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Altered serum levels of brain-derived neurotrophic factor (BDNF) are consistently linked with neurological disorders. BDNF is also increasingly implicated in the pathogenesis of neurodevelopmental disorders, particularly those found more frequently in males. At birth, male infants naturally have significantly lower serum BDNF levels (∼10-20% lower than females), which may render them more vulnerable to neurodevelopmental disorders. We previously characterized serum BDNF levels in mothers and their newborn infants as part of the Grown in Wales Study. Here, we analyzed whether cord serum BDNF levels at birth correlate with sex-specific outcomes at one year. The Bayley Scale of Infant Development, Third Edition (BSID-III) and Laboratory Temperament Assessment Battery (Lab-TAB) tasks were used to assess infant behavior and neurodevelopment at 12-14 months (mean ± SD: 13.3 ± 1.6 months; 46% male; n = 56). We found no relationship between serum BDNF levels at birth and BSID-III neurodevelopmental outcomes (cognitive or language), nor with infant behaviors in the Lab-TAB unpredictable mechanical toy or maternal separation tasks. In the sustained attention task, there was a significant positive relationship between serum BDNF and infant negative affect (B = 0.06, p = 0.018) and, for boys only, between serum BDNF and intensity of facial interest (B = 0.03, p = 0.005). However, only the latter remained after correction for multiple testing. This sex-specific association between cord serum BDNF and a parameter of attention at 12-14 months provides some support for the hypothesis that reduced serum BDNF levels at birth are linked to an increased risk for neurodevelopmental disorders.

It is unknown why attention deficit hyperactivity disorder (ADHD) is more common in males, whereas anxiety and depression show a female population excess. We tested the hypothesis that anxiety and depression risk alleles manifest as ADHD in males. We also tested whether anxiety and depression in children with ADHD show a different etiology to typical anxiety and depression and whether this differs by sex. The primary clinical ADHD sample consisted of 885 (14% female) children. Psychiatric symptoms were assessed using standardized interviews. Polygenic risk scores (PRS) were derived using large genetic studies. Replication samples included independent clinical ADHD samples (N = 3,794; 25.7% female) and broadly defined population ADHD samples (N = 995; 33.4% female). We did not identify sex differences in anxiety or depression PRS in children with ADHD. In the primary sample, anxiety PRS were associated with social and generalized anxiety in males, with evidence of a sex-by-PRS interaction for social anxiety. These results did not replicate in the broadly defined ADHD sample. Depression PRS were not associated with comorbid depression symptoms. The results suggest that anxiety and depression genetic risks are not more likely to lead to ADHD in males. Also, the evidence for shared etiology between anxiety symptoms in those with ADHD and typical anxiety was weak and needs replication.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are generally considered early-onset disorders so most research has therefore tended to focus on children. Differences between ADHD/ASD in adult life and childhood have been noted, but few population-based studies have examined them in adulthood. Furthermore, the interpretation of findings is hampered by changes in measure and from parent report to self-report.METHOD: We examined continuous/trait measures of parent- and self-rated ADHD and ASD in adulthood (age 25 years) in a UK prospective longitudinal sample ALPSAC (the Avon Longitudinal Study of Parents and Children), using many of the same measures that parents reported on in childhood (N = 6,064). Our aim was to investigate these traits in this population for mean-level sex differences, overlaps with other cognitive, learning and communication problems and their associations with polygenic risk scores (PRS) for neuropsychiatric disorders (ADHD, ASD, schizophrenia, depression and anxiety).RESULTS: ADHD and ASD traits in adulthood, as in childhood, showed associations with childhood cognitive, learning and communication problems and adult communication/language measures, although less so for self-ratings than parent-ratings. Males had higher ADHD and ASD trait levels, but this was not as marked as in childhood. In adulthood, ADHD (both parent- and self-rated) and ASD (parent-rated) symptoms showed associations with ADHD PRS; self-reported ADHD also showed association with depression PRS, whereas self-reported ASD did not show strong PRS associations.CONCLUSIONS: Our findings suggest that in young adults, ADHD and ASD symptoms have similar characteristics as they do in childhood. Associations with other cognitive, learning and communication problems, and ADHD PRS were somewhat less pronounced for self-reported adult ADHD and ASD symptoms, suggesting that even at age 25, parent reports, where available, could be clinically useful.

Background Maternal smoking in pregnancy is associated with low birth weight (LBW), child conduct problems, hyperactivity and lower cognitive attainment, but associations may reflect measured and unmeasured confounding. Cross-cohort designs can aid causal inference through comparison of associations across populations with different confounding structures. We compared associations between maternal smoking in pregnancy and child conduct and hyperactivity problems, cognition and LBW across two cohorts born four decades apart. Methods Two national UK cohorts born in 1958 (n = 12 415) and 2000/01 (n = 11 800) were compared. Maternal smoking in pregnancy and child birth weight was assessed at or shortly after birth. Parents rated children’s conduct problems and hyperactivity, and children completed standardized tests of reading and mathematics. Results Maternal smoking in pregnancy was less common and more strongly associated with social disadvantage in 2000/01 compared with 1958 (interactions P < 0.001). Maternal smoking in pregnancy was robustly and equivalently associated with infant LBW in both cohorts [interactions: boys odds ratio (OR) = 1.01 (0.89, 1.16), P = 0.838; girls OR = 1.01 (0.91, 1.17), P = 0.633]. Maternal smoking was more strongly associated with conduct problems, hyperactivity and reading in the 2000/01 cohort (interactions P < 0.001). Conclusions Marked cross-cohort change in associations between maternal smoking and child conduct problems, hyperactivity and reading highlights the likely role of confounding factors. In contrast, association with LBW was unaffected by change in prevalence of maternal smoking and patterns of confounding. The study highlights the utility of cross-cohort designs in helping triangulate conclusions about the role of putative causal risk factors in observational epidemiology.

Objective: To estimate phenotypic and familial association between early-life injuries and attention-deficit/hyperactivity disorder (ADHD) and the genetic contribution to the association using polygenic risk score for ADHD (PRS-ADHD) and genetic correlation analyses.Methods: Children born in Denmark between 1995-2010 (n = 786,543) were followed from age 5 years until a median age of 14 years (interquartile range: 10-18 years). Using ICD-10 diagnoses, we estimated hazard ratios (HRs) and absolute risks of ADHD by number of hospital/emergency ward-treated injuries by age 5. In a subset of ADHD cases and controls born 1995 to 2005 who had genetic data available (n = 16,580), we estimated incidence rate ratios (IRRs) for the association between PRS-ADHD and number of injuries before age 5 and the genetic correlation between ADHD and any injury before age 5.Results: Injuries were associated with ADHD (HR = 1.61; 95% CI, 1.55-1.66) in males (HR = 1.59; 1.53-1.65) and females (HR = 1.65; 1.54-1.77), with a dose-response relationship with number of injuries. The absolute ADHD risk by age 15 was 8.4% (3+ injuries) vs 3.1% (no injuries). ADHD was also associated with injuries in relatives, with a stronger association in first- than second-degree relatives. PRS-ADHD was marginally associated with the number of injuries in the general population (IRR = 1.06; 1.00-1.14), with a genetic correlation of 0.53 (0.21-0.85).Conclusions: Early-life injuries in individuals and their relatives were associated with a diagnosis of ADHD. However, even in children with the most injuries, more than 90% were not diagnosed with ADHD by age 15. Despite a low positive predictive value and that the impact of unmeasured factors such as parental behavior remains unclear, results indicate that the association is partly explained by genetics, suggesting that early-life injuries may represent or herald early behavioral manifestations of ADHD.

Context & Objectives The Controlled Antenatal Thyroid Screening (CATS) study was the first randomized controlled trial to investigate effects of treating suboptimal gestational thyroid function (SGTF) on child cognition. Since observational studies indicated that SGTF may also increase symptoms of autism and attention-deficit/hyperactivity disorder (ADHD), the CATS cohort was used to investigate whether treatment of mothers affected their children’s behavior. Design & Participants Mothers (N = 475) completed 3 questionnaires: the Strengths and Difficulties Questionnaire (SDQ), the Child ADHD Questionnaire, and the Social Communication Questionnaire (SCQ, used as a screen for autism spectrum disorder [ASD]), about their children (mean age 9.5 years). Group comparisons of total scores, numbers of children above clinical thresholds, and association between high maternal free thyroxine (FT4) (> 97.5th percentile of the UK cohort, “overtreated”) and child neurodevelopment were reported. Results There were no differences in total scores between normal gestational thyroid function (GTF) (n = 246), treated (n = 125), and untreated (n = 104) SGTF groups. More children of treated mothers scored above clinical thresholds, particularly the overtreated. Scores were above thresholds in SDQ conduct (22% vs 7%), SCQ total scores (7% vs 1%), and ADHD hyperactivity (17% vs 5%) when comparing overtreated (n = 40) and untreated (N = 100), respectively. We identified significantly higher mean scores for SDQ conduct (adjusted mean difference [AMD] 0.74; 95% confidence interval [CI], 0.021-1.431; P = 0.040, effect size 0.018) and ADHD hyperactivity (AMD 1.60, 95% CI, 0.361-2.633; P = 0.003, effect size 0.028) comparing overtreated with normal-GTF children. Conclusions There was no overall association between SGTF and offspring ADHD, ASD, or behavior questionnaire scores. However, children of “overtreated” mothers displayed significantly more ADHD symptoms and behavioral difficulties than those of normal-GTF mothers. Thyroxine supplementation during pregnancy requires monitoring to avoid overtreatment.

Objective:Autism spectrum disorder (ASD) is currently considered an early-onset neurodevelopmental condition. Follow-up studies of clinic-ascertained autism suggest that autistic symptoms typically decline with age, although symptom improvement is limited for some. To date there have been no population-based prospective studies investigating the natural history of autistic symptoms from childhood to adulthood. The aim of this study was to characterize the development and heterogeneity of autistic symptoms in a population-based cohort from childhood to age 25.Methods:Data were analyzed in a prospective U.K. population-based cohort (ALSPAC). Trajectories were derived using five assessments of the parent-rated Social and Communication Disorders Checklist (SCDC) spanning ages 7–25. Additional measures were used to validate symptom trajectories.Results:Three distinct SCDC symptom trajectory classes were identified: low (88.5%), declining (5.0%), and late-emerging (6.5%). Both the declining and late-emerging trajectory classes were associated with child and adult ASD measures, low IQ, communication problems, peer problems, and worse adult functioning compared with the low trajectory class. Male sex was associated with a higher likelihood of being in the declining trajectory class (odds ratio=2.84, 95% CI=2.19, 3.69). This sex difference was not observed in the late-emerging class (odds ratio=1.00, 95% CI=0.80, 1.24) compared with the low trajectory class.Conclusions:ASD symptom levels that emerged early tended to decline across development, although impairment was still present in adulthood for some. For others, autistic symptoms emerged across adolescence and adulthood. This challenges our current understanding that ASD symptoms inevitably first manifest early in development.

AIMS: 1) To investigate whether genetic liability to attention-deficit/hyperactivity disorder (ADHD), indexed by polygenic risk scores for ADHD (PRS-ADHD), is associated with substance use disorders (SUD) in individuals with ADHD. 2) To investigate whether other individual- or family-related risk factors for SUD could mediate or confound this association.DESIGN: Population-based cohort study SETTING AND PARTICIPANTS: ADHD cases in the iPSYCH sample (a Danish case-cohort sample of genotyped cases with specific mental disorders), born in Denmark between 1981 and 2003 (N = 13 116). Register-based information on hospital diagnoses of SUD was available until December 31, 2016.MEASUREMENTS: We estimated odds ratios (ORs) with 95% confidence intervals (CIs) for any SUD as well as for different SUD types (alcohol, cannabis, and other illicit drugs) and severities (use, abuse, and addiction), with effect sizes corresponding to a comparison of the highest PRS-ADHD decile to the lowest.FINDINGS: PRS-ADHD were associated with any SUD (OR = 1.30, 95% CI: 1.11-1.51). Estimates were similar across different types and severity levels of SUD. Other risk factors for SUD (male sex, age at ADHD diagnosis, comorbid conduct problems, and parental factors including SUD, mental disorders, and socio-economic status) were independently associated with increased risk of SUD. PRS-ADHD explained a minor proportion of the variance in SUD (0.2% on the liability scale) compared to the other risk factors. The association between PRS-ADHD and any SUD was slightly attenuated (OR = 1.21, 95% CI: 1.03-1.41) after adjusting for the other risk factors for SUD. Furthermore, associations were nominally higher in females than in males (ORfemales = 1.59, 95% CI: 1.19-2.12, ORmales = 1.18, 95% CI: 0.98-1.42).CONCLUSIONS: A higher genetic liability to attention-deficit/hyperactivity disorder appears to be associated with higher risks of substance use disorders in individuals with attention-deficit/hyperactivity disorder.

Most homeless young people have experienced multiple adversities, with potential implications for the development of Executive Functions (EFs), higher-order cognitive processes important for adaptation. EFs have been identified as putative contributors to the capacity to exit homelessness, however, little research has investigated EFs in homeless young people. To address gaps in current knowledge, this study compared executive function performance between homeless and housed young people. Relationships between EFs and short-term housing outcomes were also explored. Sixty-eight homeless young people (16–19 years) and 37 age-matched housed young people participated in this study. Computerized EF tasks spanned the domains of working memory, set shifting/flexibility, planning, impulsivity/risky decision making, selective attention/inhibition, and verbal fluency. Homeless young people demonstrated worse performance than housed youth on several EF tasks, particularly working memory and impulsivity/risky decision making. Working memory predicted progression into more independent accommodation; those with longer working memory spans were twice as likely to have progressed to more independent housing rather than maintained their current housing status after six months. Poorer EFs are associated with youth homelessness and also with an individual’s ability to progress towards independence. As such, EFs should not continue to be overlooked by researchers and service providers. Emerging adulthood, as a sensitive period for EF development, is an opportune time for intervention to increase the likelihood of positive housing outcomes in homeless young people.

Aim Few personalised medicine investigations have been conducted for mental health. We aimed to generate and validate a risk tool that predicts adult attention-deficit/hyperactivity disorder (ADHD). Methods Using logistic regression models, we generated a risk tool in a representative population cohort (ALSPAC – UK, 5113 participants, followed from birth to age 17) using childhood clinical and sociodemographic data with internal validation. Predictors included sex, socioeconomic status, single-parent family, ADHD symptoms, comorbid disruptive disorders, childhood maltreatment, ADHD symptoms, depressive symptoms, mother's depression and intelligence quotient. The outcome was defined as a categorical diagnosis of ADHD in young adulthood without requiring age at onset criteria. We also tested Machine Learning approaches for developing the risk models: Random Forest, Stochastic Gradient Boosting and Artificial Neural Network. The risk tool was externally validated in the E-Risk cohort (UK, 2040 participants, birth to age 18), the 1993 Pelotas Birth Cohort (Brazil, 3911 participants, birth to age 18) and the MTA clinical sample (USA, 476 children with ADHD and 241 controls followed for 16 years from a minimum of 8 and a maximum of 26 years old). Results The overall prevalence of adult ADHD ranged from 8.1 to 12% in the population-based samples, and was 28.6% in the clinical sample. The internal performance of the model in the generating sample was good, with an area under the curve (AUC) for predicting adult ADHD of 0.82 (95% confidence interval (CI) 0.79–0.83). Calibration plots showed good agreement between predicted and observed event frequencies from 0 to 60% probability. In the UK birth cohort test sample, the AUC was 0.75 (95% CI 0.71–0.78). In the Brazilian birth cohort test sample, the AUC was significantly lower –0.57 (95% CI 0.54–0.60). In the clinical trial test sample, the AUC was 0.76 (95% CI 0.73–0.80). The risk model did not predict adult anxiety or major depressive disorder. Machine Learning approaches did not outperform logistic regression models. An open-source and free risk calculator was generated for clinical use and is available online at https://ufrgs.br/prodah/adhd-calculator/. Conclusions The risk tool based on childhood characteristics specifically predicts adult ADHD in European and North-American population-based and clinical samples with comparable discrimination to commonly used clinical tools in internal medicine and higher than most previous attempts for mental and neurological disorders. However, its use in middle-income settings requires caution.

Identifying prenatal environmental factors that have genuinely causal effects on psychopathology is an important research priority, but it is crucial to select an appropriate research design. In this review we explain why and what sorts of designs are preferable and focus on genetically informed/sensitive designs. In the field of developmental psychopathology, causal inferences about prenatal risks have not always been based on evidence generated from appropriate designs. We focus on reported links between maternal smoking during pregnancy and offspring attention-deficit/hyperactivity disorder or conduct problems. Undertaking a systematic review of findings from genetically informed designs and “triangulating” evidence from studies with different patterns of bias, we conclude that at present findings suggest it is unlikely that there is a substantial causal effect of maternal smoking in pregnancy on either attention-deficit/hyperactivity disorder or conduct problems. In contrast, for offspring birth weight (which serves as a positive control) findings strongly support a negative causal effect of maternal smoking in pregnancy. For maternal pregnancy stress, too few studies use genetically sensitive designs to draw firm conclusions, but continuity with postnatal stress seems important. We highlight the importance of moving beyond observational designs, for systematic evaluation of the breadth of available evidence and choosing innovative designs. We conclude that a broader set of prenatal risk factors should be examined, including those relevant in low- and middle-income contexts. Future directions include a greater use of molecular genetically informed designs such as Mendelian randomization to test causal hypotheses about prenatal exposure and offspring outcome.

Objective: The objective of this study was to examine the association between parent mental health (ADHD and depression) and offspring performance on neurocognitive tasks in children with ADHD. Method: The clinical sample consisted of 570 children (85% males, mean age: 10.77 years) with ADHD who completed neurocognitive tasks measuring working memory, attention set-shifting, and motivational deficits. Questionnaire measures were used to assess ADHD and depression symptom presence in parents. Results: Controlling for ADHD severity, children of parents with ADHD had poorer working memory (B = −0.25, 95% confidence interval [CI] [−0.45, −0.07], p = .01) and increased errors on the extra dimensional shift stage of the set-shifting task (B = 0.26 95% CI [0.02, 0.50], p = .04). Parent depression was not associated with offspring performance on any of the assessed neurocognitive tasks. Conclusion: Children with ADHD who have a parent with ADHD symptom presence are a subgroup of children who may have additional neurocognitive impairments that have potential implications when implementing interventions that target cognition and learning.

Background Access to healthcare services for undocumented migrants is one of the main public health issues currently being debated among European countries. Exclusion from primary healthcare services may lead to serious consequences for migrants' health. We analyzed the risk among undocumented migrants, in comparison with regular migrants, of being hospitalized for preventable conditions in the Region of Sicily (Italy). We performed a hospital-based cross-sectional study of the foreign population hospitalized in the Sicily region between 1 January 2003 and 31 December 2013. The first outcome was the proportion of avoidable hospitalization (AHs) among regular and irregular migrants. Second outcomes were the subcategories of AHs for chronic, acute and vaccine preventable diseases. 85 309 hospital admissions were analyzed. In the hospitalized population, in comparison to regular migrants, undocumented migrants show a higher proportion of hospitalization for diseases preventable through primary and preventive care (AOR1·48, 95%CI 1·37-1·59). The proportion of avoidable hospitalizations associated with the lack of legal status is higher for vaccine preventable conditions (AOR 2·06, 95%CI 1·66-2·56) than for chronic conditions (AOR 1·47, 95%CI 1·42-1·63) and acute conditions (AOR 1·37; 95%CI 1·23-1·53). Between 2003 and 2013, the proportion of avoidable hospitalizations decreased both in regular and undocumented migrants but decreased faster for regular than for undocumented migrants. Undocumented migrants experience higher proportion of hospitalization for preventable conditions in comparison with regular migrants probably due to a lack of access to the national healthcare service. Policies and strategies to involve them in primary healthcare and preventive services should be developed to tackle this inequality.

Previous cross-sectional research has shown that parents of children with attention deficit hyperactivity disorder (ADHD) have high rates of psychopathology, especially ADHD and depression. However, it is not clear whether different types of parent psychopathology contribute to the course and persistence of ADHD in the child over time. The aim of this two wave study was to investigate if mother self-reported ADHD and depression influence persistence of offspring ADHD and conduct disorder symptom severity in adolescents diagnosed with ADHD in childhood. A sample of 143 males with a confirmed diagnosis of ADHD participated in this study. ADHD and conduct disorder symptoms were assessed at baseline and reassessed 4 years later. The boys in this sample had a mean age of 10.7 years at Time 1 (SD 2.14, range 6–15 years) and 13.73 years at Time 2 (SD 1.74, range 10–17 years). Questionnaire measures were used to assess ADHD and depression symptoms in mothers at Time 1. Mother self-reported ADHD was not associated with a change in child ADHD or conduct symptom severity over time. Mother self-reported depression was found to predict an increase in child conduct disorder symptoms, but did not contribute to ADHD symptom levels. This study provides the first evidence that concurrent depression in mothers may be a predictor of worsening conduct disorder symptoms in adolescents with ADHD. It may, therefore, be important to screen for depression in mothers of children with ADHD in clinical practice to tailor interventions accordingly.

BackgroundThere is recent evidence of some degree of shared genetic susceptibility between adult schizophrenia and childhood attention-deficit hyperactivity disorder (ADHD) for rare chromosomal variants.AimsTo determine whether there is overlap between common alleles conferring risk of schizophrenia in adults with those that do so for ADHD in children.MethodWe used recently published Psychiatric Genome-wide Association Study (GWAS) Consortium (PGC) adult schizophrenia data to define alleles over-represented in people with schizophrenia and tested whether those alleles were more common in 727 children with ADHD than in 2067 controls.ResultsSchizophrenia risk alleles discriminated ADHD cases from controls (P = 1.04 × 104, R2 = 0.45%); stronger discrimination was given by alleles that were risk alleles for both adult schizophrenia and adult bipolar disorder (also derived from a PGC data-set) (P = 9.98 ×10−6, R2 × 0.59%).ConclusionsThis increasing evidence for a small, but significant, shared genetic susceptibility between adult schizophrenia and childhood ADHD highlights the importance of research work across traditional diagnostic boundaries.

Although Attention Deficit Hyperactivity Disorder (ADHD) is recognised to be a familial and heritable disorder, little is known about the broader family characteristics of having a parent with ADHD problems. The main aim of this study was to investigate the relationship between parent ADHD problems, child clinical presentation and family functioning in a sample of children with ADHD. The sample consisted of 570 children with ADHD. Child psychopathology was assessed using a semi-structured diagnostic interview. Questionnaires were used to assess ADHD in the parents (childhood and current symptoms), family environment and mother/father-child relationship. Parental ADHD problems were associated with a range of adverse clinical outcomes in children with no difference in effects for mothers with ADHD problems compared to fathers with ADHD problems. Levels of maternal hostility were higher in families where mothers had ADHD problems, but reduced where fathers had ADHD problems. Parental ADHD problems index higher risk for more severe clinical presentation of ADHD in children and higher levels of family conflict (where there are maternal but not paternal ADHD problems). This study highlights that children with more severe behavioural symptoms are more likely to have a parent with persistent ADHD which has important implications when considering treatment and intervention strategies. Electronic supplementary material The online version of this article (doi:10.1007/s00787-013-0378-x) contains supplementary material, which is available to authorized users.

OBJECTIVE Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. METHOD Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. RESULTS Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. CONCLUSIONS Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity. OBJECTIVE Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. METHOD Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. RESULTS Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. CONCLUSIONS Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.

Young people who have experienced homelessness, foster care, or poverty are among the most disadvantaged in society. This review examines whether young people who have these experiences differ from their non-disadvantaged peers with respect to their cognitive skills and abilities, and whether cognitive profiles differ between these three groups. Three electronic databases were systematically searched for articles published between 1 January 1995 and 1 February 2015 on cognitive functioning among young people aged 15 to 24 years who have experienced homelessness, foster care, or poverty. Articles were screened using pre-determined inclusion criteria, then the data were extracted, and its quality assessed. A total of 31 studies were included. Compared to non-disadvantaged youth or published norms, cognitive performance was generally found to be impaired in young people who had experienced homelessness, foster care, or poverty. A common area of difficulty across all groups is working memory. General cognitive functioning, attention, and executive function deficits are shared by the homeless and poverty groups. Creativity emerges as a potential strength for homeless young people. The cognitive functioning of young people with experiences of impermanent housing and poverty has been relatively neglected and more research is needed to further establish cognitive profiles and replicate the findings reviewed here. As some aspects of cognitive functioning may show improvement with training, these could represent a target for intervention.

Background Irritability and the new DSM-5 diagnostic category of Disruptive Mood Dysregulation Disorder (DMDD) have been conceptualised as related to mood disorder. Irritability is common in Attention Deficit Hyperactivity Disorder (ADHD) but little is known about its association with depression risk in this group. This study aims to establish levels of irritability and prevalence of DMDD in a clinical sample of children with ADHD, and examine their association with anxiety, depression and family history of depression. Methods The sample consisted of 696 children (mean age 10.9 years) with a diagnosis of ADHD, recruited from UK child psychiatry and paediatric clinics. Parents completed the Child and Adolescent Psychiatric Assessment, a semi-structured diagnostic interview, about their child. This was used to establish prevalence of DMDD, anxiety disorder and depressive disorder, as well as obtain symptom scores for irritability, anxiety and depression. Questionnaires assessed current parental depression, and family history of depression. Result Irritability was common, with 91% endorsing at least one irritable symptom. 3-month DMDD prevalence was 31%. Children with higher levels of irritability or DMDD were more likely to have comorbid symptoms of anxiety, depression and a family history of depression. Limitations Results are based on a clinical sample, so may not be generalizable to children with ADHD in the general population. Conclusions Irritability and DMDD were common, and were associated with markers of depression liability. Longitudinal studies are needed to examine the association between irritability and depression in youth with ADHD as they get older., Highlights • Prevalence of DMDD was 31% in this clinical sample of children with ADHD. • DMDD was associated with increased impairment and comorbidity. • Irritability and DMDD were associated with markers of depression liability.

Improving children’s mental wellbeing is a recognised public health priority, but evidence on recent trends is lacking. This study updates evidence on differences in child mental health since 2008 by comparing two nationally representative cohorts in Wales, UK. Parents of 4- to 12-year-old children completed the Strengths and Difficulties Questionnaire (SDQ). No significant differences were seen for younger girls between 2007/2008 and 2012/2013. There was a decrease in conduct, hyperactivity and total difficulties symptom scores and an increase in prosocial scores for boys and older girls. These findings suggest that rates of child mental health problems are stable or falling.

Depression is known to be influenced by psychosocial stressors. For mothers with recurrent depressive illness, the presence of psychopathology in their children may have important effects on their own mental health. Although the impact of maternal depression on child mental health is well-established, no study to date, as far as we are aware, has examined the extent to which offspring psychopathology influences the course of depression in mothers with a history of recurrent depressive illness, what types of child psychopathology impact maternal mental health, or whether risks vary by child gender. Aims were to (a) Use a longitudinal design to examine whether adolescent psychopathology (depression, disruptive behavior disorder; DBD) predicts recurrence of a depressive episode and depression symptom course in women with a history of recurrent depression; and (b) To test if observed effects vary by child gender. 299 mothers with recurrent major depressive disorder and their adolescent offspring were assessed on 2 occasions, 29 months apart. Maternal depression and offspring psychopathology were assessed using semistructured interview measures. Cross-generational links across time were assessed using structural equation modeling. Analyses were adjusted for past severity of maternal depression. Offspring depression symptoms but not DBD symptoms at baseline predicted future episode recurrence in mothers. Depression symptoms in daughters (β = .16, p = .039) but not sons (β = −.07, p = .461), predicted an increase in maternal depression symptoms across time. Psychopathology in daughters is associated with long-term depressive symptoms in women (mothers) with a history of recurrent depression. Findings highlight the importance of careful assessment and management of mental health problems in adolescents for more effective management of maternal depression. This study suggests that offspring symptoms of depression may be important for the recurrence of maternal depression episodes. Girls’ symptoms of depression may be a particularly important psychosocial stressor for the development of depressive symptoms in mothers with a history of recurrent depression., This study suggests that offspring symptoms of depression may be important for the recurrence of maternal depression episodes. Girls’ symptoms of depression may be a particularly important psychosocial stressor for the development of depressive symptoms in mothers with a history of recurrent depression.

Importance: Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder that shows clinical and genetic overlap with other childhood neurodevelopmental disorders. Levels of ADHD symptoms typically decline across childhood and adolescence, although they remain elevated for some individuals. The determinants of symptom persistence and decline are not yet fully understood.Objectives: To test the hypothesis that genetic risk variant load for ADHD (indexed by polygenic risk scores [PRS]), but not for other psychiatric disorders, is associated with population-based ADHD symptom trajectories across childhood and adolescence, and to examine whether higher genetic liability for ADHD is correlated with total number of additional neurodevelopmental disorders (multimorbidity) in childhood.Design, Setting, and Participants: The Avon Longitudinal Study of Parents and Children, an ongoing prospective population-based cohort study, has been collecting data on 14 701 children, including 9757 with data on symptoms of ADHD at multiple time points, since September 6, 1990. The primary exposure variables, PRS, were generated using results of a genome-wide association study from the Psychiatric Genomics Consortium. Childhood multimorbidity scores (ages 7-9 years) were measured by total impairments in 4 domains known to share genetic liability with ADHD: IQ, social communication, pragmatic language, and conduct. Data analysis was conducted from March 1 to September 8, 2016.Main Outcomes and Measures: Attention-deficit/hyperactivity disorder symptom trajectories from ages 4 to 17 years (7 time points).Results: Among 9757 children with data on symptoms of ADHD at multiple time points (age range, 4-17 years; 4968 boys and 4789 girls), 4 ADHD symptom trajectories were identified: low (82.6%), intermediate (7.7%), childhood-limited (5.8%), and persistent (3.9%). Mean (SE) PRS for ADHD were higher in children in the persistent trajectory (0.254 [0.069]) compared with each of the other 3 trajectories (low, -0.018 [0.014], χ21 = 14.67, P Conclusions and Relevance: Persistence of ADHD symptoms across childhood and adolescence in the general population is associated with higher PRS for ADHD. Childhood multimorbidity was also associated with persistence of ADHD symptoms and may help to identify children with ADHD whose symptoms are most likely to continue into adolescence.

Maternal smoking during pregnancy is associated with attention deficit hyperactivity disorder (ADHD) in offspring. It is assumed by many that this association is causal. Others suggest that observed associations are due to unmeasured genetic factors or other confounding factors. The authors compared risks of maternal smoking during pregnancy with those of paternal smoking during pregnancy. With a causal intrauterine effect, no independent association should be observed between paternal smoking and offspring ADHD. If the association is due to confounding factors, risks of offspring ADHD should be of similar magnitudes regardless of which parent smokes. This hypothesis was tested in 8,324 children from a well-characterized United Kingdom prospective cohort study, the Avon Longitudinal Study of Parents and Children (data from 1991–2000). Associations between offspring ADHD and maternal and paternal smoking during pregnancy were compared using regression analyses. Offspring ADHD symptoms were associated with exposure to both maternal and paternal smoking during pregnancy (mothers: β = 0.25, 95% confidence interval: 0.18, 0.32; fathers: β = 0.21, 95% confidence interval: 0.15, 0.27). When paternal smoking was examined in the absence of maternal smoking, associations remained and did not appear to be due to passive smoking exposure in utero. These findings suggest that associations between maternal smoking during pregnancy and child ADHD may be due to genetic or household-level confounding rather than to causal intrauterine effects.

BackgroundSome research suggests that children with attention-deficit hyperactivity disorder (ADHD) have a higher than expected risk of bipolar affective disorder. No study has examined the prevalence of bipolar disorder in a UK sample of children with ADHD.AimsTo examine the prevalence of bipolar disorder in children diagnosed with ADHD or hyperkinetic disorder.MethodPsychopathology symptoms and diagnoses of bipolar disorder were assessed in 200 young people with ADHD (170 male, 30 female; age 6–18 years, mean 11.15, s.d. = 2.95). Rates of current bipolar disorder symptoms and diagnoses are reported. A family history of bipolar disorder in parents and siblings was also recorded.ResultsOnly one child, a 9-year-old boy, met diagnostic criteria for both ICD–10 hypomania and DSM–IV bipolar disorder not otherwise specified.ConclusionsIn a UK sample of children with ADHD a current diagnosis of bipolar disorder was uncommon.

Deletions encompassing the X-linked STS gene (encoding steroid sulfatase) have been observed in subjects with neurodevelopmental disorders, including attention deficit hyperactivity disorder (ADHD). Recently, two single nucleotide polymorphisms (SNPs) within STS (rs12861247 and rs17268988) have been reported to be associated with ADHD risk and inattentive symptoms in ADHD, respectively. Using a UK sample of ADHD subjects (aged 5-18 years), we tested the hypothesis that rs12861247 is associated with ADHD risk using a case-control approach (comparing 327 ADHD cases with 358 male controls from the Wellcome Trust Case Control Consortium). Using a subset of males from the ADHD sample, we also examined whether variation within STS is associated with symptomatology/cognitive function in ADHD. We then tested whether SNPs associated with cognitive function in ADHD were also associated with cognitive function in healthy male subjects using a German sample (n = 143, aged 18-30 years), and whether STS was expressed in brain regions pertinent to ADHD pathology during development. We did not replicate the previously identified association with rs12861247. However, in ADHD males, variation at rs17268988 was associated with inattentive symptoms, while variation within STS was significantly associated with performance on three cognitive measures. Three SNPs associated with cognitive function in ADHD males were not associated with cognitive function in healthy males. STS was highly expressed in the developing cerebellar neuroepithelium, basal ganglia, thalamus, pituitary gland, hypothalamus and choroid plexus. These data suggest that genetic variants affecting STS expression and/or activity could influence the function of brain regions perturbed in ADHD.

Summary Background Large, rare chromosomal deletions and duplications known as copy number variants (CNVs) have been implicated in neurodevelopmental disorders similar to attention-deficit hyperactivity disorder (ADHD). We aimed to establish whether burden of CNVs was increased in ADHD, and to investigate whether identified CNVs were enriched for loci previously identified in autism and schizophrenia. Methods We undertook a genome-wide analysis of CNVs in 410 children with ADHD and 1156 unrelated ethnically matched controls from the 1958 British Birth Cohort. Children of white UK origin, aged 5–17 years, who met diagnostic criteria for ADHD or hyperkinetic disorder, but not schizophrenia and autism, were recruited from community child psychiatry and paediatric outpatient clinics. Single nucleotide polymorphisms (SNPs) were genotyped in the ADHD and control groups with two arrays; CNV analysis was limited to SNPs common to both arrays and included only samples with high-quality data. CNVs in the ADHD group were validated with comparative genomic hybridisation. We assessed the genome-wide burden of large (>500 kb), rare (

Purpose: This study was designed to improve the measurement of financial exploitation (FE) by testing psychometric properties of the older adult financial exploitation measure (OAFEM), a client self-report instrument. Design and Methods: Rasch item response theory and traditional validation approaches were used. Questionnaires were administered by 22 adult protective services investigators from 7 agencies in Illinois to 227 substantiated abuse clients. Analyses included tests for dimensionality, model fit, and addi tional construct validation. Results from the OAFEM were also compared with the substantiation decision of abuse and with investigators’ assessments of FE using a staff report version. Hypotheses were generated to test hypothesized relationships. Results: The OAFEM, including the original 79-, 54-, and 30-item measures, met stringent Rasch analysis fit and unidi mensionality criteria and had high internal consistency and item reliability. The validation results were supportive, while leading to reconsideration of aspects of the hypothesized theoretical hierarchy. Thresholds were suggested to demonstrate levels of severity. Implications: The measure is now available to aid in the assessment of FE of older adults by both clinicians and researchers. Theoretical refinements devel oped using the empirically generated item hierarchy may help to improve assessment and intervention.

BackgroundChildren with attention-deficit hyperactivity disorder (ADHD) are thought to be at higher risk of psychopathy. Early biological and social adversity may contribute to this risk.AimsTo examine psychopathy traits in ADHD.MethodIn a sample of children with ADHD who had reached adolescence, total psychopathy and ‘emotional-dysfunction’ scores (e.g. callousness, lack of affect) were assessed using the Hare Psychopathy Checklist–Youth Version.ResultsA total of 156 (79%) eligible families participated. Total psychopathy and emotional-dysfunction scores were elevated in comparison to published UK norms but none scored in the clinical range for psychopathy. Adjusting for associated conduct problems, total psychopathy scores were associated with maternal smoking during pregnancy, emotional-dysfunction scores were associated with birth complications, and neither was associated with family adversity.ConclusionsChildren with ADHD show psychopathy traits but are not ‘psychopaths’. Early adversity, indexed by pre- or perinatal adversity but not family factors, appears to be associated.

Reported findings on cortisol reactivity to stress in young people with ADHD are very variable. This inconsistency may be explained by high rates of comorbidity with Conduct Disorder (CD). The present study examined cortisol responses to a psychosocial stressor in a large sample of adolescent males with ADHD (n=202), with or without a comorbid diagnosis of Conduct Disorder (CD). Associations between stress reactivity and callous-unemotional traits and internalizing symptoms were also assessed. The ADHD only (n=95) and ADHD+CD (n=107) groups did not differ in baseline cortisol, but the ADHD+CD group showed significantly reduced cortisol stress reactivity relative to the ADHD only group. Regression analyses indicated that ADHD symptom severity predicted reduced baseline cortisol, whereas CD symptom severity predicted increased baseline cortisol (ADHD β=−0.24, CD β=0.16, R=0.26) and reduced cortisol stress reactivity (β=−0.17, R=0.17). Callous-unemotional traits and internalizing symptoms were not significantly related to baseline or stress-induced cortisol. Impaired cortisol reactivity is hypothesised to reflect fearlessness and is associated with deficient emotion regulation and inhibition of aggressive and antisocial behaviour. Consequently, it may partly explain the greater severity of problems seen in those with comorbid ADHD and CD., Highlights • Cortisol stress responses were studied in 202 adolescent males with ADHD. • Males with comorbid CD showed reduced cortisol stress reactivity. • ADHD symptom severity predicted reduced baseline cortisol. • CD symptom severity predicted increased baseline cortisol and reduced cortisol stress reactivity. • Callous-unemotional traits and internalizing symptoms were not related to cortisol.

Background\ud \ud Reduced processing and experience of aversive emotional cues is a common component of theories on the development and persistence of aggression and antisocial behaviour. Yet physical pain, arguably the most basic aversive cue, has attracted comparatively little attention.\ud \ud \ud Methods\ud \ud This study measured pain sensitivity and physiological response to painful stimuli (skin conductance level, SCL) in adolescent boys with Attention-Deficit/Hyperactivity Disorder (ADHD; n = 183), who are at high risk for antisocial behaviour. We compared boys with ADHD with and without a comorbid diagnosis of Conduct Disorder (CD) on pain sensitivity, and examined patterns of association between pain measures, on the one hand, and problem severity and callous and unemotional (CU) traits, on the other.\ud \ud \ud Results\ud \ud Boys with comorbid CD exhibited a higher pain threshold and tolerance than boys with ADHD alone, but the groups did not differ in physiology at the time the pain threshold and tolerance were reported. Regression analyses showed that ADHD problem severity positively predicted pain sensitivity, whereas levels of CU traits negatively predicted pain sensitivity.\ud \ud \ud Conclusions\ud \ud These findings on physical pain processing extend evidence of impairments in aversive cue processing among those at risk of antisocial behaviour. The study highlights the importance of considering comorbidity and heterogeneity of disorders when developing interventions. The current findings could be used to identify subgroups within those with ADHD who might be less responsive to interventions that use corrective feedback to obtain behaviour change.

Several groups have reported an association between the 10-repeat allele of a dopamine transporter (DAT1) 3'UTR VNTR variant and ADHD but the finding has not been universally observed. An association between DAT1 genotype and stimulant medication response has also been reported although again there are conflicting data. We tested the DAT1 3'VNTR and three SNPs in the putative promoter region of DAT1 for association with ADHD in 263 parent-proband trios. Analyses of genotypes, alleles, and haplotypes were performed using family-based association methods. Case-control analysis of the VNTR in 263 cases and 287 controls was also conducted. In addition, we tested for association between the VNTR marker and stimulant medication response. Comparing allele 10 versus all other alleles combined, no significant association was found with ADHD, using FBAT analysis (chi2 = 0.1 (df 1), P = 0.9, (odds ratio (OR) = 1.0, 95% CI 0.8-1.2), and case-control analysis (chi2 = 0.12 (df 2), P = 0.91). No evidence of association with any of the SNPs in the promoter region was found. Haplotype analysis was also non-significant (chi2 = 3.93, (df 9) global P = 0.85). Finally, no association was found between the DAT 1 VNTR and response to stimulant medication (chi2 = 1.63 (df 3) P = 0.65). We conclude that the 3' VNTR and three additional promoter variants in DAT1 do not appear to be associated with ADHD, or response to stimulant mediation in our sample.

Attention deficit hyperactivity disorder (ADHD) is a childhood onset disorder, for which there is good evidence that genetic factors contribute to the aetiology. Recently reported linkage findings suggested evidence of a susceptibility locus on chromosome 16p13 (maximum LOD score of 4.2, P=5 x 10(-6)). The GRIN2A (glutamate receptor, ionotropic, N-methyl D-aspartate 2A) gene that encodes the N-methyl D-aspartate receptor subunit 2A (NMDA2A) maps to this region of linkage. As this is also a good functional candidate gene for ADHD, we undertook family-based association analysis in a sample of 238 families. We found significant evidence of association with a GRIN2A exon 5 polymorphism (chi(2)=5.7, P=0.01). Our data suggest that genetic variation in GRIN2A may confer increased risk for ADHD and that this, at least in part, might be responsible for the linkage result on 16p reported by Smalley et al. We conclude that replication is required and that further work examining for association of GRIN2A polymorphisms with ADHD is warranted.

OBJECTIVES: Three studies to date have found evidence (or a trend for evidence) of linkage and association between the long allele of the 44 base pair repeat insertion/deletion 5-HTT functional polymorphism (5-HTTLPR) and attention deficit hyperactivity disorder (ADHD). In an attempt to replicate these findings, we examined this polymorphism and a variable number tandem repeat in the second intron of 5-HTT for association with ADHD. METHODS: One hundred and fifty children who met diagnostic criteria for ADHD and their parents (where available) were genotyped for these polymorphisms. Analysis was undertaken using the transmission disequilibrium test and haplotype analysis, as well as case-control comparisons using a control group of 121 individuals. RESULTS: No association between either the 5-HTTLPR or the variable number tandem repeat (VNTR) in ADHD was found (extended transmission disequilibrium test; P=0.37 and P=0.62, respectively). Haplotype analysis was also non-significant. Further analysis revealed no evidence of association in the subgroups of those without conduct disorder and in medication non-responders. CONCLUSIONS: Failure to replicate findings from previous studies may be due to a lack of statistical power. However, given recent findings by Kent et al. (2002) of association with another polymorphism in the 5HTT gene, we hypothesise that previous positive findings may have arisen by the LPR and VNTR being in linkage disequilibrium with the true susceptibility polymorphism.

The transmission disequilibrium test (TDT) is widely used as a robust statistical method to test for genetic association due to linkage based upon analysis of parent-proband trios. The TDT and other family-based tests (eg haplotype relative risk method) are commonly used in association studies including those of ADHD because of concerns that the case-control design has a strong tendency for false positives due to poor matching between cases and controls. Unfortunately, it is not always possible to obtain DNA from both parents in studies of this design, even where the onset of disorder is in childhood, and usually the missing parent is the father. Despite the fact that methods exist for analysis where one parent is missing, many family-based studies are based on the collection or analysis of complete trios only. However this selection process might potentially introduce bias, particularly for studies of behavioural phenotypes like ADHD because the phenotype of proband or parents might influence family stability and therefore complete parental ascertainment. We set out to examine whether children with ADHD and for whom DNA samples from fathers were missing ('duos') differed phenotypically from children for whom genotype information was available from both parents ('trios'). Children from duos showed a significantly higher frequency of DMS-IV ADHD-combined type, significantly more co-morbid conduct disorder and conduct disorder symptoms, and a trend for higher total ADHD symptom scores. Excluding duos from sample collection and analysis may result in systematic bias. If comorbid conduct disorder and ADHD-combined type index increased genetic liability, exclusion of duos could further reduce the power of the TDT (and similar tests) to detect susceptibility genes for ADHD, or replicate effects detected by case-control analysis.

Objective Twin studies and genome-wide complex trait analysis (GCTA) are not in agreement regarding heritability estimates for behavioral traits in children from the general population. This has sparked a debate on the possible difference in genetic architecture between behavioral traits and psychiatric disorders. In this study, we test whether polygenic risk scores associated with variation in attention-deficit/hyperactivity disorder (ADHD) trait levels in children from the general population predict ADHD diagnostic status and severity in an independent clinical sample. Method Single nucleotide polymorphisms (SNPs) with p < .5 from a genome-wide association study of ADHD traits in 4,546 children (mean age, 7 years 7 months) from the Avon Longitudinal Study of Parents and Children (ALSPAC; general population sample) were selected to calculate polygenic risk scores in 508 children with an ADHD diagnosis (independent clinical sample) and 5,081 control participants. Polygenic scores were tested for association with case-control status and severity of disorder in the clinical sample. Results Increased polygenic score for ADHD traits predicted ADHD case-control status (odds ratio = 1.17 [95% CI = 1.08–1.28], p = .0003), higher ADHD symptom severity (β = 0.29 [95% CI = 0.04–0.54], p = 0.02), and symptom domain severity in the clinical sample. Conclusion This study highlights the relevance of additive genetic variance in ADHD, and provides evidence that shared genetic factors contribute to both behavioral traits in the general population and psychiatric disorders at least in the case of ADHD.

Objective:\ud To determine whether children with attention deficit hyperactivity disorder (ADHD) and mild intellectual disability (ID) are a clinically distinct ADHD subgroup.\ud \ud Study design:\ud This was a cross-sectional study comparing clinical characteristics (ADHD subtypes, total number of symptoms, and rates of common comorbidities) between children with ADHD and mild ID and those with ADHD and IQ test scores >70, and also between children with ADHD and ID and a general population sample of children with ID alone. The sample comprised a clinical sample of children with ADHD with ID (n = 97) and without ID (n = 874) and a general population sample of children with ID and without ADHD (n = 58).\ud \ud Results:\ud After correcting for multiple statistical tests, no differences were found between the 2 ADHD groups on any measure except the presence of conduct disorder (CD) symptoms and diagnoses. Children with ADHD and ID had higher rates of both (OR, 2.38; 95% CI, 1.71-3.32 and OR, 2.69; 95% CI, 1.69-4.28, respectively). Furthermore, children with ADHD and ID had significantly higher rates of oppositional defiant disorder (OR, 5.54; 95% CI, 2.86-10.75) and CD (OR, 13.66; 95% CI, 3.25-57.42) symptoms and a higher incidence of oppositional defiant disorder diagnoses (OR, 30.99; 95% CI, 6.38-150.39) compared with children with ID without ADHD.\ud \ud Conclusion:\ud Children with ADHD and mild ID appear to be clinically typical of children with ADHD except for more conduct problems. This finding has implications for clinicians treating these children in terms of acknowledging the presence and impact of ADHD symptoms above and beyond ID and dealing with a comorbid CD.

BackgroundSubmicroscopic, rare chromosomal copy number variants (CNVs) contribute to neurodevelopmental disorders but it is not known whether they define atypical clinical cases.AimsTo identify whether large, rare CNVs in attention-deficit hyperactivity disorder (ADHD) are confined to a distinct clinical subgroup.MethodA total of 567 children with ADHD aged 5–17 years were recruited from community clinics. Psychopathology was assessed using the Child and Adolescent Psychiatric Assessment. Large, rare CNVs (>500 kb, ResultsCopy number variant carriers (13.6%) showed no differences from non-carriers in ADHD symptom severity, symptom type, comorbidity, developmental features, family history or pre-/ perinatal markers. The only significant difference was a higher rate of intellectual disability (24% v. 9%, χ2 = 15.5, P = 0.001). Most CNV carriers did not have intellectual disability.ConclusionsLarge, rare CNVs are not restricted to an atypical form of ADHD but may be more highly enriched in children with cognitive problems.

Purpose Attention-deficit hyperactivity disorder (ADHD) is associated with increased use of health, social and education services. There is a lack of data to quantify the economic burden of ADHD in the UK. The aim of this study was to estimate additional education, health and social care costs amongst adolescents in the UK diagnosed with ADHD. Methods Participants were 143, 12- to 18-year-olds from the Cardiff longitudinal ADHD study. Service use relating to mental health over the previous year was measured using the children’s service interview. Individual resource use was combined with unit cost data, from national sources, to calculate costs per patient and subsequently the mean cost per patient. Mean costs, 95 % confidence intervals and median use were calculated using nonparametric bootstrapping methods. Results The mean cost per adolescent for NHS, social care and education resources used in a 12-month period related to ADHD was £5,493 (£4,415.68, £6,678.61) in 2010 prices and the median was £2,327. Education and NHS resources accounted for approximately 76 and 24 %, respectively. Estimated annual total UK costs are £670 million. Conclusions The additional costs to the NHS and education system of treating adolescents remain substantial for several years after the initial ADHD diagnosis. There exists a need to develop and evaluate early interventions which have the potential to reduce the longer-term burden, particularly on education resource use.

Purpose: This study tested key psychometric properties of the Older Adult Psychological Abuse Measure (OAPAM), one self-report scale of the Older Adult Mistreatment Assessment (OAMA). Design and Methods: Items and theory were developed in a prior concept mapping study. Subsequently, the measures were administered to 226 substantiated clients by 22 elder abuse staff from 7 agencies in a full-scale field test. The resulting database was used to estimate the psychometric properties of the OAPAM using the Rasch item response theory model and traditional validation techniques. Analyses included tests for dimensionality, model fit, and theoretical construct validation. Results from the OAPAM client report were validated against the adult protective services substantiation decision of abuse and the elder abuse staff assessment of psychological abuse (PA). Results: The client self-report measures met stringent Rasch analysis fit and unidimensionality criteria and had high person (internal consistency) and item reliability. The validity results supported the usefulness of the client measures and led to reconsideration of aspects of the hypothesized theoretical hierarchy. A short form was developed. Cut-points were proposed to distinguish levels of PA. Implications: The measure is now available to aid in the assessment of PA of older adults by both clinicians and researchers. Theoretical refinements developed using the Rasch item hierarchy may help to improve assessment and intervention.

CONTEXT: As genes associated with common disorders are increasingly identified, we need to progress from observing associations to identifying risk pathways. The high-activity COMT genotype, in the presence of attention-deficit/hyperactivity disorder (ADHD), has previously been shown to be associated with extreme antisocial behavior. The same genotype has also been implicated in affecting cognitive function in healthy individuals. Impaired cognitive function might therefore lie on the risk pathway from genotype to clinical outcome. OBJECTIVES: To replicate the association between COMT genotype and antisocial behavior in ADHD and to then test whether (1) impaired executive control or (2) impaired social understanding act as intermediate phenotypes for this association and lie on the risk pathway between COMT genotype and antisocial behavior. DESIGN: Prospective epidemiological cohort sample. SETTING: The Avon Longitudinal Study of Parents and Children. PARTICIPANTS: Four thousand three hundred sixty-five children with data on COMT Val¹⁵⁸Met genotype, ADHD symptoms and diagnoses, and measures of social cognition/understanding and executive control. MAIN OUTCOME MEASURES: Antisocial behavior at age 7.5 years assessed using DSM-IV conduct disorder symptoms. RESULTS: We replicated the association of the high-activity COMT genotype, in the presence of ADHD, with extreme antisocial behavior (odds ratio, 2.82; 95% confidence interval, 2.02-3.94; P < .001 for the most severe antisocial behavior). The high-activity COMT genotype was associated with both executive control and impaired social understanding. The strength of the association between genotype and antisocial behavior was unchanged by including executive control in the model but dropped when impaired social understanding was included (odds ratio, 1.87; 95% confidence interval, 1.26-2.76; P = .002). CONCLUSIONS: The high-activity COMT genotype in ADHD is associated with antisocial behavior in part via impaired social understanding. Impaired executive control was also associated with the high-activity COMT genotype but may not lie on the risk pathway to antisocial behavior. The findings demonstrate the importance of testing links between genotype, intermediate phenotype, and clinical outcome in the same sample to identify potential risk pathways.

BackgroundAttention-deficit hyperactivity disorder (ADHD) is recognised as a common, disabling condition. Little information is available regarding the long-term outcomes for individuals with ADHD in the UK.AimsTo examine the 5-year outcome for a UK cohort of children with diagnosed, treated ADHD and identify whether maternal and social factors predict key outcomes.MethodOne hundred and twenty-six school-aged children (mean age 9.4 years, s.d. = 1.7) diagnosed with ADHD were reassessed 5 years later during adolescence (mean age 14.5 years, s.d. = 1.7) for ADHD, conduct disorder and other antisocial behaviours.ResultsMost adolescents (69.8%) continued to meet full criteria for ADHD, were known to specialist services and exhibited high levels of antisocial behaviour, criminal activity and substance use problems. Maternal childhood conduct disorder predicted offspring ADHD continuity; maternal childhood conduct disorder, lower child IQ and social class predicted offspring conduct disorder symptoms.ConclusionsThe treatment and monitoring of ADHD need to be intensified as outcomes are poor especially in offspring of mothers with childhood conduct disorder symptoms.

Context. Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder that in some cases is accompanied by antisocial behavior. Objective. To test if variations in the catechol O-methyltransferase gene (COMT) would prove useful in identifying the subset of children with ADHD who exhibit antisocial behavior. Design. Three independent samples composed of 1 clinical sample of ADHD cases and 2 birth cohort studies. Participants Participants in the clinical sample were drawn from child psychiatry and child health clinics in England and Wales. The 2 birth cohort studies included 1 sample of 2232 British children born in 1994-1995 and a second sample of 1037 New Zealander children born in 1972-1973. Main Outcome Measures. Diagnosis of ADHD and measures of antisocial behavior. Results. We present replicated evidence that the COMT valine/methionine polymorphism at codon 158 (COMT Val158Met) was associated with phenotypic variation among children with ADHD. Across the 3 samples, valine/valine homozygotes had more symptoms of conduct disorder, were more aggressive, and were more likely to be convicted of criminal offenses compared with methionine carriers. Conclusions. The findings confirm the presence of genetic heterogeneity in ADHD and illustrate how genetic information may provide biological evidence pointing to clinical subtypes.

Contains fulltext : 70196.pdf (Publisher’s version ) (Closed access) Season of birth (SOB) has been associated with attention deficit hyperactivity disorder (ADHD) in two existing studies. One further study reported an interaction between SOB and genotypes of the dopamine D4 receptor (DRD4) gene. It is important that these findings are further investigated to confirm or refute the findings. In this study, we investigated the SOB association with ADHD in four independent samples collected for molecular genetic studies of ADHD and found a small but significant increase in summer births compared to a large population control dataset. We also observed a significant association with the 7-repeat allele of the DRD4 gene variable number tandem repeat polymorphism in exon three with probands born in the winter season, with no significant differential transmission of this allele between summer and winter seasons. Preferential transmission of the 2-repeat allele to ADHD probands occurred in those who were born during the summer season, but did not surpass significance for association, even though the difference in transmission between the two seasons was nominally significant. However, following adjustment for multiple testing of alleles none of the SOB effects remained significant. We conclude that the DRD4 7-repeat allele is associated with ADHD but there is no association or interaction with SOB for increased risk for ADHD. Our findings suggest that we can refute a possible effect of SOB for ADHD.

Background Attention Deficit Hyperactivity Disorder (ADHD) is a genetically influenced condition although indicators of environmental risk including maternal smoking during pregnancy, low birth weight and low social class have also been found to be associated with the disorder. ADHD is a phenotypically heterogeneous disorder in terms of the predominant symptom types (inattention, hyperactive-impulsivity), their severity and comorbidity, notably Conduct Disorder. It is possible that these different clinical manifestations of the disorder may arise because of the differing effects of the environmental indicators of environmental risk. We set out to test this hypothesis. Methods In a sample of 356 children diagnosed with ADHD, we sought to investigate possible effects of three indicators of environmental risk – maternal smoking during pregnancy, birth weight and social class – on comorbid Conduct Disorder, conduct disorder symptoms and inattentive and hyperactive-impulsive symptom severity. Results Multiple regression analysis revealed that, after controlling for significant covariates, greater hyperactive-impulsive symptom severity was significantly associated with maternal smoking during pregnancy (r2 = 0.02, Beta = 0.11, t = 1.96, p = 0.05) and social class (r2 = 0.02, Beta = 0.12, t = 2.19, p = 0.03) whilst none of the environmental risk indicators significantly predicted number of inattentive symptoms. Conduct Disorder symptoms were positively predicted by maternal smoking in pregnancy (r2 = 0.04, Beta = 0.18, t = 3.34, p = 0.001) whilst both maternal smoking during pregnancy and social class significantly predicted a diagnosis of Conduct Disorder (OR = 3.14, 95% CI: 1.54, 6.41, Wald = 9.95, p = 0.002) and (OR = 1.95 95% CI: 1.18, 3.23 Wald = 6.78, p = 0.009) respectively. Conclusion These findings suggest that indicators of environmental risk, in this instance maternal smoking in pregnancy and environmental adversity indexed by lower social class, independently influence the clinical presentation of the ADHD phenotype. Other types of study design are needed to investigate whether these associations between indicators of environmental risk factors and ADHD clinical heterogeneity are attributable to causal risk effects and to further establish the magnitude of these effects. These findings have implications, not only for our understanding of the aetiology of ADHD, but may also be of clinical value, enabling the identification of individuals who are at higher risk of problematic behaviours in ADHD, notably conduct disorder, to enable earlier, targeted risk reduction strategies.

Objective To examine precursors of adolescent conduct disorder (CD) in children with attention-deficit/hyperactivity disorder (ADHD), investigating the significance of childhood oppositional defiant disorder (ODD) and ADHD. Method A total of 151 children with ADHD recruited from child psychiatric and pediatric clinics were assessed through standardized diagnostic interviews at ages 6 to 13 years and in adolescence 5 years later. Using multiple regression analysis, we assessed baseline ODD diagnosis and ODD, CD, and ADHD symptom scores as clinical predictors of adolescent CD diagnosis and symptom scores. Results Childhood ODD (diagnosis and severity) was significantly associated with adolescent CD (diagnosis and severity), independent of childhood ADHD severity and childhood CD. Children with a diagnosis of ODD were almost three times more likely to develop CD in adolescence (odds ratio=2.79, 95% CI 1.16-6.70, p = .02). Childhood ADHD severity predicted adolescent CD scores but not diagnosis of CD (although there was a trend toward association). The presence of at least one CD symptom in childhood predicted adolescent CD severity. Conclusions ODD is a significant precursor of adolescent CD in children with ADHD independent of ADHD severity. Considering the negative prognosis of ADHD with comorbid CD, it is imperative that clinicians pay specific attention to the presence of childhood ODD behaviors.

Context Early-onset antisocial behavior accompanied by attention-deficit/hyperactivity disorder is a clinically severe variant of antisocial behavior that is associated with a particularly poor outcome. Identifying early predictors is thus important. Genetic and prenatal environmental risk factors and prefrontal cortical function are thought to contribute. Recent evidence suggests that prefrontal cortical function is influenced by a valine/methionine variant in the catechol O-methyltransferase (COMT) gene. Objective To test the a priori hypothesis that this genetic variant predicts early-onset antisocial behavior in a high-risk sample and further examine the effects of birth weight, an environmentally influenced index of prenatal adversity previously linked to childhood disruptive behaviors and genotype x birth weight interaction. Design, Setting, and Participants A family-based genetic study was undertaken between 1997 and 2003. Participants were prospectively recruited from child and adolescent psychiatry and child health clinics in the United Kingdom and included 240 clinic children who met diagnostic criteria for attention-deficit/hyperactivity disorder or hyperkinetic disorder. Participants underwent comprehensive standardized assessments including measures of antisocial behavior and IQ. Main Outcome Measure DSM-IV symptoms of childhood-onset conduct disorder rated by trained interviewers using a standard diagnostic interview. Results The results show main effects of the COMT gene variant (P = .002), birth weight (P = .002), and a significant gene x environment (COMT x birth weight) interaction (P = .006). Conclusions Early-onset antisocial behavior in a high-risk clinical group is predicted by a specific COMT gene variant previously linked with prefrontal cortical function and birth weight, and those possessing the val/val genotype are more susceptible to the adverse effects of prenatal risk as indexed by lower birth weight.

Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable, neurodevelopmental disorder with onset in early childhood. Genes involved in neuronal development and growth are, thus, important etiological candidates and brain-derived neurotrophic factor (BDNF), has been hypothesized to play a role in the pathogenesis of ADHD. BDNF is a member of the neurotrophin family and is involved in the survival and differentiation of dopaminergic neurons in the developing brain (of relevance because drugs that block the dopamine transporter can be effective therapeutically). The common Val66Met functional polymorphism in the human BDNF gene (rs 6265) was genotyped in a collaborative family-based sample of 341 white UK or Irish ADHD probands and their parents. We found evidence for preferential transmission of the valine (G) allele of BDNF (odds ratio, OR=1.6, P=0.02) with a strong paternal effect (paternal transmissions: OR=3.2, P=0.0005; maternal transmissions: OR=1.00; P=1.00). Our findings support the hypothesis that BDNF is involved in the pathogenesis of ADHD. The transmission difference between parents raises the possibility that an epigenetic process may be involved.

Neurobiological studies have suggested that altered dopaminergic function may contribute to the etiology of attention deficit hyperactivity disorder (ADHD). The gene encoding catechol-O-methyltransferase (COMT) is an attractive candidate for ADHD susceptibility as it plays a major role in the degradation of dopamine. Moreover, a functional Val158Met polymorphism in COMT that alters the activity of the encoded protein has been strongly implicated in frontal lobe function, with the high activity Valine allele being associated with poorer performance, and ADHD is thought to involve fronto-striatal pathways. We have examined this functional variant for association with ADHD in a family based association sample comprising 279 probands and their parents. We have also examined two other markers in the COMT gene (rs737865, rs165599) which, together with the Val/Met variant, have recently been shown to be associated with altered COMT expression rather than enzyme activity. No evidence for association was observed with any single marker or haplotype in a sample of 279 affected children and their parents.

BACKGROUND: The glutamatergic system, the major excitatory neurotransmitter system in the central nervous system (CNS) has been proposed as contributing a possible role in the etiology of attention deficit hyperactivity disorder (ADHD). This is based upon observations from animal, neuroimaging, neuroanatomical and neuropsychological studies. Genes related to glutamate function are therefore good functional candidates for this disorder. The SLC1A3 (Solute Carrier Family 1, member 3) gene encodes a glial glutamate transporter which maps to chromosome 5p12, a region of linkage that coincides in two published ADHD genome scans so far. SLC1A3 is thus both a functional and positional candidate gene for ADHD. METHODS: We have undertaken detailed association analysis of SLC1A3 using a multi-stage approach for candidate gene analysis. RESULTS: In a family-based sample (n = 299) we found a significant association between marker rs2269272 (p = .007) and ADHD. Two, two-marker haplotypes, rs2269272/rs3776581 (p = .016) and rs2269272/rs2032893 (p = .013) also yielded evidence of association. CONCLUSIONS: The results of our study suggest that genetic variation in SLC1A3 may contribute to susceptibility to ADHD.

Objective: Association between attention deficit hyperactivity disorder (ADHD) and the 7-repeat allele of a variant (a 48bp variable number of tandem repeats) in the dopamine D4 receptor gene (DRD4) has been widely documented. A meta-analysis of 21 studies revealed evidence of significant association. In this article the authors examine whether the DRD4 7-repeat allele is associated with performance on a variety of neuropsychological tasks in children with ADHD. Method: The presence or absence of the 7-repeat allele was determined in 133 drug-naive children 6 to 13 years of age who fulfilled diagnostic criteria for ADHD. These children were then assessed on several neuropsychological tests known to be associated with attention, impulse control, and response inhibition (the Continuous Performance Test, Matching Familiar Figures Test, Go/No Go Task, and Stop Task). Activity levels were assessed with an actigraph. Children with and without at least one 7-repeat allele were compared with each other and with children in a previous population-based study. Results: Children who had the 7-repeat allele had significantly more incorrect responses on the Matching Familiar Figures Test (16.1 versus 14.3) than children who did not have the allele. Children with the allele also had shorter mean reaction times for incorrect responses on the Matching Familiar Figures Test (846.1 versus 1103.7 msec) and on the Stop Task (116.6 versus 134.1 msec) than children without the allele. Children with the allele also displayed higher activity levels. The children with and without the allele did not differ significantly in number of ADHD symptoms when the symptoms were split into the areas of inattention and hyperactivity/ impulsivity. Both groups of children with ADHD were more neuropsychologically impaired than the nonpatient comparison group. Conclusions: In children with ADHD, possession of the DRD4 7-repeat allele appears to be associated with an inaccurate, impulsive response style on neuropsychological tasks that is not explained by ADHD symptom severity.