Examining intergenerational risk factors for conduct problems using polygenic scores in the Norwegian Mother, Father and Child Cohort Study.

The aetiology of conduct problems involves a combination of genetic and environmental factors, many of which are inherently linked to parental characteristics given parents' central role in children's lives across development. It is important to disentangle to what extent links between parental heritable characteristics and children's behaviour are due to transmission of genetic risk or due to parental indirect genetic influences via the environment (i.e., genetic nurture). We used 31,290 genotyped mother-father-child trios from the Norwegian Mother, Father and Child Cohort Study (MoBa), testing genetic transmission and genetic nurture effects on conduct problems using 13 polygenic scores (PGS) spanning psychiatric conditions, substance use, education-related factors, and other risk factors. Maternal or self-reports of conduct problems at ages 8 and 14 years were available for up to 15,477 children. We found significant genetic transmission effects on conduct problems for 12 out of 13 PGS at age 8 years (strongest association: PGS for smoking, ß = 0.07, 95% confidence interval = [0.05, 0.08]) and for 4 out of 13 PGS at age 14 years (strongest association: PGS for externalising problems, ß = 0.08, 95% confidence interval = [0.05, 0.11]). Conversely, we did not find genetic nurture effects for conduct problems using our selection of PGS. Our findings provide evidence for genetic transmission in the association between parental characteristics and child conduct problems. Our results may also indicate that genetic nurture via traits indexed by our polygenic scores is of limited aetiological importance for conduct problems-though effects of small magnitude or effects via parental traits not captured by the included PGS remain a possibility.

Social and genetic associations with educational performance in a Scandinavian welfare state.

Recent research has suggested that across Western developed societies, the influence of genetics on educational outcomes is relatively constant. However, the degree to which family environment matters varies, such that countries with high levels of intergenerational mobility have weaker associations of family background. Research in this vein has relied on twin-based estimates, which involve variance decomposition, so direct assessment of the association of genes and environments is not possible. In the present study, we approach the question by directly measuring the impact of child genotype, parental genetic nurture, and parental realized education on educational achievement in primary and secondary school. We deploy data from a social democratic context (Norway) and contrast our findings with those derived from more liberal welfare state contexts. Results point to genetics only confounding the relationship between parent status and offspring achievement to a small degree. Genetic nurture associations are similar to those in other societies. We find no, or very small, gene-environment interactions and parent-child genotype interactions with respect to test scores. In sum, in a Scandinavian welfare state context, both genetic and environmental associations are of similar magnitude as in societies with less-robust efforts to mitigate the influence of family background.

Parental genetically predicted liability for coronary heart disease and risk of adverse pregnancy outcomes: a cohort study.

BACKGROUND: Adverse pregnancy outcomes (APO) may unmask or exacerbate a woman's underlying risk for coronary heart disease (CHD). We estimated associations of maternal and paternal genetically predicted liability for CHD with lifelong risk of APOs. We hypothesized that associations would be found for women, but not their male partners (negative controls). METHODS: We studied up to 83,969‬ women (and up to 55,568‬ male partners) from the Norwegian Mother, Father and Child Cohort Study or the Trøndelag Health Study with genotyping data and lifetime history of any APO in their pregnancies (1967-2019) in the Medical Birth Registry of Norway (miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, small for gestational age, large for gestational age, and spontaneous preterm birth). Maternal and paternal genetic risk scores (GRS) for CHD were generated using 148 gene variants (p-value < 5 × 10-8, not in linkage disequilibrium). Associations between GRS for CHD and each APO were determined using logistic regression, adjusting for genomic principal components, in each cohort separately, and combined using fixed effects meta-analysis. RESULTS: One standard deviation higher GRS for CHD in women was related to increased risk of any hypertensive disorders of pregnancy (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.05-1.10), pre-eclampsia (OR 1.08, 95% CI 1.05-1.11), and small for gestational age (OR 1.04, 95% CI 1.01-1.06). Imprecise associations with lower odds of large for gestational age (OR 0.98, 95% CI 0.96-1.00) and higher odds of stillbirth (OR 1.04, 95% CI 0.98-1.11) were suggested. These findings remained consistent after adjusting for number of total pregnancies and the male partners' GRS and restricting analyses to stable couples. Associations for other APOs were close to the null. There was weak evidence of an association of paternal genetically predicted liability for CHD with spontaneous preterm birth in female partners (OR 1.02, 95% CI 0.99-1.05), but not with other APOs. CONCLUSIONS: Hypertensive disorders of pregnancy, small for gestational age, and stillbirth may unmask women with a genetically predicted propensity for CHD. The association of paternal genetically predicted CHD risk with spontaneous preterm birth in female partners needs further exploration.

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.

Impaired glucose tolerance and cardiovascular risk factors in relation to infertility: a Mendelian randomization analysis in the Norwegian Mother, Father, and Child Cohort Study.

STUDY QUESTION: Are impaired glucose tolerance (as measured by fasting glucose, glycated hemoglobin, and fasting insulin) and cardiovascular disease risk (as measured by low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and diastolic blood pressure) causally related to infertility? SUMMARY ANSWER: Genetic instruments suggest that higher fasting insulin may increase infertility in women. WHAT IS KNOWN ALREADY: Observational evidence suggests a shared etiology between impaired glucose tolerance, cardiovascular risk, and fertility problems. STUDY DESIGN, SIZE, DURATION: This study included two-sample Mendelian randomization (MR) analyses, in which we used genome-wide association summary data that were publicly available for the biomarkers of impaired glucose tolerance and cardiovascular disease, and sex-specific genome-wide association studies (GWASs) of infertility conducted in the Norwegian Mother, Father, and Child Cohort Study. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were 68 882 women (average age 30, involved in 81 682 pregnancies) and 47 474 of their male partners (average age 33, 55 744 pregnancies) who had available genotype data and who provided self-reported information on time-to-pregnancy and use of ARTs. Of couples, 12% were infertile (having tried to conceive for ≥12 months or used ARTs to conceive). We applied the inverse variance weighted method with random effects to pool data across variants and a series of sensitivity analyses to explore genetic instrument validity. (We checked the robustness of genetic instruments and the lack of unbalanced horizontal pleiotropy, and we used methods that are robust to population stratification.) Findings were corrected for multiple comparisons by the Bonferroni method (eight exposures: P-value < 0.00625). MAIN RESULTS AND THE ROLE OF CHANCE: In women, increases in genetically determined fasting insulin levels were associated with greater odds of infertility (+1 log(pmol/l): odds ratio 1.60, 95% CI 1.17 to 2.18, P-value = 0.003). The results were robust in the sensitivity analyses exploring the validity of MR assumptions and the role of pleiotropy of other cardiometabolic risk factors. There was also evidence of higher glucose and glycated hemoglobin causing infertility in women, but the findings were imprecise and did not pass our P-value threshold for multiple testing. The results for lipids and blood pressure were close to the null, suggesting that these did not cause infertility. LIMITATIONS, REASONS FOR CAUTION: We did not know if underlying causes of infertility were in the woman, man, or both. Our analyses only involved couples who had conceived. We did not have data on circulating levels of cardiometabolic risk factors, and we opted to conduct an MR analysis using GWAS summary statistics. No sex-specific genetic instruments on cardiometabolic risk factors were available. Our results may be affected by selection and misclassification bias. Finally, the characteristics of our study sample limit the generalizability of our results to populations of non-European ancestry. WIDER IMPLICATIONS OF THE FINDINGS: Treatments for lower fasting insulin levels may reduce the risk of infertility in women. STUDY FUNDING/COMPETING INTEREST(S): The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. This work was supported by the European Research Council [grant numbers 947684, 101071773, 293574, 101021566], the Research Council of Norway [grant numbers 262700, 320656, 274611], the South-Eastern Norway Regional Health Authority [grant numbers 2020022, 2021045], and the British Heart Foundation [grant numbers CH/F/20/90003, AA/18/1/34219]. Open Access funding was provided by the Norwegian Institute of Public Health. The funders had no role in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the article for publication. D.A.L. has received research support from National and International government and charitable bodies, Roche Diagnostics and Medtronic for research unrelated to the current work. O.A.A. has been a consultant to HealthLytix. The rest of the authors declare that no competing interests exist. TRIAL REGISTRATION NUMBER: N/A.

Genotype-environment interplay in associations between maternal drinking and offspring emotional and behavioral problems.

BACKGROUND: While maternal at-risk drinking is associated with children's emotional and behavioral problems, there is a paucity of research that properly accounts for genetic confounding and gene-environment interplay. Therefore, it remains uncertain what mechanisms underlie these associations. We assess the moderation of associations between maternal at-risk drinking and childhood emotional and behavioral problems by common genetic variants linked to environmental sensitivity (genotype-by-environment [G × E] interaction) while accounting for shared genetic risk between mothers and offspring (GE correlation). METHODS: We use data from 109 727 children born to 90 873 mothers enrolled in the Norwegian Mother, Father, and Child Cohort Study. Women self-reported alcohol consumption and reported emotional and behavioral problems when children were 1.5/3/5 years old. We included child polygenic scores (PGSs) for traits linked to environmental sensitivity as moderators. RESULTS: Associations between maternal drinking and child emotional (ß1 = 0.04 [95% confidence interval (CI) 0.03-0.05]) and behavioral (ß1 = 0.07 [0.06-0.08]) outcomes attenuated after controlling for measured confounders and were almost zero when we accounted for unmeasured confounding (emotional: ß1 = 0.01 [0.00-0.02]; behavioral: ß1 = 0.01 [0.00-0.02]). We observed no moderation of these adjusted exposure effects by any of the PGS. CONCLUSIONS: The lack of strong evidence for G × E interaction may indicate that the mechanism is not implicated in this kind of intergenerational association. It may also reflect insufficient power or the relatively benign nature of the exposure in this sample.

Intergenerational transmission of ADHD behaviors: genetic and environmental pathways.

BACKGROUND: We investigate if covariation between parental and child attention-deficit hyperactivity disorder (ADHD) behaviors can be explained by environmental and/or genetic transmission. METHODS: We employed a large children-of-twins-and-siblings sample (N = 22 276 parents and 11 566 8-year-old children) of the Norwegian Mother, Father and Child Cohort Study. This enabled us to disentangle intergenerational influences via parental genes and parental behaviors (i.e. genetic and environmental transmission, respectively). Fathers reported on their own symptoms and mothers on their own and their child's symptoms. RESULTS: Child ADHD behaviors correlated with their mother's (0.24) and father's (0.10) ADHD behaviors. These correlations were largely due to additive genetic transmission. Variation in children's ADHD behaviors was explained by genetic factors active in both generations (11%) and genetic factors specific to the children (46%), giving a total heritability of 57%. There were small effects of parental ADHD behaviors (2% environmental transmission) and gene-environment correlation (3%). The remaining variability in ADHD behaviors was due to individual-specific environmental factors. CONCLUSIONS: The intergenerational resemblance of ADHD behaviors is primarily due to genetic transmission, with little evidence for parental ADHD behaviors causing children's ADHD behaviors. This contradicts theories proposing environmental explanations of intergenerational transmission of ADHD, such as parenting theories or psychological life-history theory.

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.

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.

Development of prosocial behavior and inhibitory control in late childhood: A longitudinal exploration of sex differences and reciprocal relations.

This study examined longitudinal development of prosocial behavior, assessed by the parent-reported Strength and Difficulty Questionnaire, and inhibitory control, measured by the Opposite Worlds Task, in a sample aged 9 and 12 years (n = 9468, 49.9% girls, 85.8% White) from the Avon Longitudinal Study of Parents and Children. The goal was to assess whether the level of prosocial behavior at age 9 relates to change in inhibitory control, and vice versa. Sex differences were also explored. Latent change score models showed that low inhibitory control in boys at age 9 was associated with more decreases in prosocial behavior from 9 to 12 years of age. This may suggest that interventions targeting inhibitory control in boys may also foster their social competence.

Running in the FAMILY: understanding and predicting the intergenerational transmission of mental illness.

Over 50% of children with a parent with severe mental illness will develop mental illness by early adulthood. However, intergenerational transmission of risk for mental illness in one's children is insufficiently considered in clinical practice, nor is it sufficiently utilised into diagnostics and care for children of ill parents. This leads to delays in diagnosing young offspring and missed opportunities for protective actions and resilience strengthening. Prior twin, family, and adoption studies suggest that the aetiology of mental illness is governed by a complex interplay of genetic and environmental factors, potentially mediated by changes in epigenetic programming and brain development. However, how these factors ultimately materialise into mental disorders remains unclear. Here, we present the FAMILY consortium, an interdisciplinary, multimodal (e.g., (epi)genetics, neuroimaging, environment, behaviour), multilevel (e.g., individual-level, family-level), and multisite study funded by a European Union Horizon-Staying-Healthy-2021 grant. FAMILY focuses on understanding and prediction of intergenerational transmission of mental illness, using genetically informed causal inference, multimodal normative prediction, and animal modelling. Moreover, FAMILY applies methods from social sciences to map social and ethical consequences of risk prediction to prepare clinical practice for future implementation. FAMILY aims to deliver: (i) new discoveries clarifying the aetiology of mental illness and the process of resilience, thereby providing new targets for prevention and intervention studies; (ii) a risk prediction model within a normative modelling framework to predict who is at risk for developing mental illness; and (iii) insight into social and ethical issues related to risk prediction to inform clinical guidelines.

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.

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.

Meta-analysis of epigenome-wide associations between DNA methylation at birth and childhood cognitive skills.

Cognitive skills are a strong predictor of a wide range of later life outcomes. Genetic and epigenetic associations across the genome explain some of the variation in general cognitive abilities in the general population and it is plausible that epigenetic associations might arise from prenatal environmental exposures and/or genetic variation early in life. We investigated the association between cord blood DNA methylation at birth and cognitive skills assessed in children from eight pregnancy cohorts within the Pregnancy And Childhood Epigenetics (PACE) Consortium across overall (total N = 2196), verbal (total N = 2206) and non-verbal cognitive scores (total N = 3300). The associations at single CpG sites were weak for all of the cognitive domains investigated. One region near DUSP22 on chromosome 6 was associated with non-verbal cognition in a model adjusted for maternal IQ. We conclude that there is little evidence to support the idea that variation in cord blood DNA methylation at single CpG sites is associated with cognitive skills and further studies are needed to confirm the association at DUSP22.

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.

Bounding the average causal effect in Mendelian randomisation studies with multiple proposed instruments: An application to prenatal alcohol exposure and attention deficit hyperactivity disorder.

BACKGROUND: As large-scale observational data become more available, caution regarding causal assumptions remains critically important. This may be especially true for Mendelian randomisation (MR), an increasingly popular approach. Point estimation in MR usually requires strong, often implausible homogeneity assumptions beyond the core instrumental conditions. Bounding, which does not require homogeneity assumptions, is infrequently applied in MR. OBJECTIVES: We aimed to demonstrate computing nonparametric bounds for the causal risk difference derived from multiple proposed instruments in an MR study where effect heterogeneity is expected. METHODS: Using data from the Norwegian Mother, Father and Child Cohort Study (n = 2056) and Avon Longitudinal Study of Parents and Children (n = 6216) to study the average causal effect of maternal pregnancy alcohol use on offspring attention deficit hyperactivity disorder symptoms, we proposed 11 maternal SNPs as instruments. We computed bounds assuming subsets of SNPs were jointly valid instruments, for all combinations of SNPs where the MR model was not falsified. RESULTS: The MR assumptions were violated for all sets with more than 4 SNPs in one cohort and for all sets with more than 2 SNPs in the other. Bounds assuming one SNP was an individually valid instrument barely improved on assumption-free bounds. Bounds tightened as more SNPs were assumed to be jointly valid instruments, and occasionally identified directions of effect, though bounds from different sets varied. CONCLUSIONS: Our results suggest that, when proposing multiple instruments, bounds can contextualise plausible magnitudes and directions of effects. Computing bounds over multiple assumption sets, particularly in large, high-dimensional data, offers a means of triangulating results across different potential sources of bias within a study and may help researchers to better evaluate and emphasise which estimates are compatible with the most plausible assumptions for their specific setting.

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.

Early manifestations of genetic risk for neurodevelopmental disorders.

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (autism) and schizophrenia are highly heritable neurodevelopmental disorders, affecting the lives of many individuals. It is important to increase our understanding of how the polygenic risk for neurodevelopmental disorders manifests during childhood in boys and girls. METHODS: Polygenic risk scores (PRS) for ADHD, autism and schizophrenia were calculated in a subsample 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 multigroup framework were used to investigate associations between the three PRS and dimensional trait measures in MoBa, using sex as a grouping variable. RESULTS: Before the age of 2, the ADHD PRS was robustly associated with hyperactivity and inattention, with increasing strength up to 8 years, and with language difficulties at age 5 and 8. The autism PRS was robustly associated with language difficulties at 18 months, motor difficulties at 36 months, and hyperactivity and inattention at 8 years. We did not identify robust associations for the schizophrenia PRS. In general, the PRS associations were similar in boys and girls. The association between ADHD PRS and hyperactivity at 18 months was, however, stronger in boys. CONCLUSIONS: Polygenic risk for autism and ADHD in the general population manifests early in childhood and broadly across behavioral measures of neurodevelopmental traits.

Within family Mendelian randomization studies.

Mendelian randomization (MR) is increasingly used to make causal inferences in a wide range of fields, from drug development to etiologic studies. Causal inference in MR is possible because of the process of genetic inheritance from parents to offspring. Specifically, at gamete formation and conception, meiosis ensures random allocation to the offspring of one allele from each parent at each locus, and these are unrelated to most of the other inherited genetic variants. To date, most MR studies have used data from unrelated individuals. These studies assume that genotypes are independent of the environment across a sample of unrelated individuals, conditional on covariates. Here we describe potential sources of bias, such as transmission ratio distortion, selection bias, population stratification, dynastic effects and assortative mating that can induce spurious or biased SNP-phenotype associations. We explain how studies of related individuals such as sibling pairs or parent-offspring trios can be used to overcome some of these sources of bias, to provide potentially more reliable evidence regarding causal processes. The increasing availability of data from related individuals in large cohort studies presents an opportunity to both overcome some of these biases and also to evaluate familial environmental effects.

Risk of miscarriage in women with psychiatric disorders.

BACKGROUND: Some psychiatric disorders have been associated with increased risk of miscarriage. However, there is a lack of studies considering a broader spectrum of psychiatric disorders to clarify the role of common as opposed to independent mechanisms. AIMS: To examine the risk of miscarriage among women diagnosed with psychiatric conditions. METHOD: We studied registered pregnancies in Norway between 2010 and 2016 (n = 593 009). The birth registry captures pregnancies ending in gestational week 12 or later, and the patient and general practitioner databases were used to identify miscarriages and induced abortions before 12 gestational weeks. Odds ratios of miscarriage according to 12 psychiatric diagnoses were calculated by logistic regression. CONCLUSIONS: A wide range of psychiatric disorders were associated with increased risk of miscarriage. The heightened risk of miscarriage among women diagnosed with psychiatric disorders highlights the need for awareness and surveillance of this risk group in antenatal care.