Emotional problems across development: examining measurement invariance across childhood, adolescence and early adulthood.

Emotional problems (anxiety, depression) are prevalent in children, adolescents and young adults with varying ages at onset. Studying developmental changes in emotional problems requires repeated assessments using the same or equivalent measures. The parent-rated Strengths and Difficulties Questionnaire is commonly used to assess emotional problems in childhood and adolescence, but there is limited research about whether it captures a similar construct across these developmental periods. Our study addressed this by investigating measurement invariance in the scales' emotional problems subscale (SDQ-EP) across childhood, adolescence and early adulthood. Data from two UK population cohorts were utilised: the Millennium Cohort Study (ages 3-17 years) and the Avon Longitudinal Study of Parents and Children (4-25 years). In both samples we observed weak (metric) measurement invariance by age, suggesting that the parent-rated SDQ-EP items contribute to the underlying construct of emotional problems similarly across age. This supports the validity of using the subscale to rank participants on their levels of emotional problems in childhood, adolescence and early adulthood. However strong (scalar) measurement invariance was not observed, suggesting that the same score may correspond to different levels of emotional problems across developmental periods. Comparisons of mean parent-rated SDQ-EP scores across age may therefore not be valid.

Stratifying early-onset emotional disorders: using genetics to assess persistence in young people of European and South Asian ancestry.

BACKGROUND: Depression and anxiety are the most common mental health problems in young people. Currently, clinicians are advised to wait before initiating treatment for young people with these disorders as many spontaneously remit. However, others develop recurrent disorder but this subgroup cannot be identified at the outset. We examined whether psychiatric polygenic scores (PGS) could help inform stratification efforts to predict those at higher risk of recurrence. METHODS: Probable emotional disorder was examined in two UK population cohorts using the emotional symptoms subscale of the Strengths and Difficulties Questionnaire (SDQ). Those with emotional disorder at two or more time points between ages 5 and 25 years were classed as 'recurrent emotional disorder' (n = 1,643) and those with emotional disorder at one time point as having 'single episode emotional disorder' (n = 1,435, controls n = 8,715). We first examined the relationship between psychiatric PGS and emotional disorders in childhood and adolescence. Second, we tested whether psychiatric PGS added to predictor variables of known association with emotional disorder (neurodevelopmental comorbidity, special educational needs, family history of depression and socioeconomic status) when discriminating between single-episode and recurrent emotional disorder. Analyses were conducted separately in individuals of European and South Asian ancestry. RESULTS: Probable emotional disorder was associated with higher PGS for major depressive disorder (MDD), anxiety, broad depression, ADHD and autism spectrum disorder (ASD) in those of European ancestry. Higher MDD and broad depression PGS were associated with emotional disorder in people of South Asian ancestry. Recurrent, compared to single-episode, emotional disorder was associated with ASD and parental psychiatric history. PGS were not associated with episode recurrence, and PGS did not improve discrimination of recurrence when combined with clinical predictors. CONCLUSIONS: Our findings do not support the use of PGS as a tool to assess the likelihood of recurrence in young people experiencing their first episode of emotional disorder.

Young Adult ADHD Symptoms in the General Population and Neurocognitive Impairment.

OBJECTIVE: Neurocognitive impairments are associated with child and adult ADHD in clinical settings. However, it is unknown whether adult ADHD symptoms in the general population are associated with the same pattern of cognitive impairment. We examined this using a prospective, population-based cohort spanning birth to age 25 years. METHODS: We examined associations between self-reported adult ADHD symptoms and cognitive task performance (attention and response inhibition) in adulthood and childhood. RESULTS: Self-rated ADHD symptoms at age 25 were associated with poorer performance in age 25 cognitive tasks capturing ADHD-related functioning (attention B = -0.03, 95% CI [0.05, -0.01], p = .005; response inhibition B = -0.03, 95% CI [-0.05, -0.01], p = .002). CONCLUSIONS: Neurocognitive impairments linked to adult ADHD symptoms in the general population, are similar to those found in people with childhood ADHD symptoms and are consistent with findings in adult ADHD clinical samples.

Estimating the impact of transmitted and non-transmitted psychiatric and neurodevelopmental polygenic scores on youth emotional problems.

Anxiety and depression (emotional disorders) are familial and heritable, especially when onset is early. However, other cross-generational studies suggest transmission of youth emotional problems is explained by mainly environmental risks. We set out to test the contribution of parental non-transmitted genetic liability, as indexed by psychiatric/neurodevelopmental common polygenic liability, to youth emotional problems using a UK population-based cohort: the Millennium Cohort Study. European (N = 6328) and South Asian (N = 814) ancestries were included, as well as a subset with genomic data from both parents (European: N = 2809; South Asian: N = 254). We examined the association of transmitted (PGST) and non-transmitted polygenic scores (PGSNT) for anxiety, depression, bipolar disorder and neurodevelopmental disorders (attention-deficit/hyperactivity disorder [ADHD], autism spectrum disorder [ASD], schizophrenia) with youth emotional disorder and symptom scores, measured using the parent- and self-reported Strengths and Difficulties Questionnaire emotional subscale at 6 timepoints between ages 3-17 years. In the European sample, PGST for anxiety and depression, but not bipolar disorder, were associated with emotional disorder and symptom scores across all ages, except age 3, with strongest association in adolescence. ADHD and ASD PGST also showed association across ages 11-17 years. In the South Asian sample, evidence for associations between all PGST and outcome measures were weaker. There was weak evidence of association between PGSNT for anxiety and depression and age 17 symptom scores in the South Asian sample, but not in the European sample for any outcome. Overall, PGST for depression, anxiety, ADHD and ASD contributed to youth emotional problems, with stronger associations in adolescence. There was limited support for non-transmitted genetic effects: these findings do not support the hypothesis that parental polygenic psychiatric/neurodevelopmental liability confer risk to offspring emotional problems through non-transmitted rearing/nurture effects.

Can a nation-wide e-cohort of ADHD and ASD in childhood be established using Welsh routinely available datasets?

OBJECTIVES: We investigated the feasibility and validity of establishing a nationwide e-cohort of individuals with a diagnosis of attention deficit hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD) for future longitudinal research. DESIGN: Individuals with a childhood diagnosis of ADHD/ASD as recorded on routinely available healthcare datasets were compared with matched controls and a sample of directly assessed individuals with ADHD. SETTING: This study used data from the Welsh Secure Anonymised Information Linkage Databank in Wales, UK. Routinely collected data from primary care, emergency department and hospital admissions were linked at person level. PARTICIPANTS: All individuals in Wales, UK born between 1 January 1991 and 31 December 2000. Individuals with a recorded diagnosis of ADHD and/or ASD by age 18 years were identified using International Classification of Diseases, 10th Revision and National Health Service (NHS) READ codes and matched to 3 controls each and 154 individuals with ADHD recruited from an established research study. OUTCOME MEASURES: Recorded service use for anxiety and depression, alcohol and drug use and self-harm including emergency department use in young adulthood (age 16-25 years). RESULTS: 7726 individuals had a recorded diagnosis of ADHD (80% male) and 5001 of ASD (79% male); 1.4% and 0.9% of the population, respectively. Cox's regression analyses showed ADHD was associated with increased risks of anxiety/depression (HR: 2.36, 95% CI: 2.20 to 2.53), self-harm (HR: 5.70, 95% CI: 5.07 to 6.40), alcohol (HR: 3.95, 95% CI: 3.42 to 4.56), drug use (HR: 5.88, 95% CI: 5.08 to 6.80) and emergency department service use (HR: 1.36, 95% CI: 1.31 to 1.41). Those with ASD were at increased risk of anxiety/depression (HR: 2.11, 95% CI: 1.91 to 2.34), self-harm (HR: 2.93, 95% CI: 2.45 to 3.50) and drug use (HR: 2.21, 95% CI: 1.66 to 2.95) but not alcohol use. The ADHD e-cohort were similar to the directly assessed cohort. CONCLUSIONS: Our identification strategy demonstrated the feasibility of establishing a large e-cohort of those with ADHD/ASD with expected patterns of poorer early adult outcomes, demonstrating a valid method of identifying large samples for future longitudinal studies without selective attrition.

Validation of the Strengths and Difficulties Questionnaire (SDQ) emotional subscale in assessing depression and anxiety across development.

Emotional disorders are common in childhood, and their prevalence sharply increases during adolescence. The Strengths and Difficulties Questionnaire (SDQ) is widely used for screening emotional and behavioural difficulties in children and young people, but little is known about the accuracy of the emotional subscale (SDQ-E) in detecting emotional disorders, and whether this changes over development. Such knowledge is important in determining whether symptom changes across age are due to developmental or measurement differences. This study assessed the validity of the SDQ-E and two individual items (low mood and general worry) in differentiating between cases and non-cases of Major Depressive Disorder (MDD), Generalised Anxiety Disorder (GAD), and other anxiety disorders across ages 7, 10, 13, 15, and 25 years in a UK population cohort. Analyses showed moderate accuracy of the subscale in discriminating cases of MDD (AUC = 0.67-0.85), and high accuracy for discriminating cases of GAD (AUC = 0.80-0.93) and any anxiety disorder (AUC = 0.74-0.83) compared to non-cases. The SDQ-E performed well across ages and sex, and generally performed better than the two individual items. Together our findings validate the SDQ-E as a screen for emotional disorders during childhood, adolescence, and early adulthood, and as a tool for longitudinal research on depression and anxiety disorders.

Childhood attention-deficit hyperactivity disorder problems and mid-life cardiovascular risk: prospective population cohort study.

BACKGROUND: It is well-known that childhood attention-deficit hyperactivity disorder (ADHD) is associated with later adverse mental health and social outcomes. Patient-based studies suggest that ADHD may be associated with later cardiovascular disease (CVD) but the focus of preventive interventions is unclear. It is unknown whether ADHD leads to established cardiovascular risk factors because so few cohort studies measure ADHD and also follow up to an age where CVD risk is evident. AIMS: To examine associations between childhood ADHD problems and directly measured CVD risk factors at ages 44/45 years in a UK population-based cohort study (National Child Development Study) of individuals born in 1958. METHOD: Childhood ADHD problems were defined by elevated ratings on both the parent Rutter A scale and a teacher-rated questionnaire at age 7 years. Outcomes were known cardiovascular risk factors (blood pressure, lipid measurements, body mass index and smoking) at the age 44/45 biomedical assessment. RESULTS: Of the 8016 individuals assessed both during childhood and at the biomedical assessment 3.0% were categorised as having childhood ADHD problems. ADHD problems were associated with higher body mass index (B = 0.92 kg/m2, s.d. = 0.27-1.56), systolic (3.5 mmHg, s.d. = 1.4-5.6) and diastolic (2.2 mmHg, s.d. = 0.8-3.6) blood pressure, triglyceride levels (0.24 mol/l, s.d. = 0.02-0.46) and being a current smoker (odds ratio OR = 1.6, s.d. = 1.2-2.1) but not with LDL cholesterol. CONCLUSIONS: Childhood ADHD problems predicted multiple cardiovascular risk factors by mid-life. These findings, when taken together with previously observed associations with cardiovascular disease in registries, suggest that individuals with ADHD could benefit from cardiovascular risk monitoring, given these risk factors are modifiable with timely intervention.

Co-development of attention deficit hyperactivity disorder and autistic trait trajectories from childhood to early adulthood.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) and autism, defined as traits or disorders, commonly co-occur. Developmental trajectories of ADHD and autistic traits both show heterogeneity in onset and course, but little is known about how symptom trajectories co-develop into adulthood. METHODS: Using data from a population cohort, the Avon Longitudinal Study of Parents and Children, we examined correlations between ADHD and autistic traits across development, using the Social Communication Disorders Checklist and ADHD subscale of the Strengths and Difficulties Questionnaire. We modelled joint developmental trajectories of parent-reported ADHD and autistic traits between 4 and 25 years, then characterised trajectory classes based on sociodemographic, perinatal, psychopathology, cognition and social functioning variables and tested for associations with neurodevelopmental/psychiatric polygenic scores (PGS). RESULTS: Three classes of trajectories were identified; a typically developing majority with low-stable ADHD-autistic traits (87%), a male-predominant subgroup with child/adolescent-declining traits (6%) and a subgroup with late-emerging traits (6%). ADHD-autistic trait correlations were greatest in young adulthood for the two nontypically developing classes. There were higher rates of emotional and conduct problems, low IQ, childhood seizures and poor social functioning in the declining and late-emerging classes compared to the low-stable class. Emotional, conduct and peer problems were more prevalent during childhood in the childhood/adolescent-declining class compared to other classes, but were more prevalent in young adulthood in the late-emerging class. Neurodevelopmental/psychiatric PGS also differed: both nontypically developing classes showed elevated ADHD PGS compared to the low-stable group, and the late-emerging group additionally showed elevated schizophrenia PGS and decreased executive function PGS, whereas the declining group showed elevated broad depression PGS. CONCLUSIONS: Distinct patterns of ADHD-autism co-development are present across development in the general population, each with different characterising factors and genetic signatures as indexed by PGS.

Characterising depression trajectories in young people at high familial risk of depression.

BACKGROUND: Parental depression is a common and potent risk factor for depression in offspring. However, the developmental course of depression from childhood to early-adulthood has not been characterized in this high-risk group. METHODS: Using longitudinal data from 337 young people who had a parent with a history of recurrent major depressive disorder (MDD), we characterized trajectories of broadly defined depressive disorder using latent class growth analysis. We used clinical descriptions to further characterise trajectory classes. RESULTS: Two trajectory classes were identified: childhood-emerging (25 %) and adulthood-emerging (75 %). The childhood-emerging class showed high rates of depressive disorder from age 12.5, which persisted through the study period. The adulthood-emerging class showed low rates of depressive disorder until age 26. Individual factors (IQ and ADHD symptoms) and parent depression severity (comorbidity, persistence and impairment) differentiated the classes but there were no differences in family history score or polygenic scores associated with psychiatric disorder. Clinical descriptions indicated functional impairment in both classes, but more severe symptomatology and impairment in the childhood-emerging class. LIMITATIONS: Attrition particularly affected participation in young adulthood. Factors associated with attrition were low family income, single parent household status and low parental education. CONCLUSIONS: The developmental course of depressive disorder in children of depressed parents is variable. When followed up to adult life, most individuals exhibited some functional impairment. An earlier age-of-onset was associated with a more persistent and impairing course of depression. Access to effective prevention strategies is particularly warranted for at-risk young people showing early-onsetting and persistent depressive symptoms.

Investigating young-adult social outcomes of attention deficit hyperactivity disorder.

Objective: Attention Deficit Hyperactivity Disorder (ADHD) is associated with a range of adverse outcomes in adult life. However it is unclear whether the risk pathways to adverse adult outcomes are established during childhood or whether associations are driven by concurrent ADHD symptoms that have persisted to adulthood. Methods: We examined associations between broadly defined child-limited (remitted) and persistent ADHD (assessed using the ADHD subscale of the Strengths and Difficulties Questionnaire) with social outcomes (low emotional and instrumental support, antisocial behaviour, employment, receipt of state benefits as an indicator of socio-economic disadvantage, homelessness) at age 25 years in a UK longitudinal population sample ALPSAC (the Avon Longitudinal Study of Parents and Children, age 25 data collected between years 2017 and 2018): total N=6439. Results: Up to 20% of young-people with less favourable social outcomes at age 25 had persistent ADHD. Persistent ADHD was associated with an increased likelihood of being not in education, employment or training (NEET: OR=3.71, 95% CI=2.06 to 6.67, p=1x10-05) and receiving state benefits (OR=2.72, 95% CI=1.62 to 4.57, p=2x10-04) at age 25 years compared to those without ADHD. We did not find strong evidence of associations between child-limited ADHD and social outcomes (NEET OR=1.20, 95% CI=0.54 to 2.69, p=0.65; state benefits OR=1.38, 95% CI=0.76 to 2.51, p=0.29). Persistent ADHD associations with negative social outcomes were observed across family-of-origin income groups, sex and were not explained by comorbidity. Conclusion: Our findings highlight the importance of continued monitoring and management of ADHD symptoms and related social as well as clinical outcomes across development into adulthood. Future research is needed to identify what factors promote positive social outcomes, including effective treatment of adult ADHD symptoms.

Mental-health before and during the COVID-19 pandemic in adults with neurodevelopmental disorders.

The COVID-19 pandemic negatively impacted mental health globally. Individuals with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), are at elevated risk of mental health difficulties. We investigated the impact of the pandemic on anxiety, depression and mental wellbeing in adults with NDDs using data from the Avon Longitudinal Study of Parents and Children (n = 3058). Mental health data were collected pre-pandemic (age 21-25) and at three timepoints during the pandemic (ages 27-28) using the Short Mood and Feelings Questionnaire, Generalized Anxiety Disorder Assessment-7, and Warwick Edinburgh Mental Wellbeing Scale. ADHD and ASD were defined using validated cut-points of the Strengths and Difficulties Questionnaire and Autism Spectrum Quotient, self-reported at age 25. We used multi-level mixed-effects models to investigate changes in mental health in those with elevated ADHD/ASD traits compared to those without. Prevalences of depression, anxiety and poor mental wellbeing were higher at all timepoints (pre-pandemic and during pandemic) in those with ADHD and ASD compared to those without. Anxiety increased to a greater extent in those with ADHD (ß = 0.8 [0.2,1.4], p = 0.01) and ASD (ß = 1.2 [-0.1,2.5], p = 0.07), while depression symptoms decreased, particularly in females with ASD (ß = -3.1 [-4.6,-1.5], p = 0.0001). On average, mental wellbeing decreased in all, but to a lesser extent in those with ADHD (ß = 1.3 [0.2,2.5], p = 0.03) and females with ASD (ß = 3.0 [0.2,5.9], p = 0.04). To conclude, anxiety disproportionately increased in adults with NDDs during the pandemic, however, the related lockdowns may have provided a protective environment for depressive symptoms in the same individuals.

Young-Adult Social Outcomes of Attention-Deficit/Hyperactivity Disorder.

Objective: Attention-deficit/hyperactivity disorder (ADHD) is associated with a range of adverse outcomes in adult life. However, it is unclear whether the risk pathways to adverse adult outcomes are established during childhood or whether associations are driven by concurrent ADHD symptoms that have persisted to adulthood.Methods: We examined associations between broadly defined child-limited (remitted) and persistent ADHD (assessed using the ADHD subscale of the Strengths and Difficulties Questionnaire) with negative social outcomes (low emotional and instrumental support, antisocial behavior, employment, receipt of state benefits as an indicator of socio-economic disadvantage, homelessness) at age 25 years in a UK longitudinal population sample, the Avon Longitudinal Study of Parents and Children (age 25 data collected between years 2017 and 2018; total N = 6,439).Results: Up to 20% of young people with less favorable social outcomes at age 25 had persistent ADHD. Persistent ADHD was associated with an increased likelihood of being not in education, employment, or training (NEET) (OR = 3.71, 95% CI = 2.06 to 6.67, P = 1 × 10-05) and receiving state benefits (OR = 2.72, 95% CI = 1.62 to 4.57, P = 2 × 10-04) at age 25 years compared to those without ADHD. We did not find strong evidence of associations between child-limited ADHD and social outcomes (NEET OR = 1.20, 95% CI = 0.54 to 2.69, P = .65; state benefits OR = 1.38, 95% CI = 0.76 to 2.51, P = .29). Persistent ADHD associations with negative social outcomes were observed across family-of-origin income groups and sex and were not explained by comorbidity.Conclusions: Our findings highlight the importance of continued monitoring and management of ADHD symptoms and related social as well as clinical outcomes across development into adulthood. Future research is needed to identify what factors promote positive social outcomes, including effective treatment of adult ADHD symptoms.

Practitioner Review: Attention-deficit hyperactivity disorder and autism spectrum disorder - the importance of depression.

Young people with neurodevelopmental disorders, such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), show high rates of mental health problems, of which depression is one of the most common. Given that depression in ASD and ADHD is linked with a range of poor outcomes, knowledge of how clinicians should assess, identify and treat depression in the context of these neurodevelopmental disorders is much needed. Here, we give an overview of the latest research on depression in young people with ADHD and ASD, including possible mechanisms underlying the link between ADHD/ASD and depression, as well as the presentation, assessment and treatment of depression in these neurodevelopmental disorders. We discuss the implications for clinicians and make recommendations for critical future research in this area.

Preschool development, temperament and genetic liability as early markers of childhood ADHD: A cohort study.

Background: ADHD is associated with multiple adverse outcomes and early identification is important. The present study sets out to identify early markers and developmental characteristics during the first 30 months of life that are associated with ADHD 6 years later. Methods: 9201 participants from the prospective Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were included. Outcome measures were parent-rated ADHD symptom scores (Strengths and Difficulties Questionnaire, SDQ) and ADHD diagnosis (Development and Wellbeing Assessment, DAWBA) at age 7. Seventeen putative markers were identified from previous literature and included: pre- and peri-natal risk factors, genetic liability (ADHD polygenic risk scores, PRS), early development, temperament scores and regulatory problems. Associations were examined using regression analysis. Results: Univariable regression analysis showed that multiple early life factors were associated with future ADHD outcomes, even after controlling for sex and socio-economic status. In a multivariable linear regression model; temperament activity scores (B = 0.107, CI = 0.083-0.132), vocabulary delay (B = 0.605, CI = 0.211-0.988), fine motor delay (B = 0.693, CI = 0.360-1.025) and ADHD PRS (B = 0.184, CI = 0.074-0.294) were associated with future symptoms (R 2 = 10.7%). In a multivariable logistic regression model, ADHD PRS (OR = 1.39, CI = 1.10-1.77) and temperament activity scores (OR = 1.09, CI = 1.04-1.16) showed association with ADHD diagnosis. Conclusion: As well as male sex and lower socio-economic status, high temperament activity levels and motor and speech delays in the first 30 months of life, are associated with childhood ADHD. Intriguingly, given that genetic risk scores are known to explain little of the variance of ADHD outcomes, we found that ADHD PRS added useful predictive information. Future research needs to test whether predictive models incorporating aspects of early development and genetic risk scores are useful for predicting ADHD in clinical practice.

Early manifestations of genetic liability for ADHD, autism and schizophrenia at ages 18 and 24 months.

Background: ADHD and autism are neurodevelopmental conditions, for which non-specific precursors or early signs include difficulties with language and motor skills, and differences in temperament in the first and second year of life. These early features have also been linked to later diagnosis of schizophrenia which is widely considered to have neurodevelopmental origins. Given that ADHD, autism and schizophrenia are all highly heritable, we tested the hypothesis that in the general population, measures of toddler language development, motor development and temperament are associated with genetic liability to ADHD, autism and/or schizophrenia. Methods: Data were analysed from the Avon Longitudinal Study of Parents and Children (ALSPAC) which included motor development scores at age 18 months and language development and temperament scores at age 24 months (N=7498). Genetic liability was indexed by polygenic risk scores (PGS) for ADHD, autism and schizophrenia. Results: ADHD PGS were associated with specific temperament scales (higher activity ß=0.07, 95% CI=0.04, 0.09 and lower withdrawal ß=-0.05, 95% CI=-0.07, -0.02) as well as better gross motor scores (ß=0.04, 95% CI=0.01, 0.06). Schizophrenia PGS were associated with one specific temperament scale (negative mood ß=0.04, 95% CI=0.02, 0.07). We did not find strong evidence of association of autism PGS with any of the toddler measures; there was also not strong evidence of association with motor or language delays for any of the PGS. Conclusions: This study suggests that some specific aspects of early temperament and gross motor differences in the general population could represent part of the early manifestation of genetic liability to neurodevelopmental conditions.

Using genetic designs to identify likely causal environmental contributions to psychopathology.

The multifactorial nature of psychopathology, whereby both genetic and environmental factors contribute risk, has long been established. In this paper, we provide an update on genetically informative designs that are utilized to disentangle genetic and environmental contributions to psychopathology. We provide a brief reminder of quantitative behavioral genetic research designs that have been used to identify potentially causal environmental processes, accounting for genetic contributions. We also provide an overview of recent molecular genetic approaches that utilize genome-wide association study data which are increasingly being applied to questions relevant to psychopathology research. While genetically informative designs typically have been applied to investigate the origins of psychopathology, we highlight how these approaches can also be used to elucidate potential causal environmental processes that contribute to developmental course and outcomes. We highlight the need to use genetically sensitive designs that align with intervention and prevention science efforts, by considering strengths-based environments to investigate how positive environments can mitigate risk and promote children's strengths.

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.

Longitudinally stable, brain-based predictive models mediate the relationships between childhood cognition and socio-demographic, psychological and genetic factors.

Cognitive abilities are one of the major transdiagnostic domains in the National Institute of Mental Health's Research Domain Criteria (RDoC). Following RDoC's integrative approach, we aimed to develop brain-based predictive models for cognitive abilities that (a) are developmentally stable over years during adolescence and (b) account for the relationships between cognitive abilities and socio-demographic, psychological and genetic factors. For this, we leveraged the unique power of the large-scale, longitudinal data from the Adolescent Brain Cognitive Development (ABCD) study (n ~ 11 k) and combined MRI data across modalities (task-fMRI from three tasks: resting-state fMRI, structural MRI and DTI) using machine-learning. Our brain-based, predictive models for cognitive abilities were stable across 2 years during young adolescence and generalisable to different sites, partially predicting childhood cognition at around 20% of the variance. Moreover, our use of 'opportunistic stacking' allowed the model to handle missing values, reducing the exclusion from around 80% to around 5% of the data. We found fronto-parietal networks during a working-memory task to drive childhood-cognition prediction. The brain-based, predictive models significantly, albeit partially, accounted for variance in childhood cognition due to (1) key socio-demographic and psychological factors (proportion mediated = 18.65% [17.29%-20.12%]) and (2) genetic variation, as reflected by the polygenic score of cognition (proportion mediated = 15.6% [11%-20.7%]). Thus, our brain-based predictive models for cognitive abilities facilitate the development of a robust, transdiagnostic research tool for cognition at the neural level in keeping with the RDoC's integrative framework.

Decline in attention-deficit hyperactivity disorder traits over the life course in the general population: trajectories across five population birth cohorts spanning ages 3 to 45 years.

BACKGROUND: Trajectories of attention-deficit hyperactivity disorder (ADHD) traits spanning early childhood to mid-life have not been described in general populations across different geographical contexts. Population trajectories are crucial to better understanding typical developmental patterns. METHODS: We combined repeated assessments of ADHD traits from five population-based cohorts, spanning ages 3 to 45 years. We used two measures: (i) the Strengths and Difficulties Questionnaire (SDQ) hyperactive-inattentive subscale (175 831 observations, 29 519 individuals); and (ii) scores from DSM-referenced scales (118 144 observations, 28 685 individuals). Multilevel linear spline models allowed for non-linear change over time and differences between cohorts and raters (parent/teacher/self). RESULTS: Patterns of age-related change differed by measure, cohort and country: overall, SDQ scores decreased with age, most rapidly declining before age 8 years (-0.157, 95% CI: -0.170, -0.144 per year). The pattern was generally consistent using DSM scores, although with greater between-cohort variation. DSM scores decreased most rapidly between ages 14 and 17 years (-1.32%, 95% CI: -1.471, -1.170 per year). Average scores were consistently lower for females than males (SDQ: -0.818, 95% CI: -0.856, -0.780; DSM: -4.934%, 95% CI: -5.378, -4.489). This sex difference decreased over age for both measures, due to an overall steeper decrease for males. CONCLUSIONS: ADHD trait scores declined from childhood to mid-life, with marked variation between cohorts. Our results highlight the importance of taking a developmental perspective when considering typical population traits. When interpreting changes in clinical cohorts, it is important to consider the pattern of expected change within the general population, which is influenced by cultural context and measurement.