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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.

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/hyperactivity 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.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

Impairments in cognitive processes and their associations with dimensional measures of inattention, hyperactivity-impulsivity and anxiety were examined in children at risk of Attention-Deficit Hyperactivity Disorder. Children referred by teachers for exhibiting ADHD-type problems (n = 116; 43 meeting full diagnostic criteria for ADHD; 4–8 years) completed computerized tasks measuring episodic memory, response inhibition, visuomotor control and sustained attention, while parents were interviewed (DAWBA) to assess ADHD and anxiety symptoms. Of the 116 children assessed, 72% exhibited impaired cognitive processes; 47% had impaired visuomotor control, 37% impaired response inhibition, and 35% had impaired episodic memory. Correlational and hierarchical regression analyses using our final analytic sample (i.e., children who completed all cognitive tasks and a vocabulary assessment, n = 114) showed that poorer task performance and greater within-subject variability were significantly associated with more severe inattention symptoms but not with hyperactivity-impulsivity severity. Symptoms of separation anxiety, which were reported in over half of the sample, moderated associations between inattention and episodic memory, and between inattention and inhibition. Only children without separation anxiety showed significant correlations between ADHD symptoms and poor performance. However, separation anxiety had no moderating effect on associations between inattention and visuomotor control or sustaining attention. Children exhibiting signs of ADHD show impairments across a range of cognitive tasks. Further research to improve our understanding of these processes may be useful in the development of early interventions. Our results suggest that separation anxiety should be taken into account when considering interventions to address emerging neuropsychological deficits associated with this disorder. [ABSTRACT FROM AUTHOR]

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

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.

ObjectiveAttention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology.MethodThe authors performed a genome-wide analysis of large, rare CNVs (100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder.ConclusionsThese findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5–3.6), this locus could be an important contributor to ADHD etiology.

ObjectiveA major motivation for seeking disease-associated genetic variation is to identify novel risk processes. Although rare copy number variants (CNVs) appear to contribute to attention deficit hyperactivity disorder (ADHD), common risk variants (single-nucleotide polymorphisms [SNPs]) have not yet been detected using genome-wide association studies (GWAS). This raises the concern as to whether future larger-scale, adequately powered GWAS will be worthwhile. The authors undertook a GWAS of ADHD and examined whether associated SNPs, including those below conventional levels of significance, influenced the same biological pathways affected by CNVs.MethodThe authors analyzed genome-wide SNP frequencies in 727 children with ADHD and 5,081 comparison subjects. The gene sets that were enriched in a pathway analysis of the GWAS data (the top 5% of SNPs) were tested for an excess of genes spanned by large, rare CNVs in the children with ADHD.ResultsNo SNP achieved genome-wide significance levels. As previously reported in a subsample of the present study, large, rare CNVs were significantly more common in case subjects than comparison subjects. Thirteen biological pathways enriched for SNP association significantly overlapped with those enriched for rare CNVs. These included cholesterol-related and CNS development pathways. At the level of individual genes, CHRNA7, which encodes a nicotinic receptor subunit previously implicated in neuropsychiatric disorders, was affected by six large duplications in case subjects (none in comparison subjects), and SNPs in the gene had a gene-wide p value of 0.0002 for association in the GWAS.ConclusionsBoth common and rare genetic variants appear to be relevant to ADHD and index-shared biological pathways.

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. [ABSTRACT FROM AUTHOR]

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.

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 additional 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 unidimensionality 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 developed using the empirically generated item hierarchy may help to improve assessment and intervention.

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 = 0.02). 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. (Contains 3 tables and 1 figure.)