Assessing causal links between age at menarche and adolescent mental health: a Mendelian randomisation study.

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

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).

Prenatal organophosphate ester exposure and executive function in Norwegian preschoolers.

Organophosphate esters (OPEs) are ubiquitous chemicals, used as flame retardants and plasticizers. OPE usage has increased over time as a substitute for other controlled compounds. This study investigates the impact of prenatal OPE exposure on executive function (EF) in preschoolers. Methods: We selected 340 preschoolers from the Norwegian Mother, Father, and Child Cohort Study. Diphenyl-phosphate (DPhP), di-n-butyl-phosphate (DnBP), bis(2-butoxyethyl) phosphate (BBOEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were measured in maternal urine. EF was measured using the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P) and the Stanford-Binet fifth edition (SB-5). EF scores were scaled so a higher score indicated worse performance. We estimated exposure-outcome associations and evaluated modification by child sex using linear regression. Results: Higher DnBP was associated with lower EF scores across multiple rater-based domains. Higher DPhP and BDCIPP were associated with lower SB-5 verbal working memory (ß = 0.49, 95% CI = 0.12, 0.87; ß = 0.53, 95% CI = 0.08, 1.02), and higher BBOEP was associated with lower teacher-rated inhibition (ß = 0.34, 95% CI = 0.01, 0.63). DPhP was associated with lower parent-reported BRIEF-P measures in boys but not girls [inhibition: boys: 0.37 (95% CI = 0.03, 0.93); girls: -0.48 (95% CI = -1.27, 0.19); emotional control: boys: 0.44 (95% CI = -0.13, 1.26); girls: -0.83 (95% CI = -1.73, -0.00); working memory: boys: 0.49 (95% CI = 0.03, 1.08); girls: -0.40 (95% CI = -1.11, 0.36)]. Fewer sex interactions were observed for DnBP, BBOEP, and BDCIPP, with irregular patterns observed across EF domains. Conclusions: We found some evidence prenatal OPE exposure may impact EF in preschoolers and variation in associations by sex.

Developmental manifestations of polygenic risk for bipolar disorder from infancy to middle childhood.

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

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.

Metabolomic analysis of maternal mid-gestation plasma and cord blood in autism spectrum disorders.

The discovery of prenatal and neonatal molecular biomarkers has the potential to yield insights into autism spectrum disorder (ASD) and facilitate early diagnosis. We characterized metabolomic profiles in ASD using plasma samples collected in the Norwegian Autism Birth Cohort from mothers at weeks 17-21 gestation (maternal mid-gestation, MMG, n = 408) and from children on the day of birth (cord blood, CB, n = 418). We analyzed associations using sex-stratified adjusted logistic regression models with Bayesian analyses. Chemical enrichment analyses (ChemRICH) were performed to determine altered chemical clusters. We also employed machine learning algorithms to assess the utility of metabolomics as ASD biomarkers. We identified ASD associations with a variety of chemical compounds including arachidonic acid, glutamate, and glutamine, and metabolite clusters including hydroxy eicospentaenoic acids, phosphatidylcholines, and ceramides in MMG and CB plasma that are consistent with inflammation, disruption of membrane integrity, and impaired neurotransmission and neurotoxicity. Girls with ASD have disruption of ether/non-ether phospholipid balance in the MMG plasma that is similar to that found in other neurodevelopmental disorders. ASD boys in the CB analyses had the highest number of dysregulated chemical clusters. Machine learning classifiers distinguished ASD cases from controls with area under the receiver operating characteristic (AUROC) values ranging from 0.710 to 0.853. Predictive performance was better in CB analyses than in MMG. These findings may provide new insights into the sex-specific differences in ASD and have implications for discovery of biomarkers that may enable early detection and intervention.

Associations between health behaviours, fertility and reproductive outcomes: triangulation of evidence in the Norwegian Mother, Father and Child Cohort Study (MoBa).

BACKGROUND: Guidance to improve fertility includes reducing alcohol and caffeine consumption, achieving healthy weight-range and stopping smoking. Advice is informed by observational evidence, which is often biased by confounding. METHODS: This study primarily used data from a pregnancy cohort, the Norwegian Mother, Father and Child Cohort Study. First, we conducted multivariable regression of health behaviours (alcohol and caffeine consumption, body-mass index (BMI), and smoking) on fertility outcomes (e.g. time to conception) and reproductive outcomes (e.g. age at first birth) (n = 84,075 females, 68,002 males), adjusting for birth year, education and attention-deficit and hyperactive-impulsive (ADHD) traits. Second, we used individual-level Mendelian randomisation (MR) to explore possible causal effects of health behaviours on fertility/reproductive outcomes (n = 63,376 females, 45,460 males). Finally, we performed summary-level MR for available outcomes in UK Biobank (n = 91,462-1,232,091) and controlled for education and ADHD liability using multivariable MR. RESULTS: In multivariable regression analyses, higher BMI associated with fertility (longer time to conception, increased odds of infertility treatment and miscarriage), and smoking was associated with longer time to conception. In individual-level MR analyses, there was strong evidence for effects of smoking initiation and higher BMI on younger age at first birth, of higher BMI on increased time to conception, and weak evidence for effects of smoking initiation on increased time to conception. Age at first birth associations were replicated in summary-level MR analysis; however, effects attenuated using multivariable MR. CONCLUSIONS: Smoking behaviour and BMI showed the most consistent associations for increased time to conception and a younger age at first birth. Given that age at first birth and time to conception are positively correlated, this suggests that the mechanisms for reproductive outcomes are distinct to the mechanisms acting on fertility outcomes. Multivariable MR suggested that effects on age at first birth might be explained by underlying liability to ADHD and education.

Attainment and loss of early social-communication skills across neurodevelopmental conditions in the Norwegian Mother, Father and Child Cohort Study.

BACKGROUND: Delays and loss of early-emerging social-communication skills are often discussed as unique to autism. However, most studies of regression have relied on retrospective recall and clinical samples. Here, we examine attainment and loss of social-communication skills in the population-based Norwegian Mother, Father and Child Cohort Study (MoBa). METHODS: Mothers rated their child's attainment of 10 early-emerging social-communication skills at ages 18 and 36 months (N = 40,613, 50.9% male). Prospectively reported loss was defined as skill presence at 18 months but absence at 36 months. At 36 months, mothers also recalled whether the child had lost social-communication skills. The Norwegian Patient Registry was used to capture diagnoses of Autism Spectrum Disorder (autism) and other neurodevelopmental disabilities (NDDs). RESULTS: Delay in at least one skill was observed in 14% of the sample and loss in 5.4%. Recalled loss of social-communication skills was rare (0.86%) and showed low convergence with prospectively reported loss. Delay and especially loss were associated with elevated odds of an autism diagnosis (n = 383) versus no autism diagnosis (n = 40,230; ≥3 skills delayed: OR = 7.09[4.15,12.11]; ≥3 skills lost: OR = 30.66[17.30,54.33]). They were also associated with an increased likelihood of autism compared to some other NDDs. Delay (relative risk [RR] = 4.16[2.08, 8.33]) and loss (RR = 10.00[3.70, 25.00]) associated with increased likelihood of autism versus ADHD, and loss (RR = 4.35[1.28,14.29]), but not delay (RR = 2.00[0.78,5.26]), associated with increased likelihood of autism compared to language disability. Conversely, delay conferred decreased likelihood of autism versus intellectual disability (RR = 0.11[0.06,0.21]), and loss was not reliably associated with likelihood of autism versus intellectual disability (RR = 1.89[0.44,8.33]). CONCLUSIONS: This population-based study suggests that loss of early social communication skills is more common than studies using retrospective reports have indicated and is observed across several NDD diagnoses (not just autism). Nevertheless, most children with NDD diagnoses showed no reported delay or loss in these prospectively measured skills.

Intergenerational effects of parental educational attainment on parenting and childhood educational outcomes: Evidence from MoBa using within-family Mendelian randomization.

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 40,879 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.

Stressful life events increase the risk of major depressive episodes: A population-based twin study.

BACKGROUND: Previous studies have found that stressful life events (SLEs) are associated with an increased risk of adult depression. However, many studies are observational in nature and limited by methodological issues, such as potential confounding by genetic factors. Genetically informative research, such as the co-twin control design, can strengthen causal inference in observational studies. Discrete-time survival analysis has several benefits and multilevel survival analysis can incorporate frailty terms (random effects) to estimate the components of the biometric model. In the current study, we investigated associations between SLEs and depression risk in a population-based twin sample (N = 2299). METHODS: A co-twin control design was used to investigate the influence of the occurrence of SLEs on depression risk. The co-twin control design involves comparing patterns of associations in the full sample and within dizygotic (DZ) and monozygotic twins (MZ). Associations were modelled using discrete-time survival analysis with biometric frailty terms. Data from two time points were used in the analyses. Mean age at Wave 1 was 28 years and mean age at Wave 2 was 38 years. RESULTS: SLE occurrence was associated with increased depression risk. Co-twin control analyses indicated that this association was at least in part due to the causal influence of SLE exposure on depression risk for event occurrence across all SLEs and for violent SLEs. A minor proportion of the total genetic risk of depression reflected genetic effects related to SLEs. CONCLUSIONS: The results support previous research in implicating SLEs as important risk factors with probable causal influence on depression risk.

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.

Gestational organophosphate ester exposure and preschool attention-deficit/hyperactivity disorder in the Norwegian Mother, Father, and Child cohort study.

BACKGROUND: Attention-deficit/hyperactivity-disorder (ADHD) is a leading neurodevelopmental disorder in children worldwide; however, few modifiable risk factors have been identified. Organophosphate esters (OPEs) are ubiquitous chemical compounds that are increasingly prevalent as a replacement for other regulated chemicals. Current research has linked OPEs to neurodevelopmental deficits. The purpose of this study was to assess gestational OPE exposure on clinically-assessed ADHD in children at age 3 years. METHODS: In this nested case-control study within the Norwegian Mother, Father, and Child Cohort study, we evaluated the impact of OPE exposure at 17 weeks' gestation on preschool-age ADHD. Between 2007 and 2011, 260 ADHD cases were identified using the Preschool Age Psychiatric Assessment and compared to a birth-year-stratified control group of 549 children. We categorized bis(2-butoxyethyl) phosphate (BBOEP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) as values < limit of detection (LOD) (BBOEP N = 386, BDCIPP N = 632), ≥LOD but < limit of quantification (LOQ) (BBOEP N = 413; BDCIPP N = 75), or above LOQ (BBOEP N = 70; BDCIPP N = 102). Diphenyl phosphate (DPhP) and di-n-butyl phosphate (DnBP) were categorized as quartiles and also modeled with a log10 linear term. We estimated multivariable adjusted odds ratios (ORs) using logistic regression and examined modification by sex using an augmented product term approach. RESULTS: Mothers in the 3rd DnBP quartile had 1.71 times the odds of having a child with ADHD compared to the 1st quartile (95%CI: 1.13, 2.58); a similar trend was observed for log10 DnBP and ADHD. Mothers with BDCIPP ≥ LOD but < LOQ had 1.39 times the odds of having a child with ADHD compared to those with BDCIPP < LOD (95%CI: 0.83, 2.31). Girls had lower odds of ADHD with increasing BBOEP exposure (log10 OR: 0.55 (95%CI: 0.37, 0.93), however boys had a weakly increased odds (log10 OR: 1.25 (95%CI: 0.74, 2.11) p-interaction = 0.01]. CONCLUSIONS: We found modest increased odds of preschool ADHD with higher DnBP and BDCIPP exposure.

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.

Gestational thyroid hormone concentrations and risk of attention-deficit hyperactivity disorder in the Norwegian Mother, Father and Child Cohort Study.

BACKGROUND: Maternal thyroid function plays an important role in foetal brain development; however, little consensus exists regarding the relationship between normal variability in thyroid hormones and common neurodevelopmental disorders, such as attention-deficit hyperactivity disorder (ADHD). OBJECTIVE: We sought to examine the association between mid-pregnancy maternal thyroid function and risk of clinically diagnosed ADHD in offspring. METHODS: We conducted a nested case-control study in the Norwegian Mother, Father and Child Cohort Study. Among children born 2003 or later, we randomly sampled singleton ADHD cases obtained through linkage with the Norwegian Patient Registry (n = 298) and 554 controls. Concentrations of maternal triiodothyronine (T3), thyroxine (T4), T3-Uptake, thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (TPO-Ab) were measured in maternal plasma, collected at approximately 17 weeks' gestation. Indices of free T4 (FT4i) and free T3 (FT3i) were calculated. We used multivariable adjusted logistic regression to calculate odds ratios and accounted for missing covariate data using multiple imputation. We used restricted cubic splines to assess non-linear trends and provide flexible representations. We examined effect measure modification by dietary iodine and selenium intake. In sensitivity analyses, we excluded women with clinically significant thyroid disorders (n = 73). RESULTS: High maternal T3 was associated with increased risk of ADHD (5th vs 1st quintile odds ratio  2.27, 95% confidence interval 1.21, 4.26). For FT4i, both the lowest and highest quintiles were associated with an approximate 1.6-fold increase in risk of ADHD, with similar trends found for T4. The FT4i association was modified by dietary iodine intake such that the highest risk strata were confined to the low intake group. CONCLUSIONS: Both high and low concentrations of maternal thyroid hormones, although within population reference ranges, increase the risk of ADHD in offspring. Increased susceptibility may be found among women with low dietary intake of iodine and selenium.

Organophosphorus Pesticide Exposure at 17 Weeks' Gestation and Odds of Offspring Attention-Deficit/Hyperactivity Disorder Diagnosis in the Norwegian Mother, Father, and Child Cohort Study.

Prenatal organophosphorus pesticides (OPs) are ubiquitous and have been linked to adverse neurodevelopmental outcomes. However, few studies have examined prenatal OPs in relation to diagnosed attention-deficit/hyperactivity disorder (ADHD), with only two studies exploring this relationship in a population primarily exposed through diet. In this study, we used a nested case-control study to evaluate prenatal OP exposure and ADHD diagnosis in the Norwegian Mother, Father, and Child Cohort Study (MoBa). For births that occurred between 2003 and 2008, ADHD diagnoses were obtained from linkage of MoBa participants with the Norwegian Patient Registry (N = 297), and a reference population was randomly selected from the eligible population (N = 552). Maternal urine samples were collected at 17 weeks' gestation and molar sums of diethyl phosphates (ΣDEP) and dimethyl phosphates metabolites (ΣDMP) were calculated. Multivariable adjusted logistic regression models were used to estimate the association between prenatal OP metabolite exposure and child ADHD diagnosis. Additionally, multiplicative effect measure modification (EMM) by child sex was assessed. In most cases, mothers in the second and third tertiles of ΣDMP and ΣDEP exposure had slightly lower odds of having a child with ADHD, although confidence intervals were wide and included the null. EMM by child sex was not observed for either ΣDMP or ΣDEP. In summary, we did not find evidence that OPs at 17 weeks' gestation increased the odds of ADHD in this nested case-control study of ADHD in MoBa, a population primarily experiencing dietary exposure.

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.

Ludvig Dahl's psychiatric genetic studies in his 1859 monograph: "Contribution to the knowledge of insanity in Norway".

In 1859, Ludvig Dahl, a Norwegian alienist, wrote a rarely referenced book entitled "Contribution to The Knowledge of Insanity." In it, he describes a highly innovative psychiatric genetics research project with severable notable features. First, while the vast majority of 19th century psychiatric genetic studies were based on asylum hospital records, Dahl did field work to find cases of mental illness in certain defined areas within Norway, using census data, key-informants, record reviews, and personal interviews especially of suspected affected individuals. Second, for the first time in the history of psychiatric genetics, and perhaps more broadly in medical genetics, Dahl studied and graphed extensive pedigrees covering up to seven generations demonstrating a high density of psychiatric illness. Third, he proposed and conducted the first controlled investigation of familial aggregation of insanity. A 126 member 5-generation pedigree that he studied contained 8 individuals with confirmed insanity compared to 16 cases in the remaining 2,974 individuals in the Parish, a relative risk of nearly 12. Dahl also noted the co-segregation within pedigrees of mental handicap, deaf-mutism, and insanity. He evaluated familial-environmental sources of familial aggregation and noted, among nonpsychotic family members in his pedigrees, personalities that might reflect a "disposition" to insanity.

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.