Polygenic liabilities and treatment trajectories in early-onset depression: a Danish register-based study.

BACKGROUND: The clinical course of major depressive disorder (MDD) is heterogeneous, and early-onset MDD often has a more severe and complex clinical course. Our goal was to determine whether polygenic scores (PGSs) for psychiatric disorders are associated with treatment trajectories in early-onset MDD treated in secondary care. METHODS: Data were drawn from the iPSYCH2015 sample, which includes all individuals born in Denmark between 1981 and 2008 who were treated in secondary care for depression between 1995 and 2015. We selected unrelated individuals of European ancestry with an MDD diagnosis between ages 10-25 (N = 10577). Seven-year trajectories of hospital contacts for depression were modeled using Latent Class Growth Analysis. Associations between PGS for MDD, bipolar disorder, schizophrenia, ADHD, and anorexia and trajectories of MDD contacts were modeled using multinomial logistic regressions. RESULTS: We identified four trajectory patterns: brief contact (65%), prolonged initial contact (20%), later re-entry (8%), and persistent contact (7%). Relative to the brief contact trajectory, higher PGS for ADHD was associated with a decreased odds of membership in the prolonged initial contact (odds ratio = 1.06, 95% confidence interval = 1.01-1.11) and persistent contact (1.12, 1.03-1.21) trajectories, while PGS-AN was associated with increased odds of membership in the persistent contact trajectory (1.12, 1.03-1.21). CONCLUSIONS: We found significant associations between polygenic liabilities for psychiatric disorders and treatment trajectories in patients with secondary-treated early-onset MDD. These findings help elucidate the relationship between a patient's genetics and their clinical course; however, the effect sizes are small and therefore unlikely to have predictive value in clinical settings.

Testing maternal effects of vitamin-D and omega-3 levels on offspring neurodevelopmental traits in the Norwegian Mother, Father and Child Cohort Study.

BACKGROUND: Maternal vitamin-D and omega-3 fatty acid (DHA) deficiencies during pregnancy have previously been associated with offspring neurodevelopmental traits. However, observational study designs cannot distinguish causal effects from confounding. METHODS: First, we conducted Mendelian randomisation (MR) using genetic instruments for vitamin-D and DHA identified in independent genome-wide association studies (GWAS). Outcomes were (1) GWAS for traits related to autism and ADHD, generated in the Norwegian mother, father, and child cohort study (MoBa) from 3 to 8 years, (2) autism and ADHD diagnoses. Second, we used mother-father-child trio-MR in MoBa (1) to test causal effects through maternal nutrient levels, (2) to test effects of child nutrient levels, and (3) as a paternal negative control. RESULTS: Associations between higher maternal vitamin-D levels on lower ADHD related traits at age 5 did not remain after controlling for familial genetic predisposition using trio-MR. Furthermore, we did not find evidence for causal maternal effects of vitamin-D/DHA levels on other offspring traits or diagnoses. In the reverse direction, there was evidence for a causal effect of autism genetic predisposition on lower vitamin-D levels and of ADHD genetic predisposition on lower DHA levels. CONCLUSIONS: Triangulating across study designs, we did not find evidence for maternal effects. We add to a growing body of evidence that suggests that previous observational associations are likely biased by genetic confounding. Consequently, maternal supplementation is unlikely to influence these offspring neurodevelopmental traits. Notably, genetic predisposition to ADHD and autism was associated with lower DHA and vitamin-D levels respectively, suggesting previous associations might have been due to reverse causation.

Investigating the neurodevelopmental correlates of early adolescent-onset emotional problems.

BACKGROUND: Emotional problems (EPs) increase sharply after mid-adolescence. Earlier EPs are associated with poorer long-term outcomes, and their underlying mechanisms may differ to later-onset EPs. Given an established relationship between ADHD, autism, and later depression, we aimed to examine associations between neurodevelopmental conditions and correlates and early adolescent-onset EPs. METHODS: Adolescents in two UK population cohorts, Avon Longitudinal Study of Parents and Children (ALSPAC) and Millennium Cohort Study (MCS), were included. Individuals scoring >6 on the Strengths and Difficulties Questionnaire (SDQ) emotional problems subscale between ages 11-14 were defined as having early adolescent-onset EP, whilst those scoring >6 for the first time at 16-25 were defined as having later-onset EP. We tested associations between early adolescent-onset EP (total cases = 887, controls = 19,582) and ICD-10/DSM-5 neurodevelopmental conditions and known correlates, including: sex, birth complications, low cognitive ability, special educational needs (SEND), and epilepsy. Analyses were conducted separately in ALSPAC and MCS then meta-analysed. RESULTS: In the meta-analysis of both cohorts, early adolescent-onset EPs were associated with female sex and greater likelihood of low cognitive ability, SEND, autism, ADHD, and reading difficulties. Compared to later-onset EP, early adolescent-onset EPs were associated with male sex, low cognitive ability, SEND, epilepsy, ASD, ADHD, and reading difficulties. LIMITATIONS: A clinical definition of depression/anxiety was available only in ALSPAC, instead we primarily defined EP via questionnaires, which capture a broader phenotype. CONCLUSIONS: Individuals with early adolescent-onset EP are likely to have a co-occurring neurodevelopmental condition. Clinicians should consider assessing for neurodevelopmental conditions in young adolescents with EPs.

Sex differences in attention-deficit hyperactivity disorder diagnosis and clinical care: a national study of population healthcare records in Wales.

BACKGROUND: Population-based studies have observed sex biases in the diagnosis and treatment of attention-deficit hyperactivity disorder (ADHD). Females are less likely to be diagnosed or prescribed ADHD medication. This study uses national healthcare records, to investigate sex differences in diagnosis and clinical care in young people with ADHD, particularly regarding recognition and treatment of other mental health conditions. METHODS: The cohort included individuals diagnosed with ADHD, born between 1989 and 2013 and living in Wales between 2000 and 2019. Routine primary and secondary healthcare record data were used to derive diagnoses of ADHD and other neurodevelopmental and mental health conditions, as well as ADHD and antidepressant medications. Demographic variables included ethnicity, socioeconomic deprivation and contact with social services. RESULTS: There were 16,458 individuals diagnosed with ADHD (20.3% females, ages 3-30 years), with a male-to-female ratio of 3.9:1. Higher ratios (4.8:1) were seen in individuals diagnosed younger (<12 years), with the lowest ratio (1.9:1) in those diagnosed as adults (>18). Males were younger at first recorded ADHD diagnosis (mean = 10.9 vs. 12.6 years), more likely to be prescribed ADHD medication and younger at diagnosis of co-occurring neurodevelopmental conditions. In contrast, females were more likely to receive a diagnosis of anxiety, depression or another mental health condition and to be prescribed antidepressant medications, prior to ADHD diagnosis. These sex differences were largely stable across demographic groups. CONCLUSIONS: This study adds to the evidence base that females with ADHD are experiencing later recognition and treatment of ADHD. The results indicate that this may be partly because of diagnostic overshadowing from other mental health conditions, such as anxiety and depression, or initial misdiagnosis. Further research and dissemination of findings to the public are needed to improve awareness, timely diagnosis and treatment of ADHD in females.

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.

Irritability in Youths: A Critical Integrative Review.

Irritability, defined as proneness to anger that may impair an individual's functioning, is common in youths. There has been a recent upsurge in relevant research. The authors combine systematic and narrative review approaches to integrate the latest clinical and translational findings and provide suggestions for addressing research gaps. Clinicians and researchers should assess irritability routinely, and specific assessment tools are now available. Informant effects are prominent, are stable, and vary by age and gender. The prevalence of irritability is particularly high among individuals with attention deficit hyperactivity disorder, autism spectrum disorder, and mood and anxiety disorders. Irritability is associated with impairment and suicidality risk independent of co-occurring diagnoses. Developmental trajectories of irritability (which may begin early in life) have been identified and are differentially associated with clinical outcomes. Youth irritability is associated with increased risk of anxiety, depression, behavioral problems, and suicidality later in life. Irritability is moderately heritable, and genetic associations differ based on age and comorbid illnesses. Parent management training is effective for treating psychological problems related to irritability, but its efficacy in treating irritability should be tested rigorously, as should novel mechanism-informed interventions (e.g., those targeting exposure to frustration). Associations between irritability and suicidality and the impact of cultural context are important, underresearched topics. Analyses of large, diverse longitudinal samples that extend into adulthood are needed. Data from both animal and human research indicate that aberrant responses to frustration and threat are central to the pathophysiology of irritability, revealing important translational opportunities.

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.

Attention-Deficit/Hyperactivity Disorder and Major Depressive Disorder: Evidence From Multiple Genetically Informed Designs.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) are two highly prevalent disorders that frequently co-occur. Prior evidence from genetic and cohort studies supports an association between ADHD and MDD. However, the direction and mechanisms underlying their association remain unclear. As onset of ADHD occurs in early life, it has been hypothesized that ADHD may cause MDD. METHODS: We examined the association of ADHD with MDD using 3 different genetically informed methods to disentangle causality from confounding: 1) a nationwide longitudinal register-based full sibling comparison (N = 1,018,489) adjusting for shared familial confounding; 2) a prospective co-twin control study comprising 16,477 twins (5084 monozygotic and 11,393 dizygotic); and 3) a two-sample Mendelian randomization analysis using the largest available ADHD (N = 225,534) and MDD (N = 500,199) genome-wide association study summary statistics, adjusting for correlated and uncorrelated horizontal pleiotropy. RESULTS: Sibling and twin comparisons indicated that individuals with ADHD have an increased risk for subsequent development of MDD (hazard ratio = 4.12 [95% CI 3.62-4.69]) after adjusting for shared genetic and familial factors and that ADHD scores endorsed by parents are positively associated with subsequent MDD scores at ages 15 and 18 years (b = 0.07 [95% CI 0.05-0.08] and b = 0.09 [95% CI 0.08-0.11], respectively). Mendelian randomization analyses showed that genetic liability for ADHD is causally related to MDD (odds ratio = 1.15 [95% CI 1.08-1.23]). CONCLUSIONS: Our study provides consistent results across 3 different genetically informative approaches, strengthening the hypothesis that ADHD is causally related to MDD.

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.

Following the children of depressed parents from childhood to adult life: A focus on mood and anxiety disorders.

Background: Parental depression increases risk for anxiety and depression in offspring. The transition from adolescence to adulthood is a common risk period for onset of such disorders. However, relatively few studies have considered development of these disorders from childhood to adulthood including multiple assessments during this transition period. Method: Offspring of depressed parents aged 9-17 years at baseline were followed prospectively for 13 years (n = 337). Average length of follow-up was 16 months between the first and second waves, 13 months between the second and third, and 8 years between the third and fourth. Current (3-month) psychopathology was assessed at each wave using diagnostic interviews. We derived estimates of 3-month prevalence, age at first diagnosis, course and comorbidity of disorders. Social functioning in adult life was assessed at the final wave and we assessed how prior and current disorder impacted adult functioning. Results: A quarter of young people met criteria for a mood disorder and a third for anxiety disorder at least once. Mood and anxiety disorder prevalence increased from 4.5% and 15.8% respectively in childhood (9-11 years) to 22.3% and 20.9% respectively by age 23-28. Increased prevalence across the transition from adolescence to adulthood was particularly marked in males, while prevalence increased earlier in adolescence in females. Age at first diagnosis varied widely (mood disorder mean = 16.5 years (range 9-26); anxiety disorder mean = 14.5 years (range 9-28)). Over half (52%) reported functional impairment in early adulthood, 31% harmful alcohol use, and 10% self-harm or a suicide attempt. Both previous and current mood or anxiety disorder were associated with functional impairment in early adulthood. Conclusions: There is a prolonged risk period for mood and anxiety disorders in this group, with prevalence peaking in early adulthood. This highlights the need for prolonged vigilance and effective targeted interventions in the offspring of depressed parents.

Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD.

Autism spectrum disorder (ASD), Tourette syndrome (TS), and attention-deficit/hyperactivity disorder (ADHD) display strong male sex bias, due to a combination of genetic and biological factors, as well as selective ascertainment. While the hemizygous nature of chromosome X (Chr X) in males has long been postulated as a key point of "male vulnerability", rare genetic variation on this chromosome has not been systematically characterized in large-scale whole exome sequencing studies of "idiopathic" ASD, TS, and ADHD. Here, we take advantage of informative recombinations in simplex ASD families to pinpoint risk-enriched regions on Chr X, within which rare maternally-inherited damaging variants carry substantial risk in males with ASD. We then apply a modified transmission disequilibrium test to 13,052 ASD probands and identify a novel high confidence ASD risk gene at exome-wide significance (MAGEC3). Finally, we observe that rare damaging variants within these risk regions carry similar effect sizes in males with TS or ADHD, further clarifying genetic mechanisms underlying male vulnerability in multiple neurodevelopmental disorders that can be exploited for systematic gene discovery.

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.

Practitioner Review: Clinical utility of the QbTest for the assessment and diagnosis of attention-deficit/hyperactivity disorder - a systematic review and meta-analysis.

BACKGROUND: Several computerised cognitive tests (e.g. continuous performance test) have been developed to support the clinical assessment of attention-deficit/hyperactivity disorder (ADHD). Here, we appraised the evidence-base underpinning the use of one of these tests - the QbTest - in clinical practice, by conducting a systematic review and meta-analysis investigating its accuracy and clinical utility. METHODS: Based on a preregistered protocol (CRD42022377671), we searched PubMed, Medline, Ovid Embase, APA PsycINFO and Web of Science on 15th August 2022, with no language/type of document restrictions. We included studies reporting accuracy measures (e.g. sensitivity, specificity, or Area under the Receiver Operating Characteristics Curve, AUC) for QbTest in discriminating between people with and without DSM/ICD ADHD diagnosis. Risk of bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2). A generic inverse variance meta-analysis was conducted on AUC scores. Pooled sensitivity and specificity were calculated using a random-effects bivariate model in R. RESULTS: We included 15 studies (2,058 participants; 48.6% with ADHD). QbTest Total scores showed acceptable, rather than good, sensitivity (0.78 [95% confidence interval: 0.69; 0.85]) and specificity (0.70 [0.57; 0.81]), while subscales showed low-to-moderate sensitivity (ranging from 0.48 [0.35; 0.61] to 0.65 [0.52; 0.75]) and moderate-to-good specificity (from 0.65 [0.48; 0.78] to 0.83 [0.60; 0.94]). Pooled AUC scores suggested moderate-to-acceptable discriminative ability (Q-Total: 0.72 [0.57; 0.87]; Q-Activity: 0.67 [0.58; 0.77); Q-Inattention: 0.66 [0.59; 0.72]; Q-Impulsivity: 0.59 [0.53; 0.64]). CONCLUSIONS: When used on their own, QbTest scores available to clinicians are not sufficiently accurate in discriminating between ADHD and non-ADHD clinical cases. Therefore, the QbTest should not be used as stand-alone screening or diagnostic tool, or as a triage system for accepting individuals on the waiting-list for clinical services. However, when used as an adjunct to support a full clinical assessment, QbTest can produce efficiencies in the assessment pathway and reduce the time to diagnosis.

Networks of Neurodevelopmental Traits, Socioenvironmental Factors, Emotional Dysregulation in Childhood, and Depressive Symptoms Across Development in Two U.K. Cohorts.

OBJECTIVE: Previous population-based studies have identified associations between childhood neurodevelopmental traits and depression in childhood, adolescence, and young adulthood. However, neurodevelopmental traits are highly correlated with each other, which could confound associations when traits are examined in isolation. The authors sought to identify unique associations between multiple neurodevelopmental traits in childhood and depressive symptoms across development, while taking into account co-occurring difficulties, in multivariate analyses. METHODS: Data from two U.K. population-based cohorts, the Twins Early Development Study (TEDS) (N=4,407 independent twins) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (N=10,351), were independently analyzed. Bayesian Gaussian graphical models were estimated to investigate pairwise conditional associations between neurodevelopmental traits (autism and ADHD symptoms and general cognitive, learning, and communication abilities), socioenvironmental stressors (academic performance and peer relations), and emotional dysregulation in childhood (ages 7-11) and depressive symptoms across development (ages 12, 16, and 21). RESULTS: In both cohorts, bivariate correlations indicated several associations between neurodevelopmental traits and depressive symptoms across development. However, based on replicated findings across cohorts, these pairs of variables were mostly conditionally independent, and none were conditionally associated, after accounting for socioenvironmental stressors and emotional dysregulation. In turn, socioenvironmental stressors and emotional dysregulation were conditionally associated with both neurodevelopmental traits and depressive symptoms. Based on replicated findings across cohorts, neurodevelopmental traits in childhood could be associated only indirectly with depressive symptoms across development. CONCLUSIONS: This study indicates that associations between childhood neurodevelopmental traits and depressive symptoms across development could be explained by socioenvironmental stressors and emotional dysregulation. The present findings could inform future research aimed at the prevention of depression in youths with neurodevelopmental disorders.

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.

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

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