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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.

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.

Maternal fever during pregnancy is associated with several adverse child outcomes. We investigated associations between maternal fever and ADHD among offspring, as well as the sub-dimensions of ADHD - inattention and hyperactivity/impulsivity. Data came from the Norwegian Mother and Child Cohort Study, including more than 114,000 children. Information about children’s ADHD diagnoses was obtained from the Norwegian Patient Register. Mothers reported on inattention and hyperactivity/impulsivity symptoms in questionnaires at 8 years. Logistic regression analysis showed that children exposed to maternal fever in the first trimester received an ADHD diagnosis more often than unexposed children (Odds Ratio (OR) = 1.31, 95% confidence interval (CI) = 1.06–1.61). For children exposed twice or more in the first trimester, the OR was 2.64 (CI = 1.36–5.14). Linear regression analysis showed elevated inattention symptoms among children exposed to fever in the first (Cohen’s d = 0.09, CI = 0.03–0.15) and second (Cohen’s d = 0.05, CI = 0.01–0.09) trimester. Results were similar whether the mother had taken acetaminophen for their fever or not. Hyperactivity/impulsivity symptoms were not related to maternal fever. The results indicate that maternal fever in early pregnancy may be a risk factor for ADHD, and particularly for inattention problems. This risk is neither mitigated nor inflated by use of acetaminophen.

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

Background: Maternal acetaminophen use during pregnancy is associated with increased risk of ADHD in the child. This could reflect causal influence of acetaminophen on fetal neurodevelopment or could be due to confounding factors. The aim of the current study was to examine unmeasured familial confounding factors of this association. Methods: We used data from 26,613 children from 12,902 families participating in the prospective Norwegian Mother, Father, and Child Cohort Study (MoBa). The MoBa was linked to the Norwegian Medical Birth Register and the Norwegian Patient Registry. Siblings discordant for prenatal acetaminophen exposure were compared regarding risk of having an ADHD diagnosis. Results: Children exposed to acetaminophen up to 28 days during pregnancy did not have increased risk of receiving an ADHD diagnosis compared to unexposed children. The adjusted Hazard ratio (aHR) was 0.87 (95% C.I. = 0.70-1.08) for exposure 1 to 7 days, and 1.13 (95% C.I. = 0.82–1.49) for 8–28 days. Long-term exposure (29 days or more) was associated with a two-fold increase in risk of ADHD diagnosis (aHR = 2.02, 95% C.I = 1.17–3.25). In the sibling control model, the association between long-term acetaminophen use and ADHD in the child was aHR = 2.77 (95% C.I. = 1.48–5.05) at the between-family level, and aHR = 1.06 (95% C.I. = 0.51–2.05) at the within-family level. Conclusions: Both the exposed and the unexposed children of mothers with long-term use of acetaminophen in one of the pregnancies had increased risk of receiving an ADHD diagnosis. This indicates that the observed association between long-term acetaminophen use during pregnancy and ADHD in the child may at least partly be confounded by unobserved family factors. publishedVersion

Internalising symptoms in childhood and adolescence are as heritable as adult depression and anxiety, yet little is known of their molecular basis. This genome-wide association meta-analysis of internalising symptoms included repeated observations from 64,641 individuals, aged between 3 and 18. The N-weighted meta-analysis of overall internalising symptoms (INToverall) detected no genome-wide significant hits and showed low SNP heritability (1.66%, 95% confidence intervals 0.84-2.48%, Neffective=132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalising symptoms showing the highest heritability (5.63%, 95% confidence intervals 3.08-8.18%). Additive genetic effects on internalising symptoms appeared stable over age, with overlapping estimates of SNP heritability from early-childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the wellbeing 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. The pattern of genetic correlations suggests that childhood and adolescent internalising symptoms share substantial genetic vulnerabilities with adult internalising disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalising symptoms over time and the high comorbidity amongst childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

Background: Low educational attainment in parents is associated with child psychopathology. It is not clear whether the associations are due to risk factors that family members share or due to effects of maternal or paternal education on the offspring. We investigate whether associations between maternal and paternal educational attainment and child symptoms of attention deficit/hyperactivity disorder (ADHD), depression, and academic problems are due to shared genetic factors, shared family environmental factors, or effects of the parental phenotype educational attainment itself. Methods: This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa). The sample comprised 34,958 children (17,128 girls) in 28,372 extended‐family units. We used data from related nuclear families linked by siblings in the parent generation. We applied a quasi‐experimental extended children‐of‐twins design that included siblings in both generations and took account of nonrandom mating by including partners. Educational attainment was self‐reported by mothers and fathers. Mothers reported children's symptoms of ADHD, symptoms of depression, and academic problems by questionnaire when the children were 8 years old. Results: Children of lowly educated parents scored higher on all outcomes and had an approximate doubling of the risk of high symptom levels. The association between maternal and paternal educational attainment and child symptoms of ADHD and academic problems persisted after controlling for shared genetic and family environmental factors. Phenotypic transmission to depression was weaker and in the best fitting model fully explained by genetic factors shared by the two generations. Conclusions: Associations between educational attainment of mothers and fathers and child symptoms of ADHD and academic problems could not be ascribed to shared familial risk factors, whereas associations with symptoms of depression could. Parental education or resources and behaviors resulting from low education might be targets of interventions aimed at reducing symptoms of ADHD and academic problems. publishedVersion

Background Childhood obesity is linked to poorer emotional health and neurodevelopmental problems but it is unclear if these associations are causal. Observational study designs are vulnerable to reverse causation and confounding. Mendelian randomization (MR) studies with even large numbers of unrelated individuals can suffer from familial biases, and dynastic effects (‘genetic nurture’) can be especially pronounced for socially patterned phenotypes like obesity. We introduce a ‘within-family’ MR (WFMR) design that uses genotyped mother-father-offspring trios to overcome these biases. Methods In 5237 8-year-old children from the Norwegian Mother, Father and Child Cohort Study (MoBa), we estimated the effects of body mass index (BMI) on symptoms of depression, attention-deficit hyperactivity disorder (ADHD), anxiety, and autism spectrum disorder (ASD). Child height, weight, and outcomes were based on mother-reported information from questionnaires. We used polygenic risk scores (PRS) as instrumental variables for BMI, with and without adjustment for parents’ own PRS. PRS were calculated in PRCise, and all other analysis completed in STATAv15. PRS were calculated using genetic variants from the largest and most recent genome-wide association study (GWAS) for BMI. Results Initial MR estimates implied a one-unit higher BMI increased depression symptoms by 0.12 (95%CI 0.05,0.20) and ADHD symptoms by 0.11(0.03,0.18) standard-deviations, and reduced symptoms of anxiety by -0.11(-0.19,-0.03) and symptoms of ASD by -0.05(-0.13,0.03). For ASD, associations did not differ substantially between symptoms related to social communication (-0.03(-0.12,0.05) and to repetitive behaviour (-0.04(-0.12, 0.03). Accounting for parental genotypes in WFMR made little difference to estimates, with no strong evidence of indirect effects of parental genotypes on offspring phenotype. Next steps will be to examine relationships using gene variants associated with BMI during childhood specifically, and to investigate the influence of depressive, ADHD, anxiety and ASD symptoms on childhood BMI. Conclusion Influence of childhood BMI on emotional and neurodevelopmental health is not explained by family-level genetic biases, suggesting childhood BMI may affect these symptoms. Negative associations of BMI with anxiety are consistent with results from the UK Biobank, where genetic propensity for BMI was negatively associated with risk of self-reporting as a ‘nervous’ person. Intervening on childhood BMI may influence these outcomes.

Importance: Adult mood disorders are often preceded by behavioral and emotional problems in childhood. It is yet unclear what explains the associations between childhood psychopathology and adult traits.Objective: To investigate whether genetic risk for adult mood disorders and associated traits is associated with childhood disorders.Design, setting, and participants: This meta-analysis examined data from 7 ongoing longitudinal birth and childhood cohorts from the UK, the Netherlands, Sweden, Norway, and Finland. Starting points of data collection ranged from July 1985 to April 2002. Participants were repeatedly assessed for childhood psychopathology from ages 6 to 17 years. Data analysis occurred from September 2017 to May 2019.Exposures: Individual polygenic scores (PGS) were constructed in children based on genome-wide association studies of adult major depression, bipolar disorder, subjective well-being, neuroticism, insomnia, educational attainment, and body mass index (BMI).Main outcomes and measures: Regression meta-analyses were used to test associations between PGS and attention-deficit/hyperactivity disorder (ADHD) symptoms and internalizing and social problems measured repeatedly across childhood and adolescence and whether these associations depended on childhood phenotype, age, and rater.Results: The sample included 42 998 participants aged 6 to 17 years. Male participants varied from 43.0% (1040 of 2417 participants) to 53.1% (2434 of 4583 participants) by age and across all cohorts. The PGS of adult major depression, neuroticism, BMI, and insomnia were positively associated with childhood psychopathology (β estimate range, 0.023-0.042 [95% CI, 0.017-0.049]), while associations with PGS of subjective well-being and educational attainment were negative (β, -0.026 to -0.046 [95% CI, -0.020 to -0.057]). There was no moderation of age, type of childhood phenotype, or rater with the associations. The exceptions were stronger associations between educational attainment PGS and ADHD compared with internalizing problems (Δβ, 0.0561 [Δ95% CI, 0.0318-0.0804]; ΔSE, 0.0124) and social problems (Δβ, 0.0528 [Δ95% CI, 0.0282-0.0775]; ΔSE, 0.0126), and between BMI PGS and ADHD and social problems (Δβ, -0.0001 [Δ95% CI, -0.0102 to 0.0100]; ΔSE, 0.0052), compared with internalizing problems (Δβ, -0.0310 [Δ95% CI, -0.0456 to -0.0164]; ΔSE, 0.0074). Furthermore, the association between educational attainment PGS and ADHD increased with age (Δβ, -0.0032 [Δ 95% CI, -0.0048 to -0.0017]; ΔSE, 0.0008).Conclusions and relevance: Results from this study suggest the existence of a set of genetic factors influencing a range of traits across the life span with stable associations present throughout childhood. Knowledge of underlying mechanisms may affect treatment and long-term outcomes of individuals with psychopathology.

BackgroundGenetic liability for schizophrenia is associated with psychopathology in early life. It is not clear if these associations are time-dependent during childhood, nor if they are specific across different forms of psychopathology.MethodsUsing genotype and questionnaire data on children (N = 15,105) from the Norwegian Mother, Father, and Child Cohort Study (MoBa), we tested associations between schizophrenia polygenic risk scores and measures of childhood emotional and behavioural problems for developmental stability and domain specificity. We then sought to identify symptom profiles – across development and domains – associated with elevated schizophrenia polygenic liability.OutcomesWe found evidence for developmental stability in associations between schizophrenia polygenic risk scores and emotional and behavioural problems, with the latter being mediated via the rate of change in symptoms between 18 months and 5 years specifically (βslope = 0.032; 95% CI 0.007 – 0.057). At age 8, associations with emotional and behavioural psychopathology were found to be better explained by a model of symptom-specific polygenic risk score effects, rather than effects mediated via a general “p” factor or by domain-specific factors. Overall, individuals with higher schizophrenia polygenic risk scores were more likely (OR= 1.310 [95% CIs: 1.122-1.528]) to have increasing behavioural and emotional symptoms in early childhood, followed by relatively elevated symptoms of conduct disorder, oppositional defiant disorder, hyperactivity and inattention in middle childhood.InterpretationSchizophrenia-associated alleles are linked to specific patterns of early-life psychopathology. The associations are small, but findings of this nature can help us better understand the developmental emergence of schizophrenia.FundingLaurie Hannigan, Ziada Ayorech, and Alexandra Havdahl were supported by grants from the South-Eastern Norway Regional Health Authority (2018059, 2019097 and 2018058, respectively). Ragna Bugge Askeland and Elizabeth Corfield were supported by a grant from the Norwegian Research Council (274611). Ted Reichborn-Kjennerud was supported by a grant from the Research Council of Norway (274611). Pål Rasmus Njølstad was funded by the ERC AdG SELECTionPREDISPOSED (#293574), the Stiftelsen Kristian Gerhard Jebsen, the Trond Mohn Foundation, the Norwegian Research Council (#240413/F20), the Novo Nordisk Foundation (#54741), the University of Bergen, and the Western Norway health Authorities (Helse Vest; PERSON-MED-DIA and #911745). Ole A. Andreassen was supported the Research Council of Norway (229129; 213837; 248778; 223273; 249711); the South-East Norway Regional Health Authority (2017-112); KG Jebsen Stiftelsen (SKGJ) and H2020 grant # 847776 CoMorMent. George Davey Smith works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1). This work was partly supported by the Research Council of Norway through its Centre of Excellence funding scheme, project number 262700.Research in contextEvidence before this studyGenetic liability to schizophrenia, conferred incrementally by many genetic variants of small effect, is associated with various forms of psychopathology – both symptoms and diagnoses – in the general population during adulthood. To get an overview of the relevant evidence for how genetic liability to schizophrenia manifests in psychopathology in childhood, we performed a systematic search of the published literature using the Ovid MEDLINE and PsychINFO databases, for English-language peer-reviewed journal articles published prior to 28 January 2020. We found 7 studies of core relevance (i.e., containing assessment of symptoms or diagnoses of psychopathology in pre-adolescent children), with a further 9 studies examining outcomes potentially related to psychopathology (such as brain structure, cognitive performance, and social functioning). Of the 7 core studies, 3 used clinical samples to demonstrate that polygenic risk scores for schizophrenia are higher among children with ADHD diagnoses than controls, and among cases of the rare child-onset form of schizophrenia than their healthy siblings. The remainder of studies all examined symptoms of psychopathology among children in the general population, finding modest but robust associations of schizophrenia polygenic risk scores with emotional and behavioural problems measured from 3 years of age, as well as with symptoms of depression, ADHD, anxiety, oppositional defiant disorder and conduct disorder in middle childhood.Added value of this studyIn this study, we present a set of analyses designed to improve our understanding of the nature of associations between schizophrenia risk alleles and childhood psychopathology. Specifically, we employ an approach that aims not just to quantify, but also to explore how the effects of schizophrenia risk manifest across childhood, and across different domains of psychopathology. We find evidence that effects of schizophrenia polygenic risk scores on symptoms of emotional and behavioural problems in early childhood are stable, influencing the overall level and rates of change in symptoms, rather than age-specific (i.e., transient or developmental). We also find evidence of specificity in the effects of schizophrenia polygenic risk scores on different domains of psychopathology in 8-year-old children. Overall, we find that higher schizophrenia polygenic risk scores are associated with a developmental symptom profile comprising elevated and increasing symptoms of behavioural problems and increasing levels of emotional problems in early childhood, as well as particularly elevated symptoms of conduct disorder, inattention, hyperactivity, and oppositional defiant disorder in middle childhood.Implications of all the available evidenceFindings of our study align with a growing body of evidence that the effects of schizophrenia risk alleles on psychopathology begin early in life, and influence the likelihood of children experiencing difficulties across development. While previous work has largely found similar effects of schizophrenia polygenic risk scores across different domains of childhood psychopathology, indicating that such effects may be mediated by a hypothetical latent ‘general psychopathology’ or ‘p’ factor, our results suggest that domain- and even symptom-level specificity may emerge by middle childhood. We may be able to improve our understanding of processes underpinning the emergence of schizophrenia later in life by paying attention to nuances in the ways that genetic risk for schizophrenia manifests across childhood and into adolescence.

Objective: To investigate the association between childhood sensorineural hearing loss (SNHL) and cohabiting/marriage rates in a large Norwegian cohort.Design: This study is based on data from the ...

The relationship between alcohol consumption and dementia risk is unclear. This investigation estimates the association between alcohol consumption reported in a population-based study in the mid-1980s and the risk for dementia up to 27 years later. The entire adult population in one Norwegian county was invited to the Nord-Trøndelag Health Study during 1984–1986 (HUNT1): 88 % participated. The sample used in this study includes HUNT1 participants born between 1905 and 1946 who completed the questionnaire assessing alcohol consumption. A total of 40,435 individuals, of whom 1084 have developed dementia, are included in the analysis adjusted for age, sex, years of education, hypertension, obesity, smoking, and symptoms of depression. When adjusting for age and sex, and compared to reporting consumption of alcohol 1–4 times during the last 14 days (drinking infrequently), both abstaining from alcohol and reporting consumption of alcohol five or more times (drinking frequently) were statistically significantly associated with increased dementia risk with hazard ratios of 1.30 (95 % CI 1.05–1.61) and 1.45 (1.11–1.90), respectively. In the fully adjusted analysis, drinking alcohol frequently was still significantly associated with increased dementia risk with a hazard ratio of 1.40 (1.07–1.84). However, the association between dementia and abstaining from alcohol was no longer significant (1.15, 0.92–1.43). Equivalent results for Alzheimer’s disease and vascular dementia indicated the same patterns of associations. When adjusting for other factors associated with dementia, frequent alcohol drinking, but not abstaining from alcohol, is associated with increased dementia risk compared to drinking alcohol infrequently. © The Author(s) 2015. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Impulsive/disinhibitory personality traits have consistently been associated with externalizing symptomatology such as delinquency and substance use problems, often starting in adolescence. Yet the etiological nature of this co-occurrence is not well understood. Using a classic twin study design with self-report data from 717 male and female twin pairs, aged 15–18 years, a hierarchical psychometric model was examined. In this model the shared variance and etiological structure between control, delinquency and substance abuse symptoms, was modeled through a common externalizing factor. Model fitting indicated that the genetic and environmental influences differed in strength between male and female adolescents. The heritability of the externalizing factor was 45% in males and 10% in females, though neither was statistically different from zero. A statistically significant influence of shared environmental factors was seen for both sexes, 21% in males and 54% in females. In both sexes, the externalizing factor accounted for little variance in control, indicating a weak association and little shared etiology with externalizing liability. These results illuminate further that facets of impulsivity are differentially associated with vulnerability for externalizing symptomatology.

Background Maternal thyroid function is a critical mediator of fetal brain development. Pregnancy-related physiologic changes and handling conditions of blood samples may influence thyroid hormone biomarkers. We investigated the reliability of thyroid hormone biomarkers in plasma of pregnant women under various handling conditions. Methods We enrolled 17 pregnant women; collected serum and plasma were immediately frozen. Additional plasma aliquots were subjected to different handling conditions before the analysis of thyroid biomarkers: storage at room temperature for 24 or 48 hours before freezing and an extra freeze-thaw cycle. We estimated free thyroid hormone indices in plasma based on T3 uptake. Results High correlations between plasma and serum (>0.94) and intraclass correlation coefficients for plasma handling conditions (0.96 to 1.00) indicated excellent reliability for all thyroid hormone biomarkers. Conclusion Delayed freezing and freeze-thaw cycles did not affect reliability of biomarkers of thyroid function in plasma during pregnancy. See video abstract at, http://links.lww.com/EDE/B180.

Importance Preterm birth is associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD); however, it is unclear to what extent this association can be explained by shared genetic and environmental risk factors and whether gestational age at birth is similarly related to inattention and hyperactivity/impulsivity and to the same extent in boys and girls. Objectives To investigate the association between gestational age at birth and symptoms of ADHD in preschool and school-age children after adjusting for unmeasured genetic and environmental risk factors. Design, Setting, and Participants In this prospective, population-based cohort study, pregnant women were recruited from across Norway from January 1, 1999, through December 31, 2008. Results of a conventional cohort design were compared with results from a sibling-comparison design (adjusting for genetic and environmental factors shared within families) using data from the Norwegian Mother and Child Cohort Study. Data analysis was performed from October 1, 2017, through March 16, 2018. Exposures Analyses compared children and siblings discordant for gestational age group: early preterm (delivery at gestational weeks 22-33), late preterm (delivery at gestational weeks 34-36), early term (delivery at gestational weeks 37-38), delivery at gestational week 39, reference group (delivery at gestational week 40), delivery at gestational week 41, and late term (delivery after gestational week 41). Main Outcomes and Measures Maternally reported symptoms of ADHD in children at 5 years of age and symptoms of inattention and hyperactivity/impulsivity at 8 years of age. Covariates included child and pregnancy characteristics associated with the week of delivery and the outcomes. Results A total of 113 227 children (55 187 [48.7%] female; 31 708 [28.0%] born at gestational week 40), including 33 081 siblings (16 014 female [48.4%]; 9705 [29.3%] born at gestational week 40), were included in the study. Children born early preterm were rated with more symptoms of ADHD, inattention, and hyperactivity/impulsivity than term-born children. After adjusting for unmeasured genetic and environmental factors, children born early preterm had a mean score that was 0.24 SD (95% CI, 0.14-0.34) higher on ADHD symptom tests, 0.33 SD (95% CI, 0.24-0.42) higher on inattention tests, and 0.23 SD (95% CI, 0.14-0.32) higher on hyperactivity/impulsivity tests compared with children born at gestational week 40. Sex moderated the association of gestational age with preschool ADHD symptoms, and the association appeared to be strongest among girls. Early preterm girls scored a mean of 0.8 SD (95% CI, 0.12-1.46;P = .02) higher compared with their term-born sisters. Conclusions and Relevance After accounting for unmeasured genetic and environmental factors, early preterm birth was associated with a higher level of ADHD symptoms in preschool children. Early premature birth was associated with inattentive but not hyperactive symptoms in 8-year-old children. This study demonstrates the importance of differentiating between inattention and hyperactivity/impulsivity and stratifying on sex in the study of childhood ADHD.

Background The degree to which parental alcohol abuse is a risk factor for offspring mental distress is unclear, due to conflicting results of previous research. The inconsistencies in previous findings may be related to sample characteristics and lack of control of confounding or moderating factors. One such factor may be the gender of the abusing parent. Also, other factors, such as parental mental health, divorce, adolescent social network, school functioning or self-esteem, may impact the outcome. This study examines the impact of maternal and paternal alcohol abuse on adolescent mental distress, including potentially confounding, mediating or moderating effects of various variables. Methods Data from the Nord-Trøndelag Health Study (HUNT), a Norwegian population based health survey, from 4012 offspring and their parents were analyzed. Parental alcohol abuse was measured by numerical consumption indicators and CAGE, whereas offspring mental distress was measured by SCL-5, an abbreviated instrument tapping symptoms of anxiety and depression. Statistical method was analysis of variance. Results Maternal alcohol abuse was related to offspring mental distress, whereas no effect could be shown of paternal alcohol abuse. Effects of maternal alcohol abuse was partly mediated by parental mental distress, offspring social network and school functioning. However, all effects were relatively small. Conclusions The results indicate graver consequences for offspring of alcohol abusing mothers compared to offspring of alcohol abusing fathers. However, small effect sizes suggest that adolescent offspring of alcohol abusing parents in general manage quite well.

Background This study investigates the relationship between parental drinking and school adjustment in a total population sample of adolescents, with independent reports from mothers, fathers, and adolescents. As a group, children of alcohol abusers have previously been found to exhibit lowered academic achievement. However, few studies address which parts of school adjustment that may be impaired. Both a genetic approach and social strains predict elevated problem scores in these children. Previous research has had limitations such as only recruiting cases from clinics, relying on single responders for all measures, or incomplete control for comorbid psychopathology. The specific effects of maternal and paternal alcohol use are also understudied. Methods In a Norwegian county, 88% of the population aged 13-19 years participated in a health survey (N = 8984). Among other variables, adolescents reported on four dimensions of school adjustment, while mothers and fathers reported their own drinking behaviour. Mental distress and other control variables were adjusted for. Multivariate analysis including generalized estimation equations was applied to investigate associations. Results Compared to children of light drinkers, children of alcohol abusers had moderately elevated attention and conduct problem scores. Maternal alcohol abuse was particularly predictive of such problems. Children of abstainers did significantly better than children of light drinkers. Controlling for adolescent mental distress reduced the association between maternal abuse and attention problems. The associations between parental reported drinking and school adjustment were further reduced when controlling for the children's report of seeing their parents drunk, which itself predicted school adjustment. Controlling for parental mental distress did not reduce the associations. Conclusions Parental alcohol abuse is an independent risk factor for attention and conduct problems at school. Some of the risk associated with mothers' drinking is likely to be mediated by adolescent mental distress. Despite lowered adjustment on the externalizing dimensions, children of alcohol abusers report that they enjoy being at school as much as other children.

Background Researchers generally agree that mental disorder represents a burden to the family. The present study concerns the subjective burden of living with a person with mental disorder, more specifically the association between mental disorder in the index person and subjective well-being and symptoms of anxiety and depression in the spouse. Methods Data were obtained from questionnaires administered to the adult population of Nord-Trøndelag County, Norway during the period 1995-1997. The present study is based on a subsample where 9,740 couples were identified. Subjective burden in spouses of persons with mental disorder was compared with subjective burden in spouses of persons without mental disorder, using analysis of variance (ANOVA). All analyses were stratified by sex. Results Adjusting for several covariates, spouses of persons with mental disorder scored significantly lower on subjective well-being and significantly higher on symptoms of anxiety and depression compared to spouses of index persons without mental disorder. Although highly significant, the effect sizes were moderate, corresponding to a difference in standard deviations ranging from .34 - .51. Conclusions Our study supports the notion that there is an association between mental disorder in one partner and subjective burden in the spouse, but not to the same extent that have been reported in earlier studies, as our results do not indicate that a large proportion of the spouses reach a symptom level of anxiety and depression that reflects clinical mental disorder.