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Background\ud Attention deficit hyperactivity disorder (ADHD) is highly heritable, but little is known about the relative effects of transmitted (i.e. direct) and non-transmitted (i.e. indirect) common variant risks. Using parent-offspring trios, we tested whether polygenic liability for neurodevelopmental and psychiatric disorders and lower cognitive ability is over-transmitted to ADHD probands. We also tested for indirect or ‘genetic nurture’ effects, by examining whether non-transmitted ADHD polygenic liability is elevated. Finally, we examined whether complete trios are representative of the clinical ADHD population.\ud \ud Methods\ud Polygenic risk scores (PRS) for ADHD, anxiety, autism, bipolar disorder, depression, obsessive-compulsive disorder (OCD), schizophrenia, Tourette’s syndrome, and cognitive ability were calculated in UK controls (N=5,081), UK probands with ADHD (N=857), their biological parents (N=328 trios), and also a replication sample of 844 ADHD trios.\ud \ud Results\ud ADHD PRS were over-transmitted and cognitive ability and OCD PRS were under-transmitted. These results were independently replicated. Over-transmission of polygenic liability was not observed for other disorders. Non-transmitted alleles were not enriched for ADHD liability compared to controls. Probands from incomplete trios had more hyperactive-impulsive and conduct disorder symptoms, lower IQ, and lower socioeconomic status than complete trios. PRS did not vary by trio status.\ud \ud Conclusions\ud The results support direct transmission of polygenic liability for ADHD and cognitive ability from parents to offspring, but not for other neurodevelopmental/psychiatric disorders. They also suggest that non-transmitted neurodevelopmental/psychiatric parental alleles do not contribute indirectly to ADHD via genetic nurture. Furthermore, ascertainment of complete ADHD trios may be non-random, in terms of demographic and clinical factors.

BackgroundADHD and autism are neurodevelopmental conditions, for which non-specific precursors or early signs include difficulties with language and motor skills, and differences in temperament in the first and second year of life. These early features have also been linked to later diagnosis of schizophrenia which is widely considered to have neurodevelopmental origins. Given that ADHD, autism and schizophrenia are all highly heritable, we tested the hypothesis that in the general population, measures of toddler language development, motor development and temperament are associated with genetic liability to ADHD, autism and/or schizophrenia.MethodsData were analysed from the Avon Longitudinal Study of Parents and Children (ALSPAC) which included motor development scores at age 18 months and language development and temperament scores at age 24 months (N = 7498). Genetic liability was indexed by polygenic risk scores (PGS) for ADHD, autism and schizophrenia.ResultsADHD PGS were associated with specific temperament scales (higher activity β = 0.07, 95% CI = 0.04, 0.09 and lower withdrawal β = −0.05, 95% CI = −0.07, −0.02) as well as better gross motor scores (β = 0.04, 95% CI = 0.01, 0.06). Schizophrenia PGS were associated with one specific temperament scale (negative mood β = 0.04, 95% CI = 0.02, 0.07). We did not find strong evidence of association of autism PGS with any of the toddler measures; there was also not strong evidence of association with motor or language delays for any of the PGS.ConclusionsThis study suggests that some specific aspects of early temperament and gross motor differences in the general population could represent part of the early manifestation of genetic liability to neurodevelopmental conditions.Key pointsPrecursors or early signs of ADHD, autism and schizophrenia include difficulties with language and motor skills, and differences in temperament in the first 2 years of lifeWe investigated associations for genetic liability to ADHD, autism and schizophrenia with motor, language and temperament scores at 18–24 monthsWe found ADHD genetic liability to be associated with better gross motor scores, higher activity and lower withdrawal and schizophrenia genetic liability to be associated with increased negative mood; we did not find strong evidence of association for autism genetic liabilitySpecific aspects of toddler temperament and gross motor differences in the general population could represent part of the early manifestation of genetic liability to neurodevelopmental conditions

Purpose: Relative age within the school year (“relative age”) is associated with increased rates of symptoms and diagnoses of mental health disorders, including ADHD. We aimed to investigate how relative age influences mental health and behaviour before, during, and after school (age range: 4-25 years). Method: We used a regression discontinuity design to examine the effect of relative age on risk of mental health problems using data from a large UK population-based cohort (Avon Longitudinal Study of Parents and Children (ALSPAC); N=14643). We compared risk of mental health problems between ages 4 and 25 years using the parent-rated Strengths and Difficulties Questionnaire (SDQ), and depression using self-rated and parent-rated Short Mood and Feelings Questionnaire (SMFQ) by relative age. Results: The youngest children in the school year have greater parent-rated risk of mental health problems, measured using parent-rated SDQ total difficulties scores. We found no evidence of differences before school entry (estimated standardized mean difference (SMD) between those born on 31st August and 1st September: 0.02 [-0.05, 0.08]). We found that estimates of effect size for a one-year difference in relative age were greatest at eleven years (SMD: 0.22 [0.15, 0.29]), but attenuated to the null at twenty-five years (SMD: -0.02 [-0.11, 0.07]). We did not find consistent evidence of differences in self-rated and parent-rated depression by relative age. Conclusion: Younger relative age is associated with poorer parent-rated general mental health, but not symptoms of depression.

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.

Objective: We investigated whether “late-onset” ADHD that emerges in adolescence/adulthood is similar in risk factor profile to: (1) child-onset ADHD, but emerges later because of scaffolding/compensation from childhood resources; and (2) depression, because it typically onsets in adolescence/adulthood and shows symptom and genetic overlaps with ADHD. Methods: We examined associations between late-onset ADHD and ADHD risk factors, cognitive tasks, childhood resources and depression risk factors in a population-based cohort followed-up to age 25 years ( N=4224–9764). Results: Parent-rated late-onset ADHD was like child-onset persistent ADHD in associations with ADHD polygenic risk scores and cognitive task performance, although self-rated late-onset ADHD was not. Late-onset ADHD was associated with higher levels of childhood resources than child-onset ADHD and did not show strong evidence of association with depression risk factors. Conclusions: Late-onset ADHD shares characteristics with child-onset ADHD when parent-rated, but differences for self-reports require investigation. Childhood resources may delay the onset of ADHD.

Early-onset disruptive, aggressive, and antisocial behavior is persistent, can become increasingly serious as children grow older, and is difficult to change. In 2007, our group proposed a theoretical model highlighting the interplay between neurobiological deficits and cognitive and emotional functioning as mediators of the link between genetic influences and early social adversity, on the one hand, and antisocial behavioral problems in childhood, on the other. In this article, we review the post-2007 evidence relevant to this model. We discuss research on genetics/epigenetics, stress/arousal regulation, and emotion and executive functioning in support of the argument that antisocial children, especially those who persist in engaging in antisocial behavior as they grow older, have a range of neuropsychological characteristics that are important in explaining individual differences in the severity and persistence of antisocial behavior. Current clinical practice tends not to acknowledge these individual neuropsychological risks factors or to target them for intervention. We argue that aggressive and disruptive behavior in childhood should be regarded as a neurodevelopmental problem and that intervening at the level of mediating neuropsychological processes represents a promising way forward in tackling these serious behavioral problems. Expected final online publication date for the Annual Review of Psychology, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

ObjectivesWe investigated the feasibility and validity of establishing a nationwide e-cohort of individuals with a diagnosis of ADHD and/or ASD for future longitudinal research.DesignIndividuals 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.SettingThis study utilised data from the Welsh Secure Anonymised Information Linkage (SAIL) Databank in Wales, UK. Routinely collected data from primary care, Emergency Department and hospital admissions were linked at person level.ParticipantsAll individuals in Wales, UK born between 01/01/1991 and 31/12/2000. Individuals with a recorded diagnosis of ADHD and/or ASD by age 18 years were identified using ICD-10 and NHS Read codes and matched to three controls each and 154 individuals with ADHD recruited from an established research study.Outcome measuresRecorded service use for anxiety and depression, alcohol and drug use and self-harm including Emergency Department use in young adulthood (age 16 years to 25).Results7726 individuals had a recorded diagnosis of ADHD (80% male) and 5001 of ASD (79% male); % 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:2.20,2.53), self-harm (HR: 5.70, 95% CI:5.07,6.40), alcohol (HR:3.95, 95%CI:3.42,4.56), drug use (HR:5.88, 95%CI:5.08,6.80) and Emergency department service use (HR:1.36, 95%CI:1.31,1.41). Those with ASD were at increased risk of anxiety/depression (HR:2.11, 95%CI: 1.91,2.34), self-harm (HR:2.93, 95%CI: 2.45,3.50) and drug use (HR:2.21, 95%CI: 1.66,2.95) but not alcohol use. The ADHD e-cohort were similar to the directly assessed cohort.ConclusionsOur 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.Article summaryStrengths and limitations of this studyThis study used population wide administrative data from a well-established and comprehensive databankData from both primary and secondary care was combinedThe study utilised a directly assessed sample of those with ADHD to help validate the establishment of the administratively identified sampleNot all individuals had passed through the whole follow up period at the end of the studyStudies utilising administrative data is dependent upon that data having been collected an recorded.

Autism is a neurodevelopmental condition with a very heterogeneous presentation. Autistic people are more likely to have unmet healthcare needs, making it essential that healthcare professionals are ‘autism-aware’. In this article, we provide an overview of how autism presents and use case studies to illustrate how a neurological consultation in an outpatient clinic environment could prove challenging for a autistic person. We suggest how to improve communication with autistic patients in clinic and highlight the importance of a patient-centred and flexible approach.

Purpose To identify the magnitude and impact of seasonal variations in vitamin D in physically active, ambulatory men with cerebral palsy on neuromuscular performance outcomes and bone indices. Materials & Methods A longitudinal observational study, in sixteen ambulant men with cerebral palsy aged 21.0 ± 1.3 years and 16 healthy, physical activity matched, typically developed controls aged 25.4 ± 2.6 years, completed assessments of serum 25-hydroxyvitamin D and parathyroid hormone during winter and summer. Neuromuscular outcomes included Vastus Lateralis size, knee extensor strength, 10 m sprint, vertical jumps, and grip strength. Bone ultrasounds were performed to obtain radius and tibia T and Z scores. Results Men with cerebral palsy and typically developed controls showed a 70.5% and 85.7% increase in serum 25-hydroxyvitamin D from winter to summer months (p p

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.

Attention-Deficit Hyperactivity Disorder (ADHD) has long been recognized as being a highly heritable condition and our understanding of the genetic contributions to ADHD has grown over the past few decades. This chapter will discuss the studies that have examined its heritability and the efforts to identify specific genetic risk-variants at the molecular genetic level. We outline the various techniques that have been used to characterize genetic contributions to ADHD, describing what we have learnt so far, what there is still to learn and the methodologies that can be used to further our knowledge. In doing so we will discuss research into rare and common genetic variants, polygenic risk scores, and gene-environment interplay, while also describing what genetic studies have revealed about the biological processes involved in ADHD and what they have taught us about the overlap between ADHD and other psychiatric and somatic disorders. Finally, we will discuss the strengths and limitations of the current methodologies and clinical implications of genetic research to date.

BackgroundAttention deficit hyperactivity disorder (ADHD) is highly heritable, but little is known about the relative effects of transmitted (i.e. direct) and non-transmitted (i.e. indirect) common variant risks. Using parent-offspring trios, we tested whether polygenic liability for neurodevelopmental and psychiatric disorders and lower cognitive ability is over-transmitted to ADHD probands. We also tested for indirect or ‘genetic nurture’ effects, by examining whether non-transmitted ADHD polygenic liability is elevated. Finally, we examined whether complete trios are representative.MethodsPolygenic risk scores (PRS) for ADHD, anxiety, autism, bipolar disorder, depression, obsessive-compulsive disorder (OCD), schizophrenia, Tourette’s syndrome, and cognitive ability were calculated in UK controls (N=5,081), UK probands with ADHD (N=857), and, where available, their biological parents (N=328 trios), and also a replication sample of 844 ADHD trios.ResultsADHD PRS were over-transmitted and cognitive ability and OCD PRS were under-transmitted to probands. These results were independently replicated. Over-transmission of polygenic liability was not observed for other disorders. Non-transmitted alleles were not enriched for ADHD liability compared to controls. Probands from incomplete trios had more hyperactive-impulsive and conduct disorder symptoms, lower IQ, and lower socioeconomic status than complete trios. PRS did not vary by trio status.ConclusionsThe results support direct transmission of polygenic liability for ADHD and cognitive ability from parents to offspring, but not for other neurodevelopmental/psychiatric disorders. They also suggest that non-transmitted neurodevelopmental/psychiatric parental alleles do not contribute indirectly to ADHD via genetic nurture. Furthermore, ascertainment of complete ADHD trios may be non-random, in terms of demographic and clinical factors.

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.

The experience of stigma by autistic people is relatively understudied, despite contributing to a range of poor outcomes and having an overarching impact on well-being. The current review of the literature synthesizes research to determine what is currently known and presents a theoretical model of autism stigma. Autism stigma is primarily influenced by a public and professional understanding of autism in combination with interpretation of visible autistic traits. Moderating factors include the quality and quantity of contact with autistic people, cultural factors, sex and gender, individual differences, and diagnostic disclosure. Stigma can reduce well-being as well as increase the presence of camouflaging behaviors, which mask autistic traits. Caregivers of autistic people can experience stigma by association, that is, affiliate stigma, which can impact their own well-being. A variety of interventions and approaches to reduce stigma are discussed, including "autism friendly" spaces, positive media representation, educational and psychosocial training for the public and professionals, as well as cultural and systemic shifts that foster inclusivity and recognize neurodiversity.Autistic people are known to experience stigma. This means that they can face ignorance, prejudice, and discrimination.The purpose of the article was to review research on autism stigma. We wanted to better understand autism stigma. We looked at why autistic people and their families experienced stigma. We also looked at what factors influenced stigma and the impact of stigma. Last, we discussed how to reduce stigma for autistic people and their families.We summarized the research findings into a model. Autism stigma is affected by people's understanding of autism and by visible autistic traits. Poor understanding of autism means that visible autistic traits may be viewed negatively. Certain factors influence the amount of stigma. One factor was the quality and quantity of contact that autistic people have with others. Another factor was cultural differences, such as specific beliefs about autism. Sex and gender were important, as were other differences such as education and age. Last, whether an autistic person had shared their diagnosis affected stigma. Autism stigma had a negative impact on well-being. This included poor mental and physical health, as well as reduced social connections. Autism stigma also led to increased “camouflaging” of autistic traits. Family members also experienced stigma, which can affect their own well-being. Reducing autism stigma is important. To reduce stigma people should create more “autism friendly” spaces. They should include more positive representations of autistic people in the media. They should also improve the autism education of the public and professionals. Last, they should support neurodiversity.We need to better understand the factors that lead to autism stigma. We also need more effective ways to reduce stigma for autistic people and their families. Including the autistic community in this research process is very important.The review shows how stigma affects the autistic community. Autistic adults may find that the model helps them understand their own experiences of stigma. We hope the review will help develop more research into how to reduce autism stigma. Reducing autism stigma will improve the lives of autistic adults.

ObjectivesTo coproduce a school-based protocol and examine acceptability and feasibility of collecting saliva samples for genetic studies from secondary/high school students for the purpose of mental health research.DesignProtocol coproduction and mixed-methods feasibility pilot.SettingSecondary schools in Wales, UK.ParticipantsStudents aged 11–13 years.Primary and secondary outcome measuresCoproduced research protocol including an interactive science workshop delivered in schools; school, parental and student recruitment rates; adherence to protocol and adverse events; ability to extract and genotype saliva samples; student enjoyment of the science workshop and qualitative analysis of teacher focus groups on acceptability and feasibility.ResultsFive secondary schools participated in the coproduction phase, and three of these took part in the research study (eligible sample n=868 students). Four further schools were subsequently approached, but none participated. Parental opt-in consent was received from 98 parents (11.3% eligible sample), three parents (0.3%) actively refused and responses were not received for 767 (88.4%) parents. We obtained saliva samples plus consent for data linkage for 79 students. Only one sample was of insufficient quality to be genotyped. The science workshop received positive feedback from students. Feedback from teachers showed that undertaking research like this in schools is viewed as acceptable in principle, potentially feasible, but that there are important procedural barriers to be overcome. Key recommendations include establishing close working relationships between the research team and school classroom staff, together with improved methods for communicating with and engaging parents.ConclusionsThere are major challenges to undertaking large-scale genetic mental health research in secondary schools. Such research may be acceptable in principle, and in practice DNA collected from saliva in classrooms is of sufficient quality. However, key challenges that must be overcome include ensuring representative recruitment of schools and sufficient parental engagement where opt-in parental consent is required.

IntroductionCurrent psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic and environmental risk factors are shared across disorders. However, the relationship between shared symptomatology and shared genetic liability is still poorly understood. Well-characterised, cross-disorder samples are needed to investigate this matter, but currently few exist, and severe mental disorders are poorly represented in existing biobanking efforts. Purposely curated and aggregated data from individual research groups can fulfil this unmet need, resulting in rich resources for psychiatric research.Methods and analysesAs part of the Cardiff MRC Mental Health Data Pathfinder, we have curated and harmonised phenotypic and genetic information from 15 studies within the MRC Centre for Neuropsychiatric Genetics and Genomics to create a new data repository, DRAGON-DATA. To date, DRAGON-DATA includes over 45,000 individuals: adults or children with psychiatric diagnoses, affected probands with family members and individuals who carry a known neurodevelopmental copy number variant (ND-CNV). We have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all datasets with genotype information have undergone rigorous quality control, imputation, CNV calling and polygenic score generation.Ethics and DisseminationDRAGON-DATA combines genetic and non-genetic information and is available as a resource for research across traditional psychiatric diagnostic categories. Its structure and governance follow standard UK ethical requirements (at the level of participating studies and the project as a whole) and conforms to principles reflected in the EU data protection scheme (GDPR). Algorithms and pipelines used for data harmonisation are currently publicly available for the scientific community, and an appropriate data sharing protocol will be developed as part of ongoing projects (DATAMIND) in partnership with HDR UK.

SummaryTo investigate the accuracy of the age-at-onset criterion in those who meet other DSM-5 criteria for attention-deficit hyperactivity disorder, using a prospective population cohort we compared four different approaches to asking those aged 25 years (n = 138) when their symptoms started. Receiver operating characteristic curves showed variation between the approaches (χ(3) = 8.99, P = 0.03); all four showed low discrimination against symptoms that had been assessed when they were children (area under the curve: 0.57–0.68). Asking adults to recall specific symptoms may be preferable to recalling at what age symptoms started. However, limitations to retrospective recall add to debate on the validity of ADHD age-at-onset assessment.

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.

Attention Deficit Hyperactivity Disorder (ADHD) symptoms typically onset early and persist into adulthood for many. Robust investigation of symptom continuity and discontinuity requires repeated assessments using the same measure, but research is lacking into whether measures used to assess ADHD symptoms in childhood are also valid in adulthood. The Strengths and Difficulties Questionnaire (SDQ) is widely used to assess ADHD symptoms in children, but little is known about its utility in adulthood. The aim of this study was to assess the validity of the SDQ hyperactivity/ADHD subscale to distinguish between cases and non-cases of DSM-5 ADHD at age 25 years in a UK population cohort (N = 4121). ADHD diagnosis was derived using the Barkley Adult ADHD Rating Scale-IV. Analyses suggested that the self-rated SDQ ADHD subscale had high validity in distinguishing ADHD cases/non-cases in young adulthood (area under the curve=0.90, 95% CI=0.87–0.93) and indicated a lower cut-point for identifying those who may have an ADHD diagnosis in this age group compared to that currently recommended for younger ages. Findings were similar for parent-reports. Our findings suggest that the SDQ is suitable for ADHD research across different developmental periods, which will aid the robust investigation of ADHD from childhood to young adulthood.

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.

Background\ud The mental health consequences of school closure, social isolation, increased financial and emotional stress, and greater exposure to family conflicts are likely to be pronounced for primary school children who are known to be vulnerable. Data from prior to the pandemic are needed to provide robust assessments of the impact of COVID‐19 on vulnerable children.\ud \ud Method\ud The present study capitalises on an ongoing study of primary school children (4–8 years) identified as ‘at‐risk’ for mental health problems by teachers. We collected mental health and socio‐economic data prior to the pandemic and re‐assessed this cohort (n = 142) via researcher‐led video calls during the pandemic to evaluate the social and emotional impacts of COVID‐19 for these families.\ud \ud Results\ud Mental health problems, particularly anxiety, increased significantly in these children. Parental mental health difficulties (anxiety and depression) were also prevalent. There were higher reports of financial stress during lockdown amongst low‐income families previously identified as living in poverty, prior to the COVID‐19 pandemic. Financial strain was found to indirectly predict increases in child mental health problems through parental mental health.\ud \ud Conclusion\ud These findings show that the pandemic exacerbated mental health problems in already vulnerable children. These negative outcomes were explained by financial stress (e.g., lost employment, loss of income and inability to pay bills), which was negatively linked to parental mental health.

Attention Deficit Hyperactivity Disorder (ADHD) symptoms typically onset early in development and persist into adulthood for many. Robust investigation of symptom continuity and discontinuity requires repeated assessments using the same measure, but research is lacking into whether measures used to assess ADHD symptoms in childhood are also valid in adulthood. The Strengths and Difficulties Questionnaire (SDQ) has been widely used to measure ADHD symptoms in children, but little is known about its utility to measure ADHD in adulthood. We used Receiver Operating Characteristic (ROC) curve analyses to examine the validity of the SDQ hyperactivity/ADHD subscale to distinguish between cases and non-cases of DSM-5 ADHD classified using the Barkley Adult ADHD Rating Scale-IV (BAARS-IV) at age 25 years in a UK population cohort (N=4121). Analyses suggested that the SDQ ADHD subscale had high accuracy in distinguishing ADHD cases from non-cases in young adulthood (area under the curve=0.90, 95% CI=0.87-0.93) and indicated a lower cut-point for identifying those who may have an ADHD diagnosis in this age group compared to that currently recommended for younger ages.Our findings suggest that the SDQ is suitable for ADHD research across different developmental periods, which will aid the robust investigation of ADHD from childhood to young adulthood.HighlightsThe SDQ is widely used to measure ADHD symptoms in childrenWe investigated the validity of the SDQ to assess ADHD at age 25 yearsThe SDQ ADHD subscale had high accuracy in distinguishing DSM-5 ADHD cases from non-casesA lower cut-point is needed to identify ADHD diagnosis in young adulthood compared to younger agesThe SDQ is appropriate for ADHD research across different development periods

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.

BackgroundRecent case-control genetic studies of attention deficit hyperactivity disorder (ADHD) have implicated common and rare genetic risk alleles, highlighting the polygenic and complex aetiology of this neurodevelopmental disorder. Studies of other neurodevelopmental disorders, such as autism spectrum disorder (ASD), Tourette disorder, developmental delay/intellectual disability, and schizophrenia indicate that identification of specific risk alleles and additional insights into disorder biology can be gained by studying non-inherited de novo variation. In this study, we aimed to identify large de novo copy number variants (CNVs) in children with ADHD.MethodsChildren with a confirmed diagnosis of ADHD and their parents were genotyped and included in this sample. We used PennCNV to call large (>200kb) CNVs and identified those calls that were present in the proband and absent in both biological parents.ResultsIn 305 parent-offspring trios, we detected 14 de novo CNVs in 13 probands, giving a mutation rate of 4.6% and a per individual rate of 4.3%. This rate is higher than published reports in controls and similar to those observed for ASD, schizophrenia and Tourette disorder. We also identified de novo mutations at 4 genomic loci (15q13.1-13.2 duplication, 16p13.11 duplication, 16p12.2 deletion and 22q11.21 duplication) that have previously been implicated in other neurodevelopmental disorders, two of which (16p13.11 and 22q11.21) have also been implicated in case-control ADHD studies.ConclusionsOur study complements ADHD case-control genomic analyses and demonstrates the need for larger parent-offspring trio genetic studies to gain further insights into the complex aetiology of ADHD.

Studies have demonstrated that attention-deficit/hyperactivity disorder (ADHD) is a highly heritable disorder. The evidence for this and the investigation into specific genetic risk factors associated with the disorder are discussed in this chapter. Both common and rare genetic risk variants have been identified for the disorder, although sample sizes have limited the discovery of such risk factors to date. Identification of additional risk factors, as well as further investigation to understand the role of these factors in the pathophysiology of ADHD, are now under way. As with other multifactorial disorders, there are both genetic and environmental risks associated with ADHD, and the interplay of these different risk types, as well as how they have been studied, is discussed. ADHD is a phenotypically heterogenous disorder, and the influences of comorbid conditions and developmental age on the genetic risk factors for the disorder are considered, as well as the genetic overlap between ADHD and other psychiatric conditions.

Providing antenatal and postnatal support for women who drink alcohol in pregnancy is only possible if those at risk can be identified. However, screening will only be helpful if women feel comfortable with the method used. We conducted a survey of pregnant women and their partners to investigate self-reported beliefs and practice regarding drinking during pregnancy and the acceptability of screening. Pregnant women and their partners attending antenatal clinics in North-East England were asked to complete a short survey regarding their alcohol consumption in pregnancy, their beliefs about safe levels of alcohol in pregnancy and whether they would be happy to have their blood or their baby’s meconium analysed for alcohol biomarkers. The data were summarised using descriptive statistics and thematic analysis. A total of 171 pregnant women and 41 partners participated. Of the pregnant women, 153 (89.5%) felt women should abstain from alcohol consumption, although only 70 (40.9%) reported not drinking in pregnancy. Of 96 women who reported drinking in pregnancy and reported when they stopped, all but six (6.3%) stopped drinking when they found out they were pregnant. Of women and partners who recorded an answer, 177 (87.2%) said they would consent to blood biomarker analysis. Confusion over what level of alcohol is safe and using screening as an opportunity for education and support emerged as key themes from free-text responses. Most women viewed screening for alcohol in pregnancy positively, although its acceptability in the small number of women who continue to drink is unclear.

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.

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

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.

This chapter reviews the evidence suggesting that there is a strong genetic component to ADHD and the efforts to identify the specific genetic factors that might be involved. It discusses the different types of genetic contributions, from common to rare variants, and the evidence that these are involved in the aetiology of the disorder. An overview of the methodological strategies employed, including genome-wide association studies (GWAS), polygenic risk score, and copy number variant (CNV) analyses, is undertaken, as well as discussion of the strengths and pitfalls of such work. The contradictory findings in the field and controversies that arise as a result are also explored. Finally, this chapter considers how the heritability of ADHD and specific genetic factors involved need to be examined in the context of clinical factors such as comorbidity and how these factors affect investigations into the genetics of ADHD.