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.

A population-wide gene-environment interaction study on how genes, schools, and residential areas shape achievement.

A child's environment is thought to be composed of different levels that interact with their individual genetic propensities. However, studies have not tested this theory comprehensively across multiple environmental levels. Here, we quantify the contributions of child, parent, school, neighbourhood, district, and municipality factors to achievement, and investigate interactions between polygenic indices for educational attainment (EA-PGI) and environmental levels. We link population-wide administrative data on children's standardised test results, schools and residential identifiers to the Norwegian Mother, Father, and Child Cohort Study (MoBa), which includes >23,000 genotyped parent-child trios. We test for gene-environment interactions using multilevel models with interactions between EA-PGI and random effects for school and residential environments (thus remaining agnostic to specific features of environments). We use parent EA-PGI to control for gene-environment correlation. We found an interaction between students' EA-PGI and schools suggesting compensation: higher-performing schools can raise overall achievement without leaving children with lower EA-PGI behind. Differences between schools matter more for students with lower EA-PGI, explaining 4 versus 2% of the variance in achievement for students 2 SD below versus 2 SD above the mean EA-PGI. Neighbourhood, district, and municipality variation contribute little to achievement (<2% of the variance collectively), and do not interact with children's individual EA-PGI. Policy to reduce social inequality in achievement in Norway should focus on tackling unequal support across schools for children with difficulties.

How interactions between ADHD and schools affect educational achievement: a family-based genetically sensitive study.

BACKGROUND: Children with ADHD tend to achieve less than their peers in school. It is unknown whether schools moderate this association. Nonrandom selection of children into schools related to variations in their ADHD risk poses a methodological problem. METHODS: We linked data on ADHD symptoms of inattention and hyperactivity and parent-child ADHD polygenic scores (PGS) from the Norwegian Mother, Father, and Child Cohort Study (MoBa) to achievement in standardised tests and school identifiers. We estimated interactions of schools with individual differences between students in inattention, hyperactivity, and ADHD-PGS using multilevel models with random slopes for ADHD effects on achievement over schools. In our PGS analyses, we adjust for parental selection of schools by adjusting for parental ADHD-PGS (a within-family PGS design). We then tested whether five school sociodemographic measures explained any interactions. RESULTS: Analysis of up to 23,598 students attending 2,579 schools revealed interactions between school and ADHD effects on achievement. The variability between schools in the effects of inattention, hyperactivity and within-family ADHD-PGS on achievement was 0.08, 0.07 and 0.05 SDs, respectively. For example, the average effect of inattention on achievement was ß = -0.23 (SE = 0.009), but in 2.5% of schools with the weakest effects, the value was -0.07 or less. ADHD has a weaker effect on achievement in higher-performing schools. Schools make more of a difference to the achievements of students with higher levels of ADHD, explaining over four times as much variance in achievement for those with high versus average inattention symptoms. School sociodemographic measures could not explain the ADHD-by-school interactions. CONCLUSIONS: Although ADHD symptoms and genetic risk tend to hinder achievement, schools where their effects are weaker do exist. Differences between schools in support for children with ADHD should be evened out.

On the importance of parenting in externalizing disorders: an evaluation of indirect genetic effects in families.

BACKGROUND: Theoretical models of the development of childhood externalizing disorders emphasize the role of parents. Empirical studies have not been able to identify specific aspects of parental behaviors explaining a considerable proportion of the observed individual differences in externalizing problems. The problem is complicated by the contribution of genetic factors to externalizing problems, as parents provide both genes and environments to their children. We studied the joint contributions of direct genetic effects of children and the indirect genetic effects of parents through the environment on externalizing problems. METHODS: The study used genome-wide single nucleotide polymorphism data from 9,675 parent-offspring trios participating in the Norwegian Mother Father and child cohort study. Based on genomic relatedness matrices, we estimated the contribution of direct genetic effects and indirect maternal and paternal genetic effects on ADHD, conduct and disruptive behaviors at 8 years of age. RESULTS: Models including indirect parental genetic effects were preferred for the ADHD symptoms of inattention and hyperactivity, and conduct problems, but not oppositional defiant behaviors. Direct genetic effects accounted for 11% to 24% of the variance, whereas indirect parental genetic effects accounted for 0% to 16% in ADHD symptoms and conduct problems. The correlation between direct and indirect genetic effects, or gene-environment correlations, decreased the variance with 16% and 13% for conduct and inattention problems, and increased the variance with 6% for hyperactivity problems. CONCLUSIONS: This study provides empirical support to the notion that parents have a significant role in the development of childhood externalizing behaviors. The parental contribution to decrease in variation of inattention and conduct problems by gene-environment correlations would limit the number of children reaching clinical ranges in symptoms. Not accounting for indirect parental genetic effects can lead to both positive and negative bias when identifying genetic variants for childhood externalizing behaviors.

Genetic and environmental contributions to co-occurring ADHD and emotional problems in school-aged children.

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).

Intergenerational transmission of parental neuroticism to emotional problems in 8-year-old children: Genetic and environmental influences.

Background: Children of parents with high levels of neuroticism tend to have high neuroticism themselves as well as increased risk of experiencing symptoms of anxiety and depression. It is not yet clear how much of this link is attributable to a potential effect of parent on child (e.g., via a socializing effect) versus to shared genetic risk. We aimed to determine whether there is an intergenerational association after accounting for genetic transmission and assortative mating. Methods: We used data from the Norwegian Mother, Father and Child Cohort Study including 11,088 sibling pairs in the parental generation, their partners (N = 22,176) and their offspring (N = 26,091). Exposures were maternal and paternal neuroticism (self-reported), and the outcomes were neuroticism, symptoms of depression, and symptoms of anxiety in 8-year-old children (mother-reported). Results: After accounting for assortative mating in parents (phenotypic r = 0.26) and genetic transmission (explaining 0%-18% of the mother-offspring correlations), potential maternal effects explained 80% (95% CI = 47-95) of the association with offspring neuroticism (mother-child r = 0.31), 78% (95% CI = 66-89) of the association with offspring depressive symptoms (r = 0.31), and 98% (95% CI = 45-112) of the association with offspring anxiety symptoms (r = 0.16). Intergenerational transmission of genetic variants associated with paternal neuroticism accounted for ∼40% (CI = 22%-58%) of the father-offspring correlations with neuroticism and symptoms of depression (r = 0.13 and 0.13, respectively) but none with offspring symptoms of anxiety (r = 0.05). The remaining father-offspring correlations were explained by maternal influences through assortative mating. Conclusions: These results are consistent with direct effects between maternal and offspring neuroticism and between maternal neuroticism and offspring symptoms of anxiety and depression. Further understanding of these intergenerational processes will require an adequate model of how these constructs (neuroticism, anxiety and depression) relate to each other within generations.

A Life Course Study of Genetic and Environmental Influences on Work Incapacity.

Work incapacity is a major public health challenge and an economic burden to both society and individuals. Understanding the underlying causes is becoming ever more relevant as many countries face an aging workforce. We examined stability and change in genetic and environmental factors influencing work incapacity from age 18 until retirement, and sex differences in these effects. The large population-based sample comprised information from 28,759 twins followed for up to 23 years combined with high-quality national registry data. We measured work incapacity as the total proportion of potential workdays lost due to sickness absence, rehabilitation and disability benefits. Structural equation modeling with twin data indicated moderate genetic influences on work incapacity throughout life in both men and women, with a high degree of genetic stability from young to old adulthood. Environmental influences were mainly age-specific. Our results indicate that largely the same genetic factors influence individual differences in work incapacity throughout young, middle and older adulthood, despite major differences in degree of work incapacity and probable underlying medical causes.

Testing Genetic and Environmental Associations Between Personality Disorders and Cocaine Use: A Population-Based Twin Study.

Until now, data have not been available to elucidate the genetic and environmental sources of comorbidity between all 10 DSM-IV personality disorders (PDs) and cocaine use. Our aim was to determine which PD traits are linked phenotypically and genetically to cocaine use. Cross-sectional data were obtained in a face-to-face interview between 1999 and 2004. Subjects were 1,419 twins (µage = 28.2 years, range = 19-36) from the Norwegian Institute of Public Health Twin Panel, with complete lifetime cocaine use and criteria for all 10 DSM-IV PDs. Stepwise multiple and Least Absolute Shrinkage and Selection Operator (LASSO) regressions were used to identify PDs related to cocaine use. Twin models were fitted to estimate genetic and environmental associations between the PD traits and cocaine use. In the multiple regression, antisocial (OR = 4.24, 95% CI [2.66, 6.86]) and borderline (OR = 2.19, 95% CI [1.35, 3.57]) PD traits were significant predictors of cocaine use. In the LASSO regression, antisocial, borderline, and histrionic were significant predictors of cocaine use. Antisocial and borderline PD traits each explained 72% and 25% of the total genetic risks in cocaine use, respectively. Genetic risks in histrionic PD were not significantly related to cocaine use. Importantly, after removing criteria referencing substance use, antisocial PD explained 65% of the total genetic variance in cocaine use, whereas borderline explained only 4%. Among PD traits, antisocial is the strongest correlate of cocaine use, for which the association is driven largely by common genetic risks.

Pre-pregnancy mental distress and musculoskeletal pain and sickness absence during pregnancy - a twin cohort study.

Background: Sickness absence (SA) among pregnant women is high. The aim of this study was to examine whether factors known to predict SA in general also predict SA during pregnancy by estimating the association between prior mental distress and musculoskeletal pain and SA during pregnancy, and to assess the influence of familial (genetic and shared environmental) factors. In this prospective cohort study, data from 2076 female twins born 1967-79 who participated in a questionnaire study in 1998 were linked to register data on SA and childbirth during the years 1998-2008. Baseline measures included mental distress (symptoms of anxiety and depression; SCL-5) and musculoskeletal pain (lumbar spine, neck/shoulder and/or persisting muscular pain). SA was measured as a ratio of days on SA divided by potential working days. Negative binomial regression was performed for individual and within-pair effects. Musculoskeletal pain, but not mental distress, was prospectively associated with overall SA during pregnancy in the adjusted individual-level analyses. With each standard deviation increase in musculoskeletal pain, SA granted for any disorder increased with 12% (IRR 1.12, 95% CI = 1.07-1.17) and SA granted for pregnancy related disorders increased with 9% (IRR 1.09, 95% CI = 1.02-1.17). Within-pair estimates were similar, suggesting little or no familial confounding. Women with previous musculoskeletal pain are at increased risk of SA during pregnancy, whereas no increased risk in women with previous symptoms of mental distress could be demonstrated. SA during pregnancy seems partly to be associated with different factors than SA in general.

Genetic and environmental contributions to the relationship between internalizing disorders and sick leave granted for mental and somatic disorders.

This study investigates the degree to which internalizing disorders (anxiety and mood disorders) are prospectively associated with sick leave granted for mental and somatic disorders, and the extent to which common genetic and environmental risk factors influence these relationships. Data include self-reported symptoms of psychological distress from 7,598 young adult twins and diagnostic interviews on a subsample of 2,766 adult twins, subsequently linked to registry data on sick leave. Regression analyses and multivariate twin models were used to investigate the relationship between internalizing disorders and sick leave. Internalizing disorders were associated with sick leave granted for both mental disorders and somatic disorders. The association between internalizing disorders and sick leave granted for mental disorders was influenced by genetic and non-shared environmental factors, while the association between internalizing disorders and sick leave granted for somatic disorders could be explained by common genetic factors alone. Monozygotic twins discordant for internalizing disorders differed significantly in rates of sick leave granted for mental but not somatic disorders. In conclusion, internalizing disorders in young adults predict sick leave granted for both mental and somatic disorders. Environmental risk factors for internalizing disorders seem to influence sick leave granted for mental disorders, but not sick leave granted for somatic disorders.

More mental health problems after divorce in couples with high pre-divorce alcohol consumption than in other divorced couples: results from the HUNT-study.

BACKGROUND: Divorce is associated with mental health problems, and heavy drinking is related to higher risk of divorce. Less is known about the effects of divorce in couples where one or both drinks heavily. There are, however, reasons to expect different consequences of divorce in heavy risk using couples compared to other couples. Spouses of abusers may experience the divorce as a relief, whereas abusers may find it extra difficult to be left single. The aim of the study is to compare the effect of divorce on mental health in heavy drinking couples to the effect in couples who drink less. METHODS: Registry data were matched with data from the Nord-Trøndelag Health Study (HUNT 1 (T1) and 2 (T2)), enabling longitudinal analyses of approximately 11,000 couples. Interaction terms between 1) alcohol use on T1 and divorce between T1 and T2 (11 year time lag), and 2) alcohol use on T1 and time since divorce at T2 for all divorced couples were tested to examine changes in mental health between T1 and T2 for a) spouses of high-risk compared to low-risk users, and b) high-risk compared to low-risk users themselves. Data were analyzed using multivariate analysis of variance. RESULTS: There was a general effect of divorce on change in mental health between T1 and T2. We observed a significantly stronger worsening in mental health in female high-risk users and their spouses than in divorced low-risk users and their spouses. The results also suggest that the strain after divorce lasts longer in women with a high alcohol consumption and their spouses. CONCLUSIONS: Divorce seems to affect couples where one or both drink heavily more than couples with a low consumption. Also there was some evidence of a slower healing of mental health problems after divorce in alcohol exposed couples than in other couples. The results only reached significance for female high consumers and their spouses, but due to limited statistical power, safe conclusions about gender specific effects cannot be drawn.

Discordant and concordant alcohol use in spouses as predictors of marital dissolution in the general population: results from the Hunt study.

BACKGROUND: Previous studies have demonstrated that high alcohol consumption is a predictor of divorce. However, there is a lack of studies with prospective data from both spouses. The effects of drinking among husbands versus wives and of concordant versus discordant drinking in couples are therefore unknown. Concordant drinking may lead to increased divorce rates because the malignant effects of heavy drinking are experienced in double doses; alternatively it may lead to marital stability due to partner compatibility. METHODS: All inhabitants in a Norwegian county were invited to participate in a health study. We identified 19,977 married couples where both spouses participated. Respondents provided information on alcohol use and mental distress. Survival analysis was applied to study the risk of divorce over the next 15 years. Demographics and mental distress were used as covariates. RESULTS: Heavy drinking among men (hazard ratio [HR] = 1.39) and women (HR = 1.41) increased the risk of future marital dissolution, even after adjusting for demography (reference group "light drinkers"). The HR for divorce was 1.51 when only the husband was a heavy drinker, while it was 3.07 when only the wife was a heavy drinker. Moreover, there were strong interaction effects: concordant abstainers (HR = 0.40) and concordant heavy drinkers (HR = 0.35) had lower risks of divorce compared to the risk expected from combining the main effects. Nevertheless, couples with 2 heavy drinkers (HR = 1.63) had higher risk of divorce than couples with 2 light drinkers. CONCLUSIONS: This study demonstrated that both the level of alcohol use and compatibility in alcohol use are important predictors of marital dissolution.

Parental alcohol use and adolescent school adjustment in the general population: results from the HUNT study.

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.