the change in symptoms in a subset of Swedish adults with repeated measures, before and after COVID-19 diagnosis.FindingsDuring up to 27 months of follow-up, 22 382 participants (34.5%) were diagnosed with COVID-19. Individuals who were diagnosed with COVID-19, compared to those not diagnosed, had an overall 37% higher prevalence of severe physical symptom burden (PHQ-15 score ≥ 15, adjusted prevalence ratio [PR] 1.37 [95% confidence interval [CI] 1.23-1.52]). The prevalence was associated with acute COVID-19 severity: individuals bedridden for seven days or longer presented with the highest prevalence (PR 2.25[1.85-2.74]), while individuals never bedridden presented with similar prevalence as individuals not diagnosed with COVID-19 (PR 0.92 [0.68-1.24]). The prevalence was statistically significantly elevated among individuals diagnosed with COVID-19 for eight of the fifteen measured symptoms: shortness of breath, chest pain, dizziness, heart racing, headaches, low energy/fatigue, trouble sleeping, and back pain. The analysis of repeated measurements rendered similar results as the main analysis.InterpretationThese data suggest an elevated prevalence of some, but not all, physical symptoms during up to more than 2 years after diagnosis of COVID-19, particularly among individuals suffering a severe acute illness.FundingThis work was mainly supported by grants from NordForsk (COVIDMENT, grant number 105668 and 138929) and Horizon2020 (CoMorMent, 847776). See Acknowledgements for further details on funding.Research in contextEvidence before the studyAs the majority of the global population has contracted COVID-19, persistence of physical symptoms after SARS-CoV-2 infection (LongCOVID or post COVID-19 condition) has become a major public health concern. We searched PubMed for studies assessing physical symptoms after COVID-19, published by March 22, 2023. The search term was (physical symptoms after covid) AND LitCLONGCOVID [Pubmed filter]. We reviewed 82 studies, after excluding those not on humans or not published in English. High prevalence of multiple physical symptoms, mainly fatigue, shortness of breath, headache, muscle and chest pain, has been reported, mostly based on small samples of hospitalized patients confined to three to six months after diagnosis. A comprehensive assessment of long-term prevalence of physical symptoms beyond six months after diagnosis and among non-hospitalized patients is lacking.Added value of this studyWe included 64 880 participants from the general population of four Nordic countries, of whom 22 382 had been diagnosed with COVID-19 up to 2 years earlier (Implications of the available evidenceOur findings provide timely and valuable evidence to demonstrate the constitution of Long COVID and the long-term health consequences after recovery from COVID-19 in the general population. The long-term risk of severe physical symptom burden is distinctly associated with acute illness severity, highlighting the importance of sustained monitoring of physical symptoms among the group of patients who suffered severe acute illness course.

Conduct problems in children and adolescents affect individuals, families, and their environment. The aetiology of conduct problems involves a combination of genetic and environmental risk 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 characteristics and children’s behaviour are due to transmission of genetic risk or due to environmentally mediated genetic influences on offspring behaviour (i.e., genetic nurture). We used 31,346 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 12 polygenic scores (PGS) spanning psychiatric conditions, substance use, education-related factors, and other risk factors. Among genotyped trios, maternal reports of conduct problems at age 8 years were available for 15,516 children. We found significant genetic transmission effects on conduct problems for 11 out of 12 PGS (strongest positive association: PGS for smoking, β = 0.07 95% confidence interval = [0.05, 0.08]; strongest negative association: PGS for education, β = –0.04, 95% confidence interval = [¬–0.06, –0.02]). Conversely, we did not find strong evidence for genetic nurture effects for child conduct problems using our selection of PGS. Our findings provide evidence for genetic transmission in the association between parental characteristics like psychiatric conditions or risk behaviours and child conduct problems. Our results may also indicate that genetic nurture 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.

BackgroundLittle is known regarding the mental health impact of having a significant person (family member and/or close friend) with COVID-19 of different severity.MethodsThe study included five prospective cohorts from four countries (Iceland, Norway, Sweden, and the UK) with self-reported data on COVID-19 and symptoms of depression and anxiety during March 2020-March 2022. We calculated the prevalence ratio (PR) of depression and anxiety in relation to having a significant person with COVID-19 and performed a longitudinal analysis in the Swedish cohort to describe the temporal patterns of the results.Results162,237 and 168,783 individuals were included in the analysis of depression and anxiety, respectively, of whom 24,718 and 27,003 reported a significant person with COVID-19. Overall, the PR was 1.07 (95% CI: 1.05-1.10) for depression and 1.08 (95% CI: 1.03-1.13) for anxiety among significant others of COVID-19 patients. The respective PRs for depression and anxiety were 1.04 (95% CI: 1.01-1.07) and 1.03 (95% CI: 0.98-1.07) if the significant person was never hospitalized, 1.15 (95% CI: 1.08-1.23) and 1.24 (95% CI: 1.14-1.34) if the patient was hospitalized, 1.42 (95% CI: 1.27-1.57) and 1.45 (95% CI: 1.31-1.60) if admitted to the ICU, and 1.34 (95% CI: 1.22-1.46) and 1.36 (95% CI: 1.22-1.51) if the significant person died. Individuals of hospitalized, ICU admitted, or deceased patients showed higher prevalence of depression and anxiety during the entire 12 months after the COVID-19 diagnosis of the significant person.ConclusionsClose friends and family members of critically ill COVID-19 patients show elevated prevalence of depression and anxiety throughout the first year after the diagnosis.

The intergenerational transmission of educational attainment from parents to their children is one of the most important and studied relationships in social science. Longitudinal studies have found strong associations between parents’ and their children’s educational outcomes, which could be due to the effects of parents. Here we provide new evidence about whether parents’ educational attainment affects their parenting behaviours and children’s early educational outcomes using within-family Mendelian randomization and data from 40,907 genotyped parent-child trios from the Norwegian Mother, Father and Child Cohort (MoBa) study. We found evidence suggesting that parents’ educational attainment affects their children’s educational outcomes from age 5 to 14. More studies are needed to provide more samples of parent-child trios and assess the potential consequences of selection bias and grandparental effects.

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.

Objective: 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-environment interaction), while accounting for shared genetic risk between mothers and offspring (genotype-environment correlation). Method: 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 on child emotional and behavioral problems when children were 1.5 / 3 / 5 years. We included child polygenic scores (PGS) for traits linked to environmental sensitivity as moderators. Results: Associations between maternal drinking and child emotional (β1 = 0.04 [95% CI: 0.03-0.05]) and behavioral (β1 = 0.07 [0.06-0.08]) outcomes attenuated after controlling for measured confounders, and were almost zero when unmeasured confounding was also accounted for (emotional problems β1 = 0.01 [0.00-0.02]; behavioral problems β1 = 0.01 [0.00-0.02]). No moderation of these adjusted exposure effects by any of the PGS were observed. Conclusion: The lack of strong evidence for genotype-environment 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 Parental drinking, mental health and family socioeconomic status are all associated with offspring sleep problems, but there is a paucity of research that considers the effect of several risk factors together, as they co-occur within and across families. Also, sleep problems are closely linked with mental health problems and disentangling the effects on one or the other are important. We examined whether parental risk constellations are differently associated with offspring’s subsequent prescription drug use for sleep problems during nine years with or without prescription drug use for anxiety and/or depression. Methods The sample included 8773 adolescent offspring of 6696 two-parent families who participated in the Nord-Trøndelag Health Study in Norway. The exposures were five parental risk constellations characterized by drinking frequencies and quantities, mental health, and years of education. The outcomes were dispensed prescription drugs in offspring for a) only sleep problems b) sleep problems and anxiety/depression or c) only anxiety/depression during 2008–2016. We used multinomial logistic regression to model the odds of the outcomes. Results Compared to the overall low-risk parental constellation, none of the four risky constellations were significantly associated with increased risk of being dispensed prescription drugs only for sleep problems. Offspring from two different risk profiles were at increased risk for being dispensed both sleep and anxiety/depression prescription drugs. These were parental profiles marked by 1) low education, symptoms of mental health problems and weekly binge drinking in both parents (OR 1.90, CI = 1.06;3.42); and 2) elevated drinking in both parents and elevated symptoms of mental health problems in fathers (OR 3.32, CI = 1.49;7.39). Offspring from the risk profile with lowest parental education were at increased risk of being dispensed only anxiety/depression prescription drugs (OR 1.25, CI = 1.05;1.49). Conclusion Our findings suggest that parental risk constellations are not associated with increased risk of offspring receiving sleep medications without also receiving anxiety/depression medications, as two risk constellations were associated with increased risk of dispensation of both sleep and anxiety/depression prescription drugs during nine years. Receiving both may be an indication of severity. The findings underscore the importance of including measures of mental health problems when investigating sleep problems to avoid misattribution of effects.

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.

BackgroundAn 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. MethodsWe 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. ResultsDifferentiation 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. ConclusionsDifferentiation 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.

BackgroundThe Norwegian Mother, Father, and Child Cohort Study (MoBa) is a population-based pregnancy cohort, which includes approximately 114,500 children, 95,200 mothers, and 75,200 fathers.Genotyping of MoBa has been conducted through multiple research projects, spanning several years; using varying selection criteria, genotyping arrays, and genotyping centres. MoBa contains numerous interrelated families, which necessitated the implementation of a family-based quality control (QC) pipeline that verifies and accounts for diverse types of relatedness.MethodsThe MoBaPsychGen pipeline, comprising pre-imputation QC, phasing, imputation, and post-imputation QC, was developed based on current best-practice protocols and implemented to account for the complex structure of the MoBa genotype data. The pipeline includes QC on both single nucleotide polymorphism (SNP) and individual level. Phasing and imputation were performed using the publicly available Haplotype Reference Consortium release 1.1 panel as a reference. Information from the Medical Birth Registry of Norway and MoBa questionnaires were used to identify biological sex, year of birth, reported parent-offspring (PO) relationships, and multiple births (only available in the offspring generation).ResultsIn total, 207,569 unique individuals (90% of the unique individuals included in the study) and 6,981,748 SNPs passed the MoBaPsychGen pipeline. The relatedness checks performed throughout the pipeline allowed identification of within-generation and across-generation first-degree, second-degree, and third-degree relatives. The individuals passing post-imputation QC comprised 64,471 families ranging in size from singletons to 84 unique individuals (singletons are included as families as other family members may not have been genotyped, imputed, or passed post-imputation QC). The relationships identified include 287 monozygotic twin pairs, 22,884 full siblings, 117,004 PO pairs, 23,299 second-degree relative pairs, and 10,828 third-degree relative pairs.DiscussionMoBa contains a highly complex relatedness structure, with a variety of family structures including singletons, PO duos, full (mother, father, child) PO trios, nuclear families, blended families, and extended families. The availability of robustly quality-controlled genetic data for such a large cohort with a unique extended family structure will allow many novel research questions to be addressed. Furthermore, the MoBaPsychGen pipeline has potential utility in similar cohorts.

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.

Objective: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. Method: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. Results: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, neffective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|rg| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |rg| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Conclusion: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success. Dr. Border has received support from the National Institutes of Health (NIH; MH100141 and MH016880 ). Dr. Peterson has received support from NIH (K01MH113848) and the Brain & Behavior Research Foundation Young Investigator Grant (28632). Drs. Sallis and Munafò have served as members of the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/7). Dr. Shabalin has received support from a NARSAD Young Investigator Award. Dr. Vilor-Tejedor has received support from a post-doctoral grant, Juan de la Cierva Programme (FJC2018-038085-I), Ministerio de Ciencia, Innovación y Universidades – Spanish State Research Agency. Her research has received additional support of “la Caixa” Foundation (LCF/PR/GN17/10300004) and the Health Department of the Catalan Government (Health Research and Innovation Strategic Plan (PERIS) 2016-2020 grant# SLT002/16/00201). She has acknowledged the support of the Spanish Ministry of Science, Innovation and Universities to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya. Dr. Alemany has received support from a Juan de la Cierva – Incorporación Postdoctoral Contract from Ministerio de Economía, Industria y Competitividad (IJCI-2017-34068). Dr. Corley has received support from NIH (DA011015, AG046938, and DA035804). Dr. Evans has received support from NIH (MH100141, DA044283, and AG046938). Dr. Havdahl has received support from the South-Eastern Norway Regional Health Authority (2018059) at Nic Waals Institute, Lovisenberg Diaconal Hospital. Dr. Rimfeld has received support from a Sir Henry Wellcome Postdoctoral Fellowship. Dr. Andreassen has served as a consultant to HealthLytix and has received funding from the Research Council of Norway (223273 and 273291) and KG Jebsen Stiftelsen. Dr. Boomsma has received support from the Royal Netherlands Academy of Science Professor Award (PAH/5535). Dr. Brown has received support from NIH (DA035804). Dr. Copeland has received support from NIH (MH117559 and HD093651). Dr. Dick has received support from a mid-career award NIH K02 AA018755, NIH R01 AA015416 (Finnish Twin Study), P50 AA022537 (Alcohol Research Center), R25 AA027402 (VCU GREAT), and U10 AA008401 (COGA) from the National Institute on Alcohol Abuse and Alcoholism. Drs. Hewitt, Krauter, Smolen, and Stallings have received support from NIH (DA011015 and DA035804). Dr. Hopfer has received support from NIH (DA042755, DA035804, and DA032555). Dr. Kaprio has received support from the Academy of Finland (grants 308248 and 312073). Dr. Larsson has served as a speaker for Evolan Pharma and Shire/Takeda and has received research grants from Shire/Takeda, all outside the submitted work. Dr. Lichtenstein has received support from the Swedish Research Council for Health, Working Life and Welfare (project 2012-1678) and the Swedish Research Council (2016-1989). Dr. Lundström has received support from the Swedish Research Council ( 2017-02552 ). Dr. Magnus has received support from the Research Council of Norway through its Centers of Excellence scheme, project no 262700. Dr. Njølstad has received support from the European Research Council (AdG #293574). Stiftelsen Kristian Gerhard Jebsen has received support from the Research Council of Norway (FRIPRO 240413), the Western Norway Regional Health Authority (Strategic Fund “Personalized Medicine for Children and Adults”) and the Novo Nordisk Foundation (54741). Dr. Plomin has received support from a MRC Professorship award (G19/2). Dr. Reichborn-Kjennerud has received support from the Research Council of Norway grant 274611 . Drs. Reynolds and Wadsworth have received support from NIH (AG046938). Dr. Rose has received support from a NIH Research Scientist Award (AA-000145). Dr. Wall has received support from NIH (DA03580 and DA021905). Dr. Whitehouse has received support from an Investigator Grant from the National Health and Medical Research Council. Dr. Ystrøm has received support from the Research Council of Norway (262177 and 288083). Dr. Nivard has received support from ZonMW (849200011), the Netherlands Organisation for Health Research and Development (531003014 937), a Jacobs Foundation Research Fellowship, and a VENI grant awarded by NWO (VI.Veni.191G.030). Dr. Bartels has received support from an ERC Consolidator Grant (WELL-BEING 771057). Ms. Hagenbeek and Mr. Ip have received support from the Aggression in Children: Unraveling gene-environment interplay to inform Treatment and Intervention strategies project (ACTION). ACTION received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no 602768

Aims: Certain risk constellations of parental drinking, mental health and years of education are prospectively associated with offspring’s risk for a diagnosis of anxiety/depression, but it remains unknown how they may relate to other aspects of offspring’s mental health. We examined whether such risk constellations were also prospectively associated with the extent of offspring’s utilisation of healthcare services for anxiety/depression. Methods: The sample included 8773 adolescent offspring of 6696 two-parent families who participated in the Nord-Trøndelag Health Study in Norway. The exposures consisted of five parental risk constellations characterised by drinking frequencies and quantities, years of education and mental health previously derived based on the parental self-reports using latent profile analysis. The outcomes were the number of years in contact, and the total number of consultations/visits, with healthcare services for anxiety/depression in adolescents and young adults as recorded in healthcare registries in the period 2008–2014. Associations were examined using zero-inflated negative binomial regression models, accounting for demographics and offspring’s early mental health. Results: Parental risk constellations were not significantly associated with the extent of offspring’s healthcare utilisation for anxiety/depression during the seven-year study period, neither in respect of number of years nor in number of contacts. Conclusions: Offspring of four risky constellations were no more likely to use healthcare services for longer time periods or have more consultations/visits than offspring of the lowest-risk constellation. Parental risk constellations appear more informative for understanding disorder aetiology than for understanding management and treatment of anxiety and depression during adolescence and early adulthood.

Background: Individuals suffering from schizophrenia have a reduced life expectancy with cardiovascular disease (CVD) as a major contributor. Low educational attainment is associated with schizophrenia, as well as with all-cause and CVD mortality. However, it is unknown to what extent low educational attainment can explain the increased mortality in individuals with schizophrenia. Aim: Here, we quantify associations between educational attainment and allcause and CVD mortality in individuals with schizophrenia, and compare them with the corresponding associations in the general population. Method: All Norwegian citizens born between January 1, 1925, and December 31, 1959, were followed up from January 1, 1990, to December 31, 2014. The total sample included 1,852,113 individuals, of which 6548 were registered with schizophrenia. We estimated hazard ratios (HR) for all-cause and CVD mortality with Cox models, in addition to life years lost. Educational attainment for index persons and their parents were included in the models. Results: In the general population individuals with low educational attainment had higher risk of all-cause (HR: 1.48 [95% CI: 1.47–1.49]) and CVD (HR: 1.59 [95% CI: 1.57–1.61]) mortality. In individuals with schizophrenia these estimates were substantially lower (all-cause: HR: 1.13 [95% CI: 1.05–1.21] and CVD: HR:1.12 [95% CI: 0.98–1.27]). Low educational attainment accounted for 3.28 (3.21– 3.35) life years lost in males and 2.48 (2.42–2.55) years in females in the general population, but was not significantly associated with life years lost in individuals with schizophrenia. Results were similar for parental educational attainment. Conclusions: Our results indicate that while individuals with schizophrenia in general have lower educational attainment and higher mortality rates compared with the general population, the association between educational attainment and mortality is smaller in schizophrenia subjects than in the general population.

BACKGROUNDThe aim of this multinational study was to assess the development of adverse mental health symptoms among individuals diagnosed with COVID-19 in the general population by acute infection severity up to 16 months after diagnosis.METHODSParticipants consisted of 247 249 individuals from seven cohorts across six countries (Denmark, Estonia, Iceland, Norway, Scotland, and Sweden) recruited from April 2020 through August 2021. We used multivariable Poisson regression to contrast symptom-prevalence of depression, anxiety, COVID-19 related distress, and poor sleep quality among individuals with and without a diagnosis of COVID-19 at entry to respective cohorts by time (0-16 months) from diagnosis. We also applied generalised estimating equations (GEE) analysis to test differences in repeated measures of mental health symptoms before and after COVID-19 diagnosis among individuals ever diagnosed with COVID-19 over time.FINDINGSA total of 9979 individuals (4%) were diagnosed with COVID-19 during the study period and presented overall with a higher symptom burden of depression (prevalence ratio [PR] 1·18, 95% confidence interval [95% CI] 1·03-1·36) and poorer sleep quality (1·13, 1·03-1·24) but not with higher levels of symptoms of anxiety or COVID-19 related distress compared with individuals without a COVID-19 diagnosis. While the prevalence of depression and COVID-19 related distress attenuated with time, the trajectories varied significantly by COVID-19 acute infection severity. Individuals diagnosed with COVID-19 but never bedridden due to their illness were consistently at lower risks of depression and anxiety (PR 0·83, 95% CI 0·75-0·91 and 0·77, 0·63-0·94, respectively), while patients bedridden for more than 7 days were persistently at higher risks of symptoms of depression and anxiety (PR 1·61, 95% CI 1·27-2·05 and 1·43, 1·26-1·63, respectively) throughout the 16-month study period.CONCLUSIONAcute infection severity is a key determinant of long-term mental morbidity among COVID-19 patients.

Key features • COVIDMENT [www.covidment.is] is a NordForsk-funded research collaboration across six nations, with the overarching aim to significantly advance current knowledge on mental morbidity trajectories associated with the coronavirus disease 2019 (COVID-19) in the general population and in specific risk groups. • From March 2020 through August 2021, 392 817 individuals have been recruited to the seven COVIDMENT cohorts: the Danish Blood Donor Study (N ¼ 71 562), the Estonian Biobank COVID-19 and Mental Health Data Collection cohorts (N ¼ 13 329 and N ¼ 86 116, respectively), the Icelandic COVID-19 National Resilience Cohort (N ¼ 22 849), the Norwegian BRY.DEG2020 (N ¼ 19 343), the Norwegian Mother, Father and Child Cohort Study (N ¼ 132 486), the Scottish Generation Scotland/CovidLife (N ¼ 18 518) and the Swedish Omtanke2020 (N ¼ 28 614). Semi-harmonized questionnaire data have been collected across all COVIDMENT cohorts with longitudinal data available, e.g. through linkage to the national registers. • The average age of participants ranged from 31.8 to 58.5 years across cohorts. The prevalence of depressive symptoms above cut-off point varied considerably across cohorts (4.2–20.8%). The prevalence of depressive symptoms was highest at COVID-19 incidence of 30 cases per week per 100 000 persons, i.e. 14.3% [95% confidence interval (CI): 9.4–21.8%], which was 61.0% (95% CI: 34.0–94.1%) higher than the prevalence at COVID-19 incidence of 0 cases per week per 100 000 persons (P ¼ 1.1 x 10 ^( 6)). •

Obsessive-compulsive disorder (OCD) is a heritable disorder, but no definitive, replicated OCD susceptibility loci have yet been identified by any genome-wide association study (GWAS). Here, we report results from a GWAS in the largest OCD case-control sample (N = 14,140 OCD cases and N = 562,117 controls) to date. We explored the genetic architecture of OCD, including its genetic relationships to other psychiatric and non-psychiatric phenotypes. In the GWAS analysis, we identified one SNP associated with OCD at a genome-wide significant level. Subsequent gene-based analyses identified additional two genes as potentially implicated in OCD pathogenesis. All SNPs combined explained 16% of the heritability of OCD. We show sub-stantial positive genetic correlations between OCD and a range of psychiatric disorders, including anxiety disorders, anorexia nervosa, and major depression. We thus for the first time provide evidence of a genome-wide locus implicated in OCD and strengthen previous literature suggesting a polygenic nature of this disorder.

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).

BackgroundHigher BMI in childhood is associated with emotional and behavioural problems, but these associations may not be causal. Results of previous genetic studies imply causal effects but may reflect influence of demography and the family environment.MethodsThis study used data on 40,949 8-year-old children and their parents from the Norwegian Mother, Father and Child Cohort Study (MoBa) and Medical Birth Registry of Norway (MBRN). We investigated the impact of BMI on symptoms of depression, anxiety, and attention-deficit hyperactivity disorder (ADHD) at age 8. We applied within-family Mendelian randomization, which accounts for familial effects by controlling for parental genotype.ResultsWithin-family Mendelian randomization estimates using genetic variants associated with BMI in adults suggested that a child’s own BMI increased their depressive symptoms (per 5kg/m2increase in BMI, beta=0.26 S.D., CI=-0.01,0.52, p=0.06) and ADHD symptoms (beta= 0.38 S.D., CI=0.09,0.63, p=0.009). These estimates also suggested maternal BMI, or related factors, may independently affect a child’s depressive symptoms (per 5kg/m2increase in maternal BMI, beta=0.11 S.D., CI:0.02,0.09, p=0.01). However, within-family Mendelian randomization using genetic variants associated with retrospectively-reported childhood body size did not support an impact of BMI on these outcomes. There was little evidence from any estimate that the parents’ BMI affected the child’s ADHD symptoms, or that the child’s or parents’ BMI affected the child’s anxiety symptoms.ConclusionsWe found inconsistent evidence that a child’s BMI affected their depressive and ADHD symptoms, and little evidence that a child’s BMI affected their anxiety symptoms. There was limited evidence of an influence of parents’ BMI. Genetic studies in samples of unrelated individuals, or using genetic variants associated with adult BMI, may have overestimated the causal effects of a child’s own BMI.FundingThis research was funded by the Health Foundation. It is part of the HARVEST collaboration, supported by the Research Council of Norway. Individual co-author funding: the European Research Council, the South-Eastern Norway Regional Health Authority, the Research Council of Norway, Helse Vest, the Novo Nordisk Foundation, the University of Bergen, the South-Eastern Norway Regional Health Authority, the Trond Mohn Foundation, the Western Norway Regional Health Authority, the Norwegian Diabetes Association, the UK Medical Research Council. The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit.

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.