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

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

Why are females less likely to be diagnosed with ADHD in childhood than males?

ADHD is less likely to be diagnosed in females than males, especially in childhood. Females also typically receive the diagnosis later than males and are less likely to be prescribed ADHD medication. Understanding why these sex differences in clinical care and treatment for ADHD occur is key to improving timely diagnosis in people affected by ADHD. This Personal View is a conceptual review synthesising literature on this topic. This publication considers potential biological explanations (eg, genetic factors), influence of diagnostic practices (eg, criteria suitability, diagnostic overshadowing, and sex-specific diagnostic thresholds), and sociocultural explanations (eg, sex differences in presentation and compensatory behaviours), for the observed sex differences in ADHD clinical practice. This Personal View also outlines future research directions for improving understanding of sex differences in recognition and diagnosis of ADHD.

Polygenic Variation Underlying Educational Attainment and Attention-Deficit/Hyperactivity Disorder Indexes Behavior Ratings of Executive Functions in Child Psychiatry Outpatients.

OBJECTIVE: We leveraged common genetic variation underlying ADHD, educational attainment (EA) and cognition (COG) to understand the nature of the Behavior Rating Inventory for Executive Functions (BRIEF) and its relationship to academic functioning. METHOD: Participants were 991 youth, ages 7 to 17, consecutively referred for neuropsychiatric evaluation. Polygenic scores (PGS) for ADHD, EA, and COG were related to the BRIEF using regression analyses. Structural equation models were used to examine the associations between the PGS, BRIEF and academic outcomes (math, reading, and special education services [EDPLAN]). RESULTS: After modeling the PGS together, only the EA and ADHD PGS significantly associated with the BRIEF. The BRIEF partially mediated the relationships between EA PGS with math and EDPLAN and fully mediated the relationship between ADHD PGS and EDPLAN. CONCLUSION: Genetic data extend evidence that the BRIEF measures a construct relevant to educational success that differs from what is indexed by cognitive testing.

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

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

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

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

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

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

A twin study of genetic and environmental contributions to attention-deficit/hyperactivity disorder over time.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is an increasingly commonly diagnosed neurodevelopmental condition. One possibility is that this reflects a genuine increase in the prevalence of ADHD due to secular environmental changes, yet this hypothesis remains untested. We therefore investigated whether the genetic and environmental variance underlying ADHD, and traits of ADHD, has changed over time. METHODS: We identified twins born from 1982 to 2008 from the Swedish Twin Registry (STR). We linked the STR with the Swedish National Patient Register and Prescribed Drug Register to identify diagnoses of ADHD and prescriptions of ADHD medication for these twins. We also utilized data collected from participants in the Child and Adolescent Twin Study in Sweden (CATSS), born from 1992 to 2008. Their parents completed a structured ADHD screening tool, which was used to measure traits of ADHD and assign broad screening diagnoses of ADHD. We used the classical twin design to test whether the degree to which variation in these measures was influenced by genetic and environmental variation changed over time. RESULTS: We included 22,678 twin pairs from the STR and 15,036 pairs from CATSS. The heritability of ADHD in the STR ranged from 66% to 86% over time, although these fluctuations were not statistically significant. We observed a modest increase in variance in ADHD traits, from 0.98 to 1.09. This was driven by small increases in the underlying genetic and environmental variance, with heritability estimated as 64%-65%. No statistically significant changes in variance in screening diagnoses were observed. CONCLUSIONS: The relative contribution of genetic and environmental factors to ADHD has remained stable over time, despite its increasing prevalence. Thus, changes in the underlying etiology of ADHD over time are unlikely to explain the increase in ADHD diagnoses.

Examining neurodevelopmental problems in 15q11.2 (BP1-BP2) copy number variation carriers at ages 9/12 and 18 in a Swedish twin sample.

BACKGROUND: Several copy number variations (CNVs) are associated with increased risk for neurodevelopmental and psychiatric disorders. The CNV 15q11.2 (BP1-BP2) deletion has been associated with learning difficulties, attention deficit hyperactivity disorder (ADHD), epilepsy, and brain morphology; however, many carriers present mild or no symptoms. Carrying the reciprocal duplication does not seem to confer risk for these disorders or traits. Our aim was to examine the impact of carrying either 15q11.2 deletion and reciprocal duplication on neurodevelopmental problems in a population-based sample of children. METHODS: Twins with genotype and phenotype information in the Child and Adolescent Twin Study in Sweden (CATSS) were included (N = 12,040). We included measures of neurodevelopmental problems (NDPs), including learning problems, from the questionnaire Autism-Tics, ADHD, and other Comorbidities inventory (A-TAC) at age 9/12, ADHD and autism spectrum disorder (ASD) questionnaires at age 18, as well as information about lifetime psychiatric diagnoses and epileptic seizures. We tested the association between these phenotypic measurements and carrying the 15q11.2 deletion, the reciprocal duplication, and other CNVs with previously reported strong associations with neurodevelopmental and psychiatric disorders (i.e., psychiatric CNVs). RESULTS: We identified 57 carriers of the 15q11.2 deletion, 75 carriers of the reciprocal duplication, and 67 carriers of other psychiatric CNVs. We did not find an increased risk for NDPs or psychiatric diagnoses in the 15q11.2 deletion carriers. For 15q11.2 duplication carriers, we found an increased risk for math learning problems and fewer self-reported ADHD symptoms at age 18 but not for other NDPs. In line with previous studies, we found an increased risk of NDPs and other evaluated phenotypes in carriers of psychiatric CNVs. CONCLUSIONS: Our results support previous findings that carrying 15q11.2 deletion does not have a large effect on NDPs in children.

Quality control and analytic best practices for testing genetic models of sex differences in large populations.

Phenotypic sex-based differences exist for many complex traits. In other cases, phenotypes may be similar, but underlying biology may vary. Thus, sex-aware genetic analyses are becoming increasingly important for understanding the mechanisms driving these differences. To this end, we provide a guide outlining the current best practices for testing various models of sex-dependent genetic effects in complex traits and disease conditions, noting that this is an evolving field. Insights from sex-aware analyses will not only teach us about the biology of complex traits but also aid in achieving the goals of precision medicine and health equity for all.

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

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

DRAGON-Data: a platform and protocol for integrating genomic and phenotypic data across large psychiatric cohorts.

BACKGROUND: Current 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 symptoms and shared genetic liability is still poorly understood. AIMS: Well-characterised, cross-disorder samples are needed to investigate this matter, but few currently exist. Our aim is to develop procedures to purposely curate and aggregate genotypic and phenotypic data in psychiatric research. METHOD: As part of the Cardiff MRC Mental Health Data Pathfinder initiative, we have curated and harmonised phenotypic and genetic information from 15 studies to create a new data repository, DRAGON-Data. To date, DRAGON-Data includes over 45 000 individuals: adults and children with neurodevelopmental or psychiatric diagnoses, affected probands within collected families and individuals who carry a known neurodevelopmental risk copy number variant. RESULTS: We have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all data-sets with genotype information have undergone rigorous quality control, imputation, copy number variant calling and polygenic score generation. CONCLUSIONS: DRAGON-Data combines genetic and non-genetic information, and is available as a resource for research across traditional psychiatric diagnostic categories. 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 Health Data Research UK.

Candidate diagnostic biomarkers for neurodevelopmental disorders in children and adolescents: a systematic review.

Neurodevelopmental disorders - including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disability, motor disorders, specific learning disorders, and tic disorders - manifest themselves early in development. Valid, reliable and broadly usable biomarkers supporting a timely diagnosis of these disorders would be highly relevant from a clinical and public health standpoint. We conducted the first systematic review of studies on candidate diagnostic biomarkers for these disorders in children and adolescents. We searched Medline and Embase + Embase Classic with terms relating to biomarkers until April 6, 2022, and conducted additional targeted searches for genome-wide association studies (GWAS) and neuroimaging or neurophysiological studies carried out by international consortia. We considered a candidate biomarker as promising if it was reported in at least two independent studies providing evidence of sensitivity and specificity of at least 80%. After screening 10,625 references, we retained 780 studies (374 biochemical, 203 neuroimaging, 133 neurophysiological and 65 neuropsychological studies, and five GWAS), including a total of approximately 120,000 cases and 176,000 controls. While the majority of the studies focused simply on associations, we could not find any biomarker for which there was evidence - from two or more studies from independent research groups, with results going into the same direction - of specificity and sensitivity of at least 80%. Other important metrics to assess the validity of a candidate biomarker, such as positive predictive value and negative predictive value, were infrequently reported. Limitations of the currently available studies include mostly small sample size, heterogeneous approaches and candidate biomarker targets, undue focus on single instead of joint biomarker signatures, and incomplete accounting for potential confounding factors. Future multivariable and multi-level approaches may be best suited to find valid candidate biomarkers, which will then need to be validated in external, independent samples and then, importantly, tested in terms of feasibility and cost-effectiveness, before they can be implemented in daily clinical practice.

Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.

Oncology distress screening within predominately Black Veterans: Outcomes on supportive care utilization, hospitalizations, and mortality.

BACKGROUND: We evaluated whether patients' initial screening symptoms were related to subsequent utilization of supportive care services and hospitalizations, and whether patient-level demographics, symptoms, hospitalizations, and supportive care service utilization were associated with mortality in primarily low-income, older, Black Veterans with cancer. METHODS: This quality improvement project created collaborative clinics to conduct cancer distress screenings and refer to supportive care services at an urban, VA medical center. All patients completed a distress screen with follow-up screening every 3 months. Supportive care utilization, hospitalization rates, and mortality were abstracted through medical records. Poisson regression models and cox proportional hazard models were utilized. RESULTS: Five hundred and eighty five screened patients were older (m = 72), mostly Black 70% (n = 412), and had advanced cancer 54%. Fifty-eight percent (n = 340) were screened only once with 81% (n = 470) receiving ≥1 supportive care service and 51.5% (n = 297) being hospitalized ≥1 time 18 months following initial screen. Symptom severity was significantly related to number of hospitalizations. Low mood was significantly related to higher supportive services (p < 0.001), but not hospitalizations (p ≥ 0.52). Pain, fatigue, physical function, nutrition, and physical symptoms were significantly associated with more supportive services and hospitalizations (p < 0.01). Twenty percent (n = 168) died; Veterans who were Black, had lower stage cancers, better physical health, and utilized less supportive care services had lower odds of mortality (p ≤ 0.01). CONCLUSION: Individuals with elevated distress needs and those reporting lower physical function utilized more supportive care services and had higher hospitalization rates. Lower physical function, greater supportive care use, higher stage cancer, and being non-Black were associated with higher odds of death.

Sleep disturbances in ADHD: investigating the contribution of polygenic liability for ADHD and sleep-related phenotypes.

Sleep disturbances are common in attention deficit hyperactivity disorder (ADHD) and associated with poor outcomes. We tested whether, in children with ADHD, (1) polygenic liability for sleep phenotypes is over- or under-transmitted from parents, (2) this liability is linked to comorbid sleep disturbances, and (3) ADHD genetic risk is associated with comorbid sleep disturbances. We derived polygenic scores (PGS) for insomnia, chronotype, sleep duration, and ADHD, in 758 children (5-18 years old) diagnosed with ADHD and their parents. We conducted polygenic transmission disequilibrium tests for each sleep PGS in complete parent-offspring ADHD trios (N = 328) and an independent replication sample of ADHD trios (N = 844). Next, we tested whether insomnia, sleep duration, and ADHD PGS were associated with co-occurring sleep phenotypes (hypersomnia, insomnia, restless sleep, poor sleep quality, and nightmares) in children with ADHD. Children's insomnia and chronotype PGS did not differ from mid-parent average PGS but long sleep duration PGS were significantly over-transmitted to children with ADHD. This was supported by a combined analysis using the replication sample. Insomnia, sleep duration, and ADHD PGS were not associated with comorbid sleep disturbances. There is weak evidence that children with ADHD over-inherit polygenic liability for longer sleep duration and do not differentially inherit polygenic liability for insomnia or chronotype. There was insufficient evidence that childhood sleep disturbances were driven by polygenic liability for ADHD or sleep traits, suggesting that sleep disturbances in ADHD may be aetiologically different to general population sleep phenotypes and do not index greater ADHD genetic risk burden.

Investigating Direct and Indirect Genetic Effects in Attention-Deficit/Hyperactivity Disorder Using Parent-Offspring Trios.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is highly heritable, but little is known about the relative effects of transmitted (i.e., direct) and nontransmitted (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 overtransmitted to ADHD probands. We also tested for indirect or genetic nurture effects by examining whether nontransmitted ADHD polygenic liability is elevated. Finally, we examined whether complete trios are representative of the clinical ADHD population. METHODS: Polygenic risk scores (PRSs) for ADHD, anxiety, autism, bipolar disorder, depression, obsessive-compulsive disorder, schizophrenia, Tourette syndrome, and cognitive ability were calculated in UK control subjects (n = 5081), UK probands with ADHD (n = 857), their biological parents (n = 328 trios), and also a replication sample of 844 ADHD trios. RESULTS: ADHD PRSs were overtransmitted and cognitive ability and obsessive-compulsive disorder PRSs were undertransmitted. These results were independently replicated. Overtransmission of polygenic liability was not observed for other disorders. Nontransmitted alleles were not enriched for ADHD liability compared with control subjects. 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. CONCLUSIONS: 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 nontransmitted neurodevelopmental/psychiatric parental alleles do not contribute indirectly to ADHD via genetic nurture. Furthermore, ascertainment of complete ADHD trios may be nonrandom, in terms of demographic and clinical factors.

An agenda for future research regarding the mental health of young people with care experience.

Young people who are currently or were previously in state care have consistently been found to have much higher rates of mental health and neurodevelopmental difficulties than the general youth population. While a number of high-quality reviews highlight what research has been undertaken in relation to the mental health of young people with care experience and the gaps in our knowledge and understanding, there is, until now, no consensus, so far as we aware, as to where our collective research efforts should be directed with this important group. Through a series of UK wide workshops, we undertook a consultative process to identify an agreed research agenda between those with lived experience of being in care (n = 15), practitioners, policy makers and researchers (n = 59), for future research regarding the mental health of young people with care experience, including those who are neurodiverse/have a neurodevelopmental difficulty. This consensus statement identified 21 foci within four broad categories: how we conceptualize mental health; under-studied populations; under-studied topics; and underused methodologies. We hope that those who commission, fund and undertake research will engage in this discussion about the future agenda for research regarding the mental health of young people with care experience.

Sex Differences in Mental Health Problems and Psychiatric Hospitalization in Autistic Young Adults.

Importance: Psychiatric disorders are common among autistic children and adults. Little is known about sex differences in psychiatric disorders and hospitalization in early adulthood. Objective: To examine sex differences in psychiatric diagnoses and hospitalizations in autistic compared with nonautistic young adults. Design, Setting, and Participants: This population-based cohort study assessed all individuals born in Sweden between 1985 and 1997. A total of 1 335 753 individuals, including 20 841 autistic individuals (7129 [34.2%] female individuals), were followed up from age 16 through 24 years between 2001 and 2013. Analysis took place between June 2021 and August 2022. Exposures: Autism was defined as having received at least 1 clinical diagnosis of autism based on the International Classification of Diseases. Main Outcomes and Measures: The cumulative incidence of 11 psychiatric diagnoses up until age 25 years was estimated, and birth year-standardized risk difference was used to compare autistic female and male individuals directly. Sex-specific birth year-adjusted hazard ratios (HRs) with 95% CIs were calculated using Cox regression. Analyses were repeated for inpatient diagnoses to assess psychiatric hospitalization. Results: Of 1 335 753 individuals included in this study, 650 314 (48.7%) were assigned female at birth. Autism was clinically diagnosed in 20 841 individuals (1.6%; 7129 [34.2%] female) with a mean (SD) age of 16.1 (5.1) years (17.0 [4.8] years in female individuals and 15.7 [5.2] years in male individuals) for the first recorded autism diagnosis. For most disorders, autistic female individuals were at higher risk for psychiatric diagnoses and hospitalizations. By age 25 years, 77 of 100 autistic female individuals and 62 of 100 autistic male individuals received at least 1 psychiatric diagnosis. Statistically significant standardized risk differences were observed between autistic female and male individuals for any psychiatric disorder (-0.18; 95% CI, -0.26 to -0.10) and specifically for anxiety, depressive, and sleep disorders. Risk differences were larger among autistic than nonautistic individuals. Compared with nonautistic same-sex individuals, autistic female individuals (HR range [95% CI], 3.17 [2.50-4.04.]-20.78 [18.48-23.37]) and male individuals (HR range [95% CI], 2.98 [2.75-3.23]-18.52 [17.07-20.08]) were both at increased risk for all psychiatric diagnoses. Any psychiatric hospitalization was statistically significantly more common in autistic female individuals (32 of 100) compared with autistic male individuals (19 of 100). However, both autistic female and male individuals had a higher relative risk for psychiatric hospitalization compared with nonautistic female and male individuals for all disorders (female individuals: HR range [95% CI], 5.55 [4.63-6.66]-26.30 [21.50-32.16]; male individuals: HR range [95% CI], 3.79 [3.22-4.45]-29.36 [24.04-35.87]). Conclusions and Relevance: These findings highlight the need for profound mental health services among autistic young adults. Autistic female individuals, who experience more psychiatric difficulties at different levels of care, require increased clinical surveillance and support.

Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups.

Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental conditions, with considerable overlap in their genetic etiology. We dissected their shared and distinct genetic etiology by cross-disorder analyses of large datasets. We identified seven loci shared by the disorders and five loci differentiating them. All five differentiating loci showed opposite allelic directions in the two disorders and significant associations with other traits, including educational attainment, neuroticism and regional brain volume. Integration with brain transcriptome data enabled us to identify and prioritize several significantly associated genes. The shared genomic fraction contributing to both disorders was strongly correlated with other psychiatric phenotypes, whereas the differentiating portion was correlated most strongly with cognitive traits. Additional analyses revealed that individuals diagnosed with both ASD and ADHD were double-loaded with genetic predispositions for both disorders and showed distinctive patterns of genetic association with other traits compared with the ASD-only and ADHD-only subgroups. These results provide insights into the biological foundation of the development of one or both conditions and of the factors driving psychopathology discriminatively toward either ADHD or ASD.