The epidemiology of major depression among adults in Norway: an observational study on the concurrence between population surveys and registry data - a NCDNOR project.

BACKGROUND: Mental health problems, and major depression in particular, are important public health issues. Following trends in the prevalence of major depression is difficult because of the costs and complications of diagnostic interviews and general population self-report health surveys. Scandinavian countries, however, have several central, population-based health registries. We aimed to investigate how well these registries capture the epidemiology of major depression in the population. METHODS: In two Norwegian regional surveys of general population health, each repeated after 10 years, responders were asked to report depressive symptoms using the Hopkins Symptom Checklist (HSCL) or the Hospital Anxiety and Depression Scale (HADS). Data were linked to three central health registries capturing contact with primary care, specialist care and prescriptions for antidepressants, to investigate how well these registries reflected self-reported depressive symptoms. RESULTS: Most responders scored low on Hopkins Symptom Checklist (HSCL) and the Hospital Anxiety and Depression Scale (HADS), but 10% and 13%, respectively, scored above cut-off, with only minor changes between the two survey times. Females scored higher than males. Older people scored lower than younger, and a social gradient was visible. Around 12% of those who scored above the cut-off on either scale were recorded in the central health registries during the following year. This correlation was highest in primary care data, followed by prescription data and lowest in specialist care. Females were more often recorded in registries (p < 0.001), as were younger people (p < 0.001). CONCLUSIONS: There was a strong association between scores on screening for major depression in the general population surveys and being recorded in central health registries. There was a low sensitivity of these registries. and there was some variation in how sensitive the central health registries were in picking up depression, especially for males and older people. However, the stability of the measures over time suggests we may get an impression of the prevalence of major depression in the general population by using data from the central health registries. A combination of primary care data, prescription data and specialist care data have a higher sensitivity.

COSGAP: COntainerized Statistical Genetics Analysis Pipelines.

Summary: The collection and analysis of sensitive data in large-scale consortia for statistical genetics is hampered by multiple challenges, due to their non-shareable nature. Time-consuming issues in installing software frequently arise due to different operating systems, software dependencies, and limited internet access. For federated analysis across sites, it can be challenging to resolve different problems, including format requirements, data wrangling, setting up analysis on high-performance computing (HPC) facilities, etc. Easier, more standardized, automated protocols and pipelines can be solutions to overcome these issues. We have developed one such solution for statistical genetic data analysis using software container technologies. This solution, named COSGAP: "COntainerized Statistical Genetics Analysis Pipelines," consists of already established software tools placed into Singularity containers, alongside corresponding code and instructions on how to perform statistical genetic analyses, such as genome-wide association studies, polygenic scoring, LD score regression, Gaussian Mixture Models, and gene-set analysis. Using provided helper scripts written in Python, users can obtain auto-generated scripts to conduct the desired analysis either on HPC facilities or on a personal computer. COSGAP is actively being applied by users from different countries and projects to conduct genetic data analyses without spending much effort on software installation, converting data formats, and other technical requirements. Availability and implementation: COSGAP is freely available on GitHub (https://github.com/comorment/containers) under the GPLv3 license.

Open-door policy versus treatment-as-usual in urban psychiatric inpatient wards: a pragmatic, randomised controlled, non-inferiority trial in Norway.

BACKGROUND: Open-door policy is a recommended framework to reduce coercion in psychiatric wards. However, existing observational data might not fully capture potential increases in harm and use of coercion associated with open-door policies. In this first randomised controlled trial, we compared coercive practices in open-door policy and treatment-as-usual wards in an urban hospital setting. We hypothesised that the open-door policy would be non-inferior to treatment-as-usual on the proportion of patients exposed to coercive measures. METHODS: We conducted a pragmatic, randomised controlled, non-inferiority trial comparing two open-door policy wards and three treatment-as-usual acute psychiatric wards at Lovisenberg Diaconal Hospital in Oslo, Norway. An exemption from the consent requirements enabled inclusion and random allocation of all patients admitted to these wards using an open list (2:3 ratio) administrated by a team of ward nurses. The primary outcome was the proportion of patient stays with one or more coercive measures, including involuntary medication, isolation or seclusion, and physical and mechanical restraints. The non-inferiority margin was set to 15%. Primary and safety analyses were assessed using the intention-to-treat population. The trial is registered with ISRCTN registry and is complete, ISRCTN16876467. FINDINGS: Between Feb 10, 2021, and Feb 1, 2022, we randomly assigned 556 patients to either open-door policy wards (n=245; mean age 41·6 [SD 14·5] years; 119 [49%] male; 126 [51%] female; and 180 [73%] admitted to the ward involuntarily) or treatment-as-usual wards (n=311; mean age 41·6 [4·3] years; 172 [55%] male and 138 [45%] female; 233 [75%] admitted involuntarily). Data on race and ethnicity were not collected. The open-door policy was non-inferior to treatment-as-usual on all outcomes: the proportion of patient stays with exposure to coercion was 65 (26·5%) in open-door policy wards and 104 (33·4%) in treatment-as-usual wards (risk difference 6·9%; 95% CI -0·7 to 14·5), with a similar trend for specific measures of coercion. Reported incidents of violence against staff were 0·15 per patient stay in open-door policy wards and 0·18 in treatment-as-usual wards. There were no suicides during the randomised controlled trial period. INTERPRETATION: The open-door policy could be safely implemented without increased use of coercive measures. Our findings underscore the need for more reliable and relevant randomised trials to investigate how a complex intervention, such as open-door policy, can be efficiently implemented across health-care systems and contexts. FUNDING: South-Eastern Norway Regional Health Authority and The Research Council of Norway.

Conduct disorder - a comprehensive exploration of comorbidity patterns, genetic and environmental risk factors.

Conduct disorder (CD), a common mental disorder in children and adolescents, is characterized by antisocial behavior. Despite similarities with antisocial personality disorder (ASPD) and possible diagnostic continuity, CD has been shown to precede a range of adult-onset mental disorders. Additionally, little is known about the putative shared genetic liability between CD and adult-onset mental disorders and the underlying gene-environment interplay. Here, we interrogated comorbidity between CD and other mental disorders from the Norwegian Mother, Father and Child Cohort Study (n = 114 500) and investigated how polygenic risk scores (PRS) for mental health traits were associated with CD/CD traits in childhood and adolescence. Gene-environment interplay patterns for CD was explored with data on bullying and parental education. We found CD to be comorbid with several child and adult-onset mental disorders. This phenotypic overlap corresponded with associations between PRS for mental disorders and CD. Additionally, our findings support an additive gene-environment model. Previously conceptualized as a precursor of ASPD, we found that CD was associated with polygenic risk for several child- and adult-onset mental disorders. High comorbidity of CD with other psychiatric disorders reflected on the genetic level should inform research studies, diagnostic assessments and clinical follow-up of this heterogenous group.

Lipid Biomarker Research in Bipolar Disorder: A Scoping Review of Trends, Challenges, and Future Directions.

Bipolar disorder (BD) is a disabling disorder with heterogeneous symptom profiles and trajectories. Like many other neuropsychiatric disorders, clinical decision making related to diagnoses and choice of treatment is based on clinical assessments alone, and risk prediction for treatment success or resistance at an individual level remains sparse. An enormous effort to add biological markers to this risk prediction is ongoing. The role of lipids in normal brain functioning is well established, and several hypotheses about the role of lipids in the pathogenesis of neuropsychiatric disorders, including BD, have been made. The frequent comorbidity between neuropsychiatric disorders and cardiovascular disease, the genetic overlap of risk genes for severe mental disorders and genes involved in lipid regulation, and the lipid-altering effects of antipsychotics and mood stabilizers indicate that lipids could hold promise as biomarkers for neuropsychiatric disorders, including BD. To date, reviews of lipid biomarkers in schizophrenia and major depression have noted caveats for future investigations, while reviews of lipid biomarker research in BD is missing. In the current scoping review, we present a comprehensive overview of trends in previous research on lipid biomarkers in BD. The current literature varies greatly in the phenotypes investigated and study designs, leading to divergent findings. Small sample size; potential confounders related to physical activity, nutritional status, and medication use; and cross-sectional designs were frequently reported limitations. Future research may benefit from pivoting toward utilization of newer laboratory techniques such as lipidomics, but consistent use of study methods across cohorts is also needed.

Common genetic and environmental risk for personality disorders and psychotic-like experiences in young adult twins.

INTRODUCTION: Psychotic-like experiences (PLE) have been associated with the subsequent emergence of psychotic disorders as well as several other domains of psychopathology. In this twin study, we estimated the genetic and environmental correlations between PLE and 10 personality disorders (PD). METHODS: Diagnoses of 10 PDs according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and PLE from the Composite International Diagnostic Interview (CIDI) were retrieved for 2793 young adult twins from the Norwegian Twin Registry. Risk for having a PD and PLEs was modeled using item response theory. Biometric twin models were fitted to estimate the genetic and environmental correlations between PDs and PLEs. Co-twin control analysis was performed to estimate additional within-family risk for PLEs when having a PD. RESULTS: Phenotypic overlap between PDs and PLEs ranged from 14% to 44% in males and from 11% to 39% in females, with the highest overlap for borderline PD in both sexes. In general, we found higher genetic correlations (r = 0.14-0.72) than environmental correlations (r = 0.06-0.28) between PDs and PLEs. The highest genetic correlations between PLE and PDs were found for borderline (r = 0.72), paranoid (r = 0.56), schizotypal (r = 0.56) and antisocial PD (r = 0.49). CONCLUSION: We found that the co-occurrence between PDs and PLE is the best explained by shared genetic determinants, with minor contributions from environmental factors. Interestingly, borderline PD was highly genetically correlated with PLE, warranting molecular genetic studies of this association.

Epidemiological overview of major depressive disorder in Scandinavia using nationwide registers.

Background: Major depressive disorder (MDD) is a common psychiatric disorder associated with a high disease burden. This study gives a comprehensive overview of the prevalence, outcomes, treatment, and genetic epidemiology of MDD within and across the Scandinavian countries. Methods: This study has aimed to assess and compare across Norway, Denmark, and Sweden 1) the prevalence and trajectories of MDD and comorbidity, 2) outcomes and treatment, and 3) heritability (Denmark and Sweden only). The analyses leveraged data on 272,944 MDD cases (and 6.2 million non-cases) from Norway, Sweden, and Denmark in specialist care in national longitudinal health registers covering 1975-2013. Relying on harmonized public data global comparisons of socioeconomic and health metrics were performed to assess to what extent findings are generalizable. Findings: MDD ranked among the most prevalent psychiatric disorders. For many cases, the disorder trajectory was severe, with varying proportions experiencing recurrence, developing comorbid disorders, requiring inpatient treatment, or dying of suicide. Important country differences in specialist care prevalence and treatment were observed. Heritability estimates were moderate (35-48%). In terms of socioeconomic and health indices, the Scandinavian nations were comparable to one another and grouped with other Western nations. Interpretation: The Scandinavian countries were similar with regards to MDD epidemiological measures, but we show that differences in health care organization need to be taken into consideration when comparing countries. This study demonstrates the utility of using comprehensive population-wide registry data, outlining possibilities for other applications. The findings will be of use to policy makers for developing better prevention and intervention strategies. Funding: Swedish Research Council (Vetenskapsrådet, award D0886501 to PFS), US National Institutes of Mental HealthR01 MH123724 (to PFS), European Union's Horizon 2020 Research and Innovation Program (847776 and 964874, to OA) and European Research Council grant (grant agreement ID 101042183, to YL).

Developmental milestones in early childhood and genetic liability to neurodevelopmental disorders.

BACKGROUND: Timing of developmental milestones, such as age at first walking, is associated with later diagnoses of neurodevelopmental disorders. However, its relationship to genetic risk for neurodevelopmental disorders in the general population is unknown. Here, we investigate associations between attainment of early-life language and motor development milestones and genetic liability to autism, attention deficit hyperactivity disorder (ADHD), and schizophrenia. METHODS: We use data from a genotyped sub-set (N = 25699) of children in the Norwegian Mother, Father and Child Cohort Study (MoBa). We calculate polygenic scores (PGS) for autism, ADHD, and schizophrenia and predict maternal reports of children's age at first walking, first words, and first sentences, motor delays (18 months), and language delays and a generalised measure of concerns about development (3 years). We use linear and probit regression models in a multi-group framework to test for sex differences. RESULTS: We found that ADHD PGS were associated with earlier walking age (ß = -0.033, padj < 0.001) in both males and females. Additionally, autism PGS were associated with later walking (ß = 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. CONCLUSIONS: Genetic liabilities for neurodevelopmental disorders show some specific associations with the age at which children first walk unsupported. Associations are small but robust and, in the case of autism PGS, differentiated by sex. These findings suggest that early-life motor developmental milestone attainment is associated with genetic liability to ADHD and autism in the general population.

Estimated vaccine effectiveness against SARS-CoV-2 Delta and Omicron infections among health care workers and the general adult population in Norway, August 2021 - January 2022.

BACKGROUND: Health care workers (HCW) have a higher exposure to SARS-CoV-2 virus than other professionals and to protect both HCW and patients, HCW have been prioritized for vaccination against SARS-CoV-2 in many countries. Estimating the COVID-19 vaccine effectiveness among HCW is important to provide recommendations to protect risk groups. METHODS: We estimated vaccine effectiveness against SARS-CoV-2 infections using Cox proportional hazard models among HCW with comparisons in the general population, from 1 August 2021 to 28 January 2022. Vaccine status is specified as a time-varying covariate and all models incorporated explicit time and were adjusted for age, sex, comorbidities, county of residence, country of birth, and living conditions. Data from the adult Norwegian population (aged 18-67 years) and HCW workplace data (as registered 1 January 2021) were collated from the National Preparedness Register for COVID-19 (Beredt C19). RESULTS: Vaccine effectiveness was higher for Delta than for the Omicron variant in HCW (71 % compared to 19 %) as well as in non-HCW (69 % compared to -32 %). For the Omicron variant a 3rd dose provides significantly better protection against infection than 2 doses in both HCW (33 %) and non-HCW (10 %). Further, HCW seem to have better vaccine effectiveness than non-HCW for the Omicron, but not for the Delta variant. CONCLUSIONS: Vaccine effectiveness were comparable between HCW and non-HCW for the delta variant, but significantly higher in HCW than non-HCW for the omicron variant. Both HCW and non-HCW got increased protection from a third dose.

Associations Between Symptoms of Premenstrual Disorders and Polygenic Liability for Major Psychiatric Disorders.

Importance: Premenstrual disorders are heritable, clinically heterogenous, with a range of affective spectrum comorbidities. It is unclear whether genetic predispositions to affective spectrum disorders or other major psychiatric disorders are associated with symptoms of premenstrual disorders. Objective: To assesss whether symptoms of premenstrual disorders are associated with the genetic liability for major psychiatric disorders, as indexed by polygenic risk scores (PRSs). Design, Setting, and Participants: Women from the Norwegian Mother, Father and Child Cohort Study were included in this genetic association study. PRSs were used to determine whether genetic liability for major depression, bipolar disorder, schizophrenia, attention-deficit/hyperactivity disorder, and autism spectrum disorder were associated with the symptoms of premenstrual disorders, using the PRS for height as a somatic comparator. The sample was recruited across Norway between June 1999 and December 2008, and analyses were performed from July 1 to October 14, 2022. Main Outcomes and Measures: The symptoms of premenstrual disorders were assessed at recruitment at week 15 of pregnancy with self-reported severity of depression and irritability before menstruation. Logistic regression was applied to test for the association between the presence of premenstrual disorder symptoms and the PRSs for major psychiatric disorders. Results: The mean (SD) age of 56 725 women included in the study was 29.0 (4.6) years. Premenstrual disorder symptoms were present in 12 316 of 56 725 participants (21.7%). The symptoms of premenstrual disorders were associated with the PRSs for major depression (ß = 0.13; 95% CI, 0.11-0.15; P = 1.21 × 10-36), bipolar disorder (ß = 0.07; 95% CI, 0.05-0.09; P = 1.74 × 10-11), attention deficit/hyperactivity disorder (ß = 0.07; 95% CI, 0.04-0.09; P = 1.58 × 10-9), schizophrenia (ß = 0.11; 95% CI, 0.09-0.13; P = 7.61 × 10-25), and autism spectrum disorder (ß = 0.03; 95% CI, 0.01-0.05; P = .02) but not with the PRS for height. The findings were confirmed in a subsample of women without a history of psychiatric diagnosis. Conclusions: The results of this genetic association study show that genetic liability for both affective spectrum disorder and major psychiatric disorders was associated with symptoms of premenstrual disorders, indicating that premenstrual disorders have overlapping genetic foundations with major psychiatric disorders.

Polygenic risk for schizophrenia and bipolar disorder in relation to cardiovascular biomarkers.

Individuals with schizophrenia and bipolar disorder are at an increased risk of cardiovascular disease (CVD), and a range of biomarkers related to CVD risk have been found to be abnormal in these patients. Common genetic factors are a putative underlying mechanism, alongside lifestyle factors and antipsychotic medication. However, the extent to which the altered CVD biomarkers are related to genetic factors involved in schizophrenia and bipolar disorder is unknown. In a sample including 699 patients with schizophrenia, 391 with bipolar disorder, and 822 healthy controls, we evaluated 8 CVD risk biomarkers, including BMI, and fasting plasma levels of CVD biomarkers from a subsample. Polygenic risk scores (PGRS) were obtained from genome-wide associations studies (GWAS) of schizophrenia and bipolar disorder from the Psychiatric Genomics Consortium. The CVD biomarkers were used as outcome variables in linear regression models including schizophrenia and bipolar disorder PGRS as predictors, age, sex, diagnostic category, batch and 10 principal components as covariates, controlling for multiple testing by Bonferroni correction for the number of independent tests. Bipolar disorder PGRS was significantly (p = 0.03) negatively associated with BMI after multiple testing correction, and schizophrenia PGRS was nominally negatively associated with BMI. There were no other significant associations between bipolar or schizophrenia PGRS, and other investigated CVD biomarkers. Despite a range of abnormal CVD risk biomarkers in psychotic disorders, we only found a significant negative association between bipolar disorder PGRS and BMI. This has previously been shown for schizophrenia PGRS and BMI, and warrants further exploration.

Alcohol consumption and lower risk of cardiovascular and all-cause mortality: the impact of accounting for familial factors in twins.

BACKGROUND: A moderate to high alcohol consumption is associated with a lower risk of cardiovascular disease (CVD) mortality in comparison with low consumption. The mechanisms underlying this association are not clear and have been suggested to be caused by residual confounding. The main objective of this study was to separate the familial and individual risk for CVD mortality and all-cause mortality related to alcohol consumption. This will be done by estimating the risk for CVD mortality and all-cause mortality in twin pairs discordant for alcohol consumption. METHODS: Alcohol consumption was assessed at two time points using self-report questionnaires in the Norwegian Twin Registry. Data on CVD mortality was obtained from the Norwegian Cause of Death Registry. Exposure-outcome associations for all-cause mortality and mortality due to other causes than CVD were estimated for comparison. RESULTS: Coming from a family with moderate to high alcohol consumption was protective against cardiovascular death (HR = 0.54, 95% CI 0.65-0.83). Moderate and high alcohol consumption levels were associated with a slightly increased risk of CVD mortality at the individual level (HR = 1.33, 95% CI 1.02-1.73). There was no association between alcohol consumption and all-cause mortality both at the familial nor at the individual level. CONCLUSIONS: The protective association of moderate to high alcohol consumption with a lower risk of CVD mortality was accounted for by familial factors in this study of twins. Early life genetic and environmental familial factors may mask an absence of health effect of moderate to high alcohol consumption on cardiovascular mortality.

Genetic nurture versus genetic transmission of risk for ADHD traits in the Norwegian Mother, Father and Child Cohort Study.

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 (pΔß = 9.95 × 10-17 for maternal and pΔß = 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.

Childhood temperamental, emotional, and behavioral characteristics associated with mood and anxiety disorders in adolescence: A prospective study.

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.

Body mass index and childhood symptoms of depression, anxiety, and attention-deficit hyperactivity disorder: A within-family Mendelian randomization study.

Background: Higher 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. Methods: This 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. Results: Within-family Mendelian randomization estimates using genetic variants associated with BMI in adults suggested that a child's own BMI increased their depressive symptoms (per 5 kg/m2 increase 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 5 kg/m2 increase 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. Conclusions: We 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. Funding: This 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.

Some studies show that children with obesity are more likely to receive a diagnosis of depression, anxiety, or attention-deficit hyperactivity disorder (ADHD). But this does not necessarily mean obesity causes these conditions. Depression, anxiety, or ADHD could cause obesity. A child's environment, including family income or their parents' mental health, could also affect a child's weight and mental health. Understanding the nature of these relationships could help scientists develop better interventions for both obesity and mental health conditions. Genetic studies may help scientists better understand the role of the environment in these conditions, but it's important to consider both the child's and their parents' genetics in these analyses. This is because parents and children share not only genes, but also environmental conditions. For example, families that carry genetic variants associated with higher body weight might also have lower incomes, if parents have been affected by biases against heavier people in society and the workplace. Children in these families could have worse mental health because of effects of their parent's weight, rather than their own weight. Looking at both child and adult genetics can help disentangle these processes. Hughes et al. show that a child's own body mass index, a ratio of weight and height, is not strongly associated with the child's mental health symptoms. They analysed genetic, weight, and health survey data from about 41,000 8-year-old children and their parents. The results suggest that a child's own BMI does not have a large effect on their anxiety symptoms. There was also no clear evidence that a child's BMI affected their symptoms of depression or ADHD. These results contradict previous studies, which did not account for parental genetics. Hughes et al. suggest that, at least for eight-year-olds, factors linked with adult weight and which differ between families may be more critical to a child's mental health than a child's own weight. For older children and adolescents, this may not be the case, and the individual's own weight may be more important. As a result, policies designed to reduce obesity in mid-childhood are unlikely to greatly improve the mental health of children. On the other hand, policies targeting the environmental or societal factors contributing to higher body weights, bias against people with higher weights, and poor child mental health directly may be more beneficial.

The age of violence: Mapping brain age in psychosis and psychopathy.

Young chronological age is one of the strongest predictors for antisocial behaviour in the general population and for violent offending in individuals with psychotic disorders. An individual's age can be predicted with high accuracy using neuroimaging and machine-learning. The deviation between predicted and chronological age, i.e., brain age gap (BAG) has been suggested to reflect brain health, likely relating partly to neurodevelopmental and aging-related processes and specific disease mechanisms. Higher BAG has been demonstrated in patients with psychotic disorders. However, little is known about the brain-age in violent offenders with psychosis and the possible associations with psychopathy traits. We estimated brain-age in 782 male individuals using T1-weighted MRI scans. Three machine learning models (random forest, extreme gradient boosting with and without hyper parameter tuning) were first trained and tested on healthy controls (HC, n = 586). The obtained BAGs were compared between HC and age matched violent offenders with psychosis (PSY-V, n = 38), violent offenders without psychosis (NPV, n = 20) and non-violent psychosis patients (PSY-NV, n = 138). We ran additional comparisons between BAG of PSY-V and PSY-NV and associations with Positive and Negative Syndrome Scale (PANSS) total score as a measure of psychosis symptoms. Psychopathy traits in the violence groups were assessed with Psychopathy Checklist-revised (PCL-R) and investigated for associations with BAG. We found significantly higher BAG in PSY-V compared with HC (4.9 years, Cohen'sd = 0.87) and in PSY-NV compared with HC (2.7 years, d = 0.41). Total PCL-R scores were negatively associated with BAG in the violence groups (d = 1.17, p < 0.05). Additionally, there was a positive association between psychosis symptoms and BAG in the psychosis groups (d = 1.12, p < 0.05). While the significant BAG differences related to psychosis and not violence suggest larger BAG for psychosis, the negative associations between BAG and psychopathy suggest a complex interplay with psychopathy traits. This proof-of-concept application of brain age prediction in severe mental disorders with a history of violence and psychopathy traits should be tested and replicated in larger samples.

Associations Between Pregnancy-Related Predisposing Factors for Offspring Neurodevelopmental Conditions and Parental Genetic Liability to Attention-Deficit/Hyperactivity Disorder, Autism, and Schizophrenia: The Norwegian Mother, Father and Child Cohort Study (MoBa).

Importance: Several maternal exposures during pregnancy are considered predisposing factors for offspring neurodevelopmental conditions. However, many of these exposures may be noncausal and biased by maternal genetic liability. Objective: To assess whether pregnancy-related predisposing factors for offspring neurodevelopmental conditions are associated with maternal genetic liability for attention-deficit/hyperactivity disorder (ADHD), autism, and schizophrenia and to compare associations for maternal genetic liability with those for paternal genetic liability, which could indicate that paternal exposures are not suitable negative controls for maternal exposures. Design, Setting, and Participants: The Norwegian Mother, Father and Child Cohort Study (MoBa) is a population-based pregnancy cohort that recruited parents from June 1999 to December 2008. Polygenic scores (PGS) for ADHD, autism, and schizophrenia were derived in mothers and fathers. The associations between maternal PGS and 37 pregnancy-related measures were estimated, and these results were compared with those from paternal PGS predicting paternal measures during the mother's pregnancy. Analysis took place between March 2021 and March 2022. Exposures: PGS for ADHD, autism, and schizophrenia, calculated (using discovery effect size estimates and threshold of P < .05) from the largest available genome-wide association studies. Main Outcomes and Measures: Self-reported pregnancy-related measures capturing lifestyle behaviors, metabolism, infectious and autoimmune diseases, other physical health conditions, and medication use. Results: Data were available for up to 14 539 mothers (mean [SD] age, 30.00 [4.45] years) and 14 897 fathers (mean [SD] age, 32.46 [5.13] years) of European ancestry. Modest but robust associations were observed between specific pregnancy-related measures and maternal PGS, including ADHD PGS with asthma (odds ratio [OR], 1.15 [95% CI, 1.06-1.25]), smoking (OR, 1.26 [95% CI, 1.19-1.33]), prepregnancy body mass index (ß, 0.25 [95% CI, 0.18-0.31]), pregnancy weight gain (ß, 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 (ß, -0.18 [95% CI, -0.25 to -0.11]), and pregnancy weight gain (ß, 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.

Cardiovascular disease risk in people with severe mental disorders: an update and call for action.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is a major cause of premature death in people with severe mental disorders (SMDs). This review provides an update on the level of CVD mortality and morbidity, as well as the socioeconomic, psychosocial and genetic factors associated with the comorbidity, and offer directions for improved interventions to reduce CVD in SMDs. RECENT FINDINGS: The level of CVD mortality and morbidity has sustained high in people with SMDs during the past decades, but the causal mechanism must be further elucidated. Psychosocial and socioeconomic challenges are frequent in SMDs as well as in CVD. Further, recent studies have revealed genetic variants jointly associated with SMDs, CVD risk and social factors. These findings highlight the need for more targeted interventions, prediction tools and psychosocial approaches to comorbid CVD in SMDs. SUMMARY: The level of CVD comorbidity remains high in SMDs, indicating that most people with SMDs have not benefitted from recent medical advances. A complex interplay between genetic and social vulnerability to CVD, which differs across subgroups of patients, seems to be involved. Further research is required to meet the urgent need for earlier, more efficient intervention approaches and preventive strategies for comorbid CVD in SMD.

Shared genetic loci between depression and cardiometabolic traits.

Epidemiological and clinical studies have found associations between depression and cardiovascular disease risk factors, and coronary artery disease patients with depression have worse prognosis. The genetic relationship between depression and these cardiovascular phenotypes is not known. We here investigated overlap at the genome-wide level and in individual loci between depression, coronary artery disease and cardiovascular risk factors. We used the bivariate causal mixture model (MiXeR) to quantify genome-wide polygenic overlap and the conditional/conjunctional false discovery rate (pleioFDR) method to identify shared loci, based on genome-wide association study summary statistics on depression (n = 450,619), coronary artery disease (n = 502,713) and nine cardiovascular risk factors (n = 204,402-776,078). Genetic loci were functionally annotated using FUnctional Mapping and Annotation (FUMA). Of 13.9K variants influencing depression, 9.5K (SD 1.0K) were shared with body-mass index. Of 4.4K variants influencing systolic blood pressure, 2K were shared with depression. ConjFDR identified 79 unique loci associated with depression and coronary artery disease or cardiovascular risk factors. Six genomic loci were associated jointly with depression and coronary artery disease, 69 with blood pressure, 49 with lipids, 9 with type 2 diabetes and 8 with c-reactive protein at conjFDR < 0.05. Loci associated with increased risk for depression were also associated with increased risk of coronary artery disease and higher total cholesterol, low-density lipoprotein and c-reactive protein levels, while there was a mixed pattern of effect direction for the other risk factors. Functional analyses of the shared loci implicated metabolism of alpha-linolenic acid pathway for type 2 diabetes. Our results showed polygenic overlap between depression, coronary artery disease and several cardiovascular risk factors and suggest molecular mechanisms underlying the association between depression and increased cardiovascular disease risk.