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Childhood psychiatric symptoms are often diffuse but can coalesce into discrete mental illnesses during late adolescence. We leveraged polygenic scores (PGSs) to parse genomic risk for childhood symptoms and to uncover related neurodevelopmental mechanisms with transcriptomic and neuroimaging data. In independent samples (Adolescent Brain Cognitive Development, Generation R) a narrow cross-disorder neurodevelopmental PGS, reflecting risk for attention deficit hyperactivity disorder, autism, depression and Tourette syndrome, predicted psychiatric symptoms through early adolescence with greater sensitivity than broad cross-disorder PGSs reflecting shared risk across eight psychiatric disorders, the disorder-specific PGS individually or two other narrow cross-disorder (Compulsive, Mood-Psychotic) scores. Neurodevelopmental PGS-associated genes were preferentially expressed in the cerebellum, where their expression peaked prenatally. Further, lower gray matter volumes in cerebellum and functionally coupled cortical regions associated with psychiatric symptoms in mid-childhood. These findings demonstrate that the genetic underpinnings of pediatric psychiatric symptoms differ from those of adult illness, and implicate fetal cerebellar developmental processes that endure through childhood.

Suicide is among the leading causes of death in children and adolescents. There are well-known risk factors of suicide, including childhood abuse, family conflicts, social adversity, and psychopathology. While suicide risk is also known to be heritable, few studies have investigated genetic risk in younger individuals.Using polygenic risk score analysis, we examined whether genetic susceptibility to major psychiatric disorders is associated with suicidal behaviors among 11,878 children enrolled in the ABCD (Adolescent Brain Cognitive Development) Study. Suicidal ideation and suicide attempt data were assessed using the youth report of the Kiddie Schedule for Affective Disorders and Schizophrenia for DSM-5. After performing robust quality control of genotype data, unrelated individuals of European descent were included in analyses (n = 4344).Among 8 psychiatric disorders we examined, depression polygenic risk scores were associated with lifetime suicide attempts both in the baseline (odds ratio = 1.55, 95% CI = 1.10-2.18, p = 1.27 × 10The largest genetic sample of suicide risk data in U.S. children suggests a significant genetic basis of suicide risk related to attention-deficit/hyperactivity disorder and depression. Further research is warranted to examine whether incorporation of genomic risk may facilitate more targeted screening and intervention efforts.

Large, population-based MRI studies of adolescents promise transformational insights into neurodevelopment and mental illness risk1, 2. However, MRI studies of youth are especially susceptible to motion and other artifacts3, 4. These artifacts may go undetected by automated quality control (QC) methods that are preferred in high-throughput imaging studies,5and can potentially introduce non-random noise into clinical association analyses. Here we demonstrate bias in structural MRI analyses of children due to inclusion of lower quality images, as identified through rigorous visual quality control of 11,263 T1 MRI scans obtained at age 9-10 through the Adolescent Brain Cognitive Development (ABCD) Study6. Compared to the best-rated images (44.9% of the sample), lower-quality images generally associated with decreased cortical thickness and increased cortical surface area measures (Cohen’s d 0.14-2.84). Variable image quality led to counterintuitive patterns in analyses that associated structural MRI and clinical measures, as inclusion of lower-quality scans altered apparent effect sizes in ways that increased risk for both false positives and negatives. Quality-related biases were partially mitigated by controlling for surface hole number, an automated index of topological complexity that differentiated lower-quality scans with good specificity at Baseline (0.81-0.93) and in 1,000 Year 2 scans (0.88-1.00). However, even among the highest-rated images, subtle topological errors occurred during image preprocessing, and their correction through manual edits significantly and reproducibly changed thickness measurements across much of the cortex (d 0.15-0.92). These findings demonstrate that inadequate QC of youth structural MRI scans can undermine advantages of large sample size to detect meaningful associations.

There is growing evidence that processing speed (PS) deficits in youth with neuropsychiatric conditions are associated with functional difficulties. However, there is no consistent definition of slower PS; specifically, whether slower PS should be defined as a discrepancy from same-aged peers (normative weakness) or as an intrapersonal deficit relative to overall cognitive ability (relative weakness). In a sample of clinically-referred youth, we calculated slower PS both ways and examined the impact on adaptive, academic, and psychopathology outcomes in relation to different levels of cognitive ability. Significant PS x cognitive ability interactions were found on adaptive and academic outcomes. A norm-based weakness in PS (PSI Standard Score

The ectodermal dysplasias are a group of rare genetic disorders that are caused by abnormalities in cell and tissue development of the embryonic ectoderm. A paucity of research has systematically examined the cognitive, academic, and psychological phenotype of individuals with ectodermal dysplasia. We describe the neuropsychological profile of a female adolescent with ectodermal dysplasia with hypohidrosis. Using a battery of standardized tests, we assessed the adolescent's intellectual functioning, language processing, visuospatial and visuomotor functioning, perceptual reasoning, sensory-motor functioning, memory, executive functioning, academic functioning, emotional and behavioral functioning, and adaptive functioning. Results from the testing indicated that the adolescent possessed relative verbal strengths, with scores generally falling in the low average to average range. However, she exhibited severe deficits in visuospatial functioning, visuomotor construction/organization, visuomotor integration, visual memory, executive functioning, reading, and math. She also presented with symptoms of anxiety and depression but had relatively strong adaptive skills. Based on the testing results from our evaluation, the adolescent met the criteria for specific learning disorders with impairment in reading and math, generalized anxiety disorder, and major depressive disorder. To our knowledge, this is the first case report to comprehensively characterize the full neuropsychological and academic profile of an adolescent female with ectodermal dysplasia with hypohidrosis. Recommendations from the evaluation are presented to inform clinical practice with, and future research of, this population.

While slow processing speed (PS) is well documented in youth with ADHD, growing evidence suggests that this difficulty affects children with other neuropsychiatric conditions. Clarifying the relationship between slow PS and different forms of psychopathology is important clinically, given the potential impact of PS on academic functioning, and conceptually. In 751 youth, ages 6–21, consecutively referred for neuropsychiatric evaluation, we examined the association between slow PS (i.e., Wechsler PS Index

Behavior rating scales of executive functions (EFs) are convenient and associate with academic and other outcomes; however, prior studies indicate limited correlations with psychometric tests of EFs. To better understand their potential for clinical utility, we examined the extent to which parent ratings on the Behavior Rating Inventory of Executive Function (BRIEF) related to psychopathology constructs and psychometric test scores in a sample of N = 692 psychiatric outpatients aged 8–17. Then, in a subsample of the youth (N = 261), we related the BRIEF, psychopathology constructs, and psychometric test scores to teacher ratings of school functioning. BRIEF scales were significantly associated with multiple types of psychopathology including ADHD, autism spectrum, mood, anxiety, conduct, oppositional defiant, and psychotic disorders. While the BRIEF showed limited associations with psychometric EF tests, its Global Executive Composite score explained additional variance in teacher-reported functioning beyond what was predicted by clinical diagnoses (additional explained variance of 9.9% in study skills) and psychometric tests (additional explained variance of 2.1% in learning problems and 4.5% in study skills). The Global Executive Composite was not significantly related to teacher-rated school functioning after psychiatric symptoms were accounted for. These findings support further investigation of the unique contribution of the BRIEF in clinical practice.

Background Studies are documenting the impact of the COVID-19 pandemic on youth mental health. We extended this literature by characterizing a child psychiatric outpatient sample in the United States during the middle of the 2020–2021 school year. We also used a computational strategy to identify distinct patterns of psychopathology symptom change and examined correlates and predictors of such change. Among potential predictors were cognition and clinical diagnoses, which have not been studied in this context previously. Methods Participants were 171 youth (aged 10.6 ± 3.1) referred for neuropsychiatric evaluation who enrolled in research and whose parents filled out a survey on COVID-19. The questionnaire included eight psychiatric and six psychosocial domains rated retrospectively prior to the pandemic and currently at the time of evaluation. We examined change in severity of individual domains with Wilcoxon signed-rank tests. We used a latent profile analysis (LPA) to identify groups with distinct symptom change profiles. Using multinomial logistic regression, we examined potential predictors and correlates of LPA-derived groups. Models controlled for age, sex, and assessment date and corrected for multiple testing. Results Although the majority of individual psychopathology domains were worse on average during the 2020–2021 school year, youth showed distincive patterns of symptom change. In addition to a large group (72.2%) with relatively stable symptoms and a small group (6.4%) that improved on most symptoms, there were two groups with different constellations of worsening symptoms. These latter groups both showed increased sadness, anxiety and oppositionality; however, one had increased hyperactivity/impulsivity and no change in hopelessness while the other showed greater hopelessness and no change in hyperactivity. Symptoms related to the distinguishable domains of these groups predicted group membership, and changes in screen time, conflict with parents and social isolation were correlates of worsening. Cognition and lifetime clinical diagnoses failed to predict group membership. Conclusions In youth outpatients, psychiatric and psychosocial difficulties were worse on average during the school year following the spring 2020 COVID-19 lockdown; yet, some youth experienced greater and distinctive symptom change. A personalized approach to support may be needed as youth emerge from this period.

Objective Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. Methods We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. Results There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from −0.18 to 0.18) and would not survive study-wide correction for multiple testing. Conclusion Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait., Journal of Child Psychology and Psychiatry, 62 (10), ISSN:0021-9630, ISSN:1469-7610

ImportanceSuicide rates have been increasing among youth in the US. While the heritability of suicide risk is well established, there is limited understanding of how genetic risk is associated with suicidal thoughts and behaviors in young children.ObjectiveTo examine whether genetic susceptibility to suicide attempts (SAs) is associated with suicidal thoughts and behaviors in children.Design, Setting, and ParticipantsThis case-control study examined data from the Adolescent Brain Cognitive Development (ABCD) study, a population-based longitudinal study of 11 878 US children enrolled at age 9 and 10 years from September 2016 to November 2018. Youth reports of suicidal ideation (SI) and SAs were obtained from the Kiddie Schedule for Affective Disorder and Schizophrenia at baseline and 2 subsequent years. After conservative quality control of genotype data, this analysis focused on 4344 unrelated individuals of European ancestry. Data analysis was conducted from November 2020 to February 2022.Main Outcomes and MeasuresChildren’s lifetime experiences of SI and SAs were assessed each year from ages 9 to 10 years to ages 11 to 12 years. Polygenic risk scores (PRSs) for SAs were calculated for ABCD study participants based on the largest genome-wide association study of SA cases and controls of European ancestry (total sample n = 518 612).ResultsOf 4344 children of European ancestry (2045 [47.08%] female; mean [SD] age, 9.93 [0.62] years), significant associations were found between children’s SA PRSs and their lifetime SAs with the most robust association in the follow-up year 2 (odds ratio, 1.43 [95% CI, 1.18-1.75]; corrected P = 1.85 × 10−3; Nagelkerke pseudo R2 = 1.51%). These associations remained significant after accounting for children’s sociodemographic backgrounds, psychopathology symptoms, parental histories of suicide and mental health, and PRSs for major depression and attention-deficit/hyperactivity disorder (likelihood ratio test P P −16). Children’s behavioral problems, such as attention problems, rule-breaking behavior, and social problems, also partially mediated the association of SA PRSs with SAs (mediation analysis false discover rate Conclusions and RelevanceThis study’s findings indicate that there may be genetic factors associated with SA risk across the life span and suggest behaviors and conditions through which the risk could be mediated in childhood. Further research is warranted to examine whether incorporating genetic data could improve the identification of children at risk for suicide.

Objective To determine the degree to which dimensional psychopathology predicts length of stay in an emergency department (ED) and need for hospital admission among children with psychiatric complaints. Method Electronic health records of children age 4–17 years who presented to the ED of a large academic medical center were analyzed using a natural language processing tool to estimate Research Domain Criteria (RDoC) symptom scores. These scores' association with length of stay and probability of admission versus discharge to home were evaluated. Results We identified 3061 children and adolescents who presented to the ED and were evaluated by the psychiatry service between November 2008 and March 2015. Median length of stay was 7.8 h (interquartile range 5.2–14.3 h) and 1696 (55.4%) were admitted to the hospital. Higher estimated RDoC arousal, cognitive, positive, and social domain scores were associated with increased length of stay in multiple regression models, adjusted for age, sex, race, private insurance, voluntary admission, and diagnostic categories. In similarly adjusted models, odds of hospital admission were increased by higher RDoC arousal and cognitive domain scores and decreased by higher negative domain scores. Conclusions A natural language processing tool to characterize dimensional psychopathology identified features associated with differential outcomes in children in the psychiatric ED, most notably symptoms reflecting arousal and cognitive function. Methodologically, this in silico approach to risk stratification should facilitate precision psychiatry in children within the emergency setting.

The association between slow processing speed and sluggish cognitive tempo (SCT), a phenotype described within attention-deficit/hyperactivity disorder (ADHD) samples over the past decade, remains unclear. We examined whether SCT and processing speed predict different functional correlates within children and adolescents with ADHD. Participants were 193 clinically-referred youth meeting DSM ADHD criteria without comorbid conditions (mean age = 9.9 years, SD = 2.5; age range 6-16). The incremental utility of SCT and processing speed to predict (1) adaptive functioning and (2) academic achievement, after controlling for age, sex, medication status, and ADHD symptom burden, was assessed using hierarchical multiple regressions. SCT symptoms significantly predicted adaptive functioning, accounting for 6% of the variance, but did not predict academic achievement. Processing speed did not add incrementally to the prediction of adaptive functioning, but did predict academic achievement, accounting for 4% of the variance. Results suggest that SCT and processing speed differentially predict functional abilities not accounted for by ADHD symptom burden.

On average, compared to non-referred youth, child psychiatric outpatients show elevated rates of suicidal thoughts and behaviors (STBs), which are predictors of completed suicide. Determining the psychopathology features that associate with highest risk for STBs among youth outpatients may yield opportunities for targeted prevention/intervention. Yet, outpatient studies are limited and have not systematically examined comorbidity and dimensional psychopathology. In 758 youth, aged 6-18, consecutively referred for neuropsychiatric evaluation, we examined the extent to which diagnostic groups, comorbid subgroups and dimensional symptoms associated with STBs. After controlling for comorbidity, mood, anxiety and conduct disorders associated with elevated STB risk. Regarding dimensions, symptoms of depression, aggression and psychosis all contributed to higher STB risk. Although ADHD (as a diagnosis or dimension) did not associate with elevated STB risk independently, ADHD that was comorbid with other conditions did. Suicide prevention/intervention efforts should be investigated in youth outpatients with the highest risk for STBs.

BackgroundA recent genome-wide association study (GWAS) identified 12 independent loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). Polygenic risk scores (PRS), derived from the GWAS, can be used to assess genetic overlap between ADHD and other traits. Using ADHD samples from several international sites, we derived PRS for ADHD from the recent GWAS to test whether genetic variants that contribute to ADHD also influence two cognitive functions that show strong association with ADHD: attention regulation and response inhibition, captured by reaction time variability (RTV) and commission errors (CE).MethodsThe discovery GWAS included 19 099 ADHD cases and 34 194 control participants. The combined target sample included 845 people with ADHD (age: 8–40 years). RTV and CE were available from reaction time and response inhibition tasks. ADHD PRS were calculated from the GWAS using a leave-one-study-out approach. Regression analyses were run to investigate whether ADHD PRS were associated with CE and RTV. Results across sites were combined via random effect meta-analyses.ResultsWhen combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, β = 0.088, p = 0.02) but not for CE (R2 = 0.011, β = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10).ConclusionsWe detected a significant association between PRS for ADHD and RTV (but not CE) in individuals with ADHD, suggesting that common genetic risk variants for ADHD influence attention regulation.

ObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders.MethodsStructural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures).ResultsWe found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed.ConclusionOur findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.

Objective Genomic discoveries should be investigated in generalizable child psychiatric samples in order to justify and inform studies that will evaluate their use for specific clinical purposes. In youth consecutively referred for neuropsychiatric evaluation, we examined 1) the convergent and discriminant validity of attention-deficit/hyperactivity disorder (ADHD) polygenic risk scores (PRSs) in relation to DSM-based ADHD phenotypes; 2) the association of ADHD PRSs with phenotypes beyond ADHD that share its liability and have implications for outcome; and 3) the extent to which youth with high ADHD PRSs manifest a distinctive clinical profile. Method Participants were 433 youth, ages 7–18 years, from the Longitudinal Study of Genetic Influences on Cognition. We used logistic/linear regression and mixed effects models to examine associations with ADHD-related polygenic variation from the largest ADHD genome-wide association study to date. We replicated key findings in 5,140 adult patients from a local health system biobank. Results Among referred youth, ADHD PRSs were associated with ADHD diagnoses, cross-diagnostic ADHD symptoms and academic impairment (odds ratios ∼1.4; R2 values ∼2%–3%), as well as cross-diagnostic variation in aggression and working memory. In adults, ADHD PRSs were associated with ADHD and phenotypes beyond the condition that have public health implications. Finally, youth with a high ADHD polygenic burden showed a more severe clinical profile than youth with a low burden (β coefficients ∼.2). Conclusion Among child and adolescent outpatients, ADHD polygenic risk was associated with ADHD and related phenotypes as well as clinical severity. These results extend the scientific foundation for studies of ADHD polygenic risk in the clinical setting and highlight directions for further research.

The ectodermal dysplasias are a group of rare genetic disorders that are caused by abnormalities in cell and tissue development of the embryonic ectoderm. A paucity of research has systematically examined the cognitive, academic, and psychological phenotype of individuals with ectodermal dysplasia. We describe the neuropsychological profile of a female adolescent with ectodermal dysplasia with hypohidrosis. Using a battery of standardized tests, we assessed the adolescent's intellectual functioning, language processing, visuospatial and visuomotor functioning, perceptual reasoning, sensory-motor functioning, memory, executive functioning, academic functioning, emotional and behavioral functioning, and adaptive functioning. Results from the testing indicated that the adolescent possessed relative verbal strengths, with scores generally falling in the low average to average range. However, she exhibited severe deficits in visuospatial functioning, visuomotor construction/organization, visuomotor integration, visual memory, executive functioning, reading, and math. She also presented with symptoms of anxiety and depression but had relatively strong adaptive skills. Based on the testing results from our evaluation, the adolescent met the criteria for specific learning disorders with impairment in reading and math, generalized anxiety disorder, and major depressive disorder. To our knowledge, this is the first case report to comprehensively characterize the full neuropsychological and academic profile of an adolescent female with ectodermal dysplasia with hypohidrosis. Recommendations from the evaluation are presented to inform clinical practice with, and future research of, this population.

Individual differences in educational attainment are linked to differences in intelligence, and predict important social, economic, and health outcomes. Previous studies have found common genetic factors that influence educational achievement, cognitive performance and total brain volume (i.e., brain size). Here, in a large sample of participants from the UK Biobank, we investigate the shared genetic basis between educational attainment and fine-grained cerebral cortical morphological features, and associate this genetic variation with a related aspect of cognitive ability. Importantly, we execute novel statistical methods that enable high-dimensional genetic correlation analysis, and compute high-resolution surface maps for the genetic correlations between educational attainment and vertex-wise morphological measurements. We conduct secondary analyses, using the UK Biobank verbal–numerical reasoning score, to confirm that variation in educational attainment that is genetically correlated with cortical morphology is related to differences in cognitive performance. Our analyses relate the genetic overlap between cognitive ability and cortical thickness measurements to bilateral primary motor cortex as well as predominantly left superior temporal cortex and proximal regions. These findings extend our understanding of the neurobiology that connects genetic variation to individual differences in educational attainment and cognitive performance.

Objectives:Studies suggest that impairments in some of the same domains of cognition occur in different neuropsychiatric conditions, including those known to share genetic liability. Yet, direct, multi-disorder cognitive comparisons are limited, and it remains unclear whether overlapping deficits are due to comorbidity. We aimed to extend the literature by examining cognition across different neuropsychiatric conditions and addressing comorbidity.Methods:Subjects were 486 youth consecutively referred for neuropsychiatric evaluation and enrolled in the Longitudinal Study of Genetic Influences on Cognition. First, we assessed general ability, reaction time variability (RTV), and aspects of executive functions (EFs) in youth with non-comorbid forms of attention-deficit/hyperactivity disorder (ADHD), mood disorders and autism spectrum disorder (ASD), as well as in youth with psychosis. Second, we determined the impact of comorbid ADHD on cognition in youth with ASD and mood disorders.Results:For EFs (working memory, inhibition, and shifting/ flexibility), we observed weaknesses in all diagnostic groups when participants’ own ability was the referent. Decrements were subtle in relation to published normative data. For RTV, weaknesses emerged in youth with ADHD and mood disorders, but trend-level results could not rule out decrements in other conditions. Comorbidity with ADHD did not impact the pattern of weaknesses for youth with ASD or mood disorders but increased the magnitude of the decrement in those with mood disorders.Conclusions:Youth with ADHD, mood disorders, ASD, and psychosis show EF weaknesses that are not due to comorbidity. Whether such cognitive difficulties reflect genetic liability shared among these conditions requires further study. (JINS, 2018,24, 91–103)

Altres ajuts: VR has served on the speakers for Eli Lilly, Rubio, and Shire in the last 5 years. She has received travel awards from Eli Lilly and Co. and Shire for participating in psychiatric meetings. The ADHD Program has received unrestricted educational and research support from Eli Lilly and Co., Janssen-Cilag, Shire, Rovi, Psious, and Laboratorios Rubió in the past 2 years. MC received travel awards for taking part in psychiatric meetings from Shire. CF received travel awards for taking part in psychiatric meetings from Shire and Lundbeck. GEM received travel awards for taking part in psychiatric meetings from Shire. EJSS-B received speaker fees, consultancy, research funding, and conference support from Shire Pharma. Consultancy from Neurotech Solutions, Copenhagen University and Berhanderling, Skolerne & KU Leuven. Book royalties from OUP and Jessica Kingsley. Financial support-Arhus University and Ghent University for visiting Professorship. Editor-in-Chief JCPP-supported by a buy-out of time to University of Southampton and personal Honorarium. King's College London received payments for work conducted by PA: consultancy for Shire, Eli Lilly, Novartis, and Lundbeck; educational and/or research awards from Shire, Eli Lilly, Novartis, Vifor Pharma, GW Pharma, and QbTech; speaker at events sponsored by Shire, Eli Lilly, Janssen-Cilag, and Novartis. JKB has been in the past 3 years a consultant to/member of advisory board of and/or speaker for Shire, Roche, Medice, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. In the past year, SVF received income, potential income, travel expenses continuing education support and/or research support from Tris, Otsuka, Arbor, Ironshore, Shire, Akili Interactive Labs, Enzymotec, Sunovion, Supernus, and Genomind. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child's Mental Health, Oxford University Press: Schizophrenia: The Facts and Elsevier: ADHD: Non-Pharmacologic Interventions. He is principal investigator of www.adhdinadults.com. JK has given talks at educational events sponsored by Medice; all funds are received by King's College London and used for studies of ADHD. HL has served as a speaker for Evolan Pharma and Shire and has received research grants from Shire; all outside the submitted work. K-PL served as a speaker for Eli Lilly and received research support from Medice, and travel support from Shire, all outside the submitted work. LAR reported receiving honoraria, serving on the speakers' bureau/advisory board, and/or acting as a consultant for Eli Lilly, Janssen-Cilag, Novartis, and Shire in the last 3 years; receiving authorship royalties from Oxford Press and ArtMed; and receiving travel awards from Shire for his participation in the 2015 WFADHD meetings and from Novartis to take part of the 2016 AACAP meeting. The ADHD and juvenile bipolar disorder outpatient programs chaired by him received unrestricted educational and research support from the following pharmaceutical companies in the last 3 years: Janssen-Cilag, Novartis, and Shire. MC has received travel grants and research support from Eli Lilly and Co., Janssen-Cilag, Shire, and Lundbeck and served as consultant for Eli Lilly and Co., Janssen-Cilag, Shire, and Lundbeck. BF has received educational speaking fees from Medice and Shire. JAR-Q was on the speakers' bureau and/or acted as consultant for Eli Lilly, Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, Braingaze, Sincrolab, Medice, and Rubió in the last 5 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire, Medice, and Eli- Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 5 years: Eli Lilly, Lundbeck, Janssen- Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Psious, and Rubió. The other authors have nothing to disclose. All members of the 23andMe Research Team are current or former employees of 23andMe, Inc. and hold stock or stock options in 23andMe. Authors of the ADHD Working group of the PGC that participated in this study: Catharina A. Hartman, Ziarih Hawi, Jennifer Crosbie, Sandra Loo, Josephine Elia, Russell Schachar, Christie Burton, Ted Reichborn-Kjennerud, Aribert Rothenberger, Søren Dalsgaard, Irwin Waldman, Mark Bellgrove, Hakon Hakonarson, Johannes Hebebrand, Anke Hinney, and Robert Oades have nothing to disclose. Joseph Biederman 2019-2020: he received research support from Genentech, Headspace Inc., Lundbeck AS, Neurocentria Inc, Pfizer Pharmaceuticals, Roche TCRC Inc., Shire Pharmaceuticals Inc., Sunovion Pharmaceuticals Inc., and Tris. He was a consultant for Akili, Avekshan, Jazz Pharma, and Shire/Takeda. Through MGH CTNI, he participated in a scientific advisory board for Supernus. Dr Biederman's program has received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Bracket Global, Ingenix, Prophase, Shire, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH. Tobias Banaschewski served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire, and Infectopharm. He received conference support or speaker's fee by Lilly, Medice, and Shire. He received royalties from Hogrefe, Kohlhammer, CIP Medien, and Oxford University Press. James McGough is an expert testimony for Eli Lilly; DSMB for Sunovion. Benjamin Neale is a member of the scientific advisory board at Deep Genomics and consultant for Camp4 Therapeutics, Takeda Pharmaceutical, and Biogen. Ole Andreas Andreassen received speaker's honorarium from Lundbeck, and is a consultant for HealthLytix. The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 602805 (Aggressotype) as well as from the European Union H2020 Programme (H2020/2014-2020). The work was also supported by the ECNP Network "ADHD across the Lifespan" (https://www.ecnp.eu/research-innovation/ECNP-networks/List-ECNP-Networks/ADHD.aspx). Over the course of this investigation, PR is a recipient of a pre-doctoral fellowship from the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR), Generalitat de Catalunya, Spain. The iPSYCH project is funded by the Lundbeck Foundation (grant nos. R102-A9118 and R155-2014-1724) and the universities, and university hospitals of Aarhus and Copenhagen. ADB and NRM's work is also supported by the EU's Horizon 2020 programme. Data handling and analysis was supported by NIMH (1U01MH109514-01 to Michael O'Donovan and ADB). CSM is a recipient of a Sara Borrell contract from the Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad, Spain. K-PL and his team are supported by the Deutsche Forschungsgemeinschaft (DFG: CRU 125, CRC TRR 58 A1/A5, no. 44541416), ERA-Net NEURON/RESPOND, no. 01EW1602B, ERA-Net NEURON/DECODE, no. 01EW1902, and 5-100 Russian Academic Excellence Project. JH thanks Stiftelsen K.G. Jebsen, University of Bergen, the Western Norwegian Health Authorities (Helse Vest). HL thanks the Swedish research council. BC received financial support from the Spanish "Ministerio de Economía y Competitividad" and AGAUR. MSA is a recipient of a contract from the Biomedical Network Research Center on Mental Health (CIBERSAM), Madrid, Spain. MR is a recipient of a Miguel de Servet contract from the Instituto de Salud Carlos III, Spain. The research leading to these results has received funding from the Instituto de Salud Carlos III , and cofinanced by the European Regional Development Fund (ERDF), from the Pla estratègic de recerca i innovació en salut (PERIS); Generalitat de Catalunya, from "la Marató de TV3" (092330/31) and from the Agència de Gestió d'Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya. ES's work is supported by a personal Hypatia grant from the Radboud University Medical Center. MH received a Veni grant from of the Netherlands Organization for Scientific Research (NWO, grant number 91619115). The NeuroIMAGE study was supported by NIH Grant R01MH62873 (to SVF), NWO Large Investment Grant 1750102007010 (to JKB), ZonMW grant 60-60600-97-193, NWO grants 056-13-015 and 433-09-242, and matching grants from Radboud University Nijmegen Medical Center, University Medical Center Groningen and Accare, and Vrije Universiteit Amsterdam. Organization for Scientific Research (NWO; grant 016-130-669). BF and MK's work is supported by the Dutch National Science Agenda (NWA) for the NeurolabNL project (grant 400-17-602). This paper represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. BF received additional funding from a personal Vici grant of the Dutch. Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

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.

Contains fulltext : 204879pub.pdf (Publisher’s version ) (Open Access) Contains fulltext : 204879pos.pdf (Author’s version postprint ) (Open Access) OBJECTIVE: Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies. METHODS: Cortical thickness and surface area (based on the Desikan-Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707). RESULTS: In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen's d=-0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample. CONCLUSIONS: Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.

We initiated a program for early detection of diabetes and hypertension, the main causes of kidney failure in Guyana, South America. We trained local high school students with the goal that these students would stay in the villages for long-term, become health advocates and shift the reliance away from physicians. This project involved 7 high school students who were taught to monitor the health of one village of 1000–1500 population each. The program will be implemented for 3 years in which the entire population of seven villages (approximately 10,000 people) will be covered. This represents 1.3% population in Guyana. We present data from the pilot study from the sample of 619 people. The prevalence of diabetes mellitus was 13.9%. Among diabetics, 33.7% were using insulin and 86% oral hypoglycemic agents. Prevalence of hypertension was 29.4%, 63.2% were overweight and 17% were obese. About 9.9% patients were unaware about the existence of hypertension. We have shown in our study that high school students can be used to collect health data and monitor diabetes and hypertension. There was also a significant incidence of undetected diabetes and hypertension.

Background Recent initiatives in psychiatry emphasize the utility of characterizing psychiatric symptoms in a multidimensional manner. However, strategies for applying standard self-report scales for multiaxial assessment have not been well-studied, particularly where the aim is to support both categorical and dimensional phenotypes. Methods We propose a method for applying natural language processing to derive dimensional measures of psychiatric symptoms from questionnaire data. We utilized nine self-report symptom measures drawn from a large cellular biobanking study that enrolled individuals with mood and psychotic disorders, as well as healthy controls. To summarize questionnaire results we used word embeddings, a technique to represent words as numeric vectors preserving semantic and syntactic meaning. A low-dimensional approximation to the embedding space was used to derive the proposed succinct summary of symptom profiles. To validate our embedding-based disease profiles, these were compared to presence or absence of axis I diagnoses derived from structured clinical interview, and to objective neurocognitive testing. Results Unsupervised and supervised classification to distinguish presence/absence of axis I disorders using survey-level embeddings remained discriminative, with area under the receiver operating characteristic curve up to 0.85, 95% confidence interval (CI) (0.74,0.91) using Gaussian mixture modeling, and cross-validated area under the receiver operating characteristic curve 0.91, 95% CI (0.88,0.94) using logistic regression. Derived symptom measures and estimated Research Domain Criteria scores also associated significantly with performance on neurocognitive tests. Conclusions Our results support the potential utility of deriving dimensional phenotypic measures in psychiatric illness through the use of word embeddings, while illustrating the challenges in identifying truly orthogonal dimensions.

Deficits in a range of skill domains (including executive functioning, emotion regulation, social cognition and language/communication) are associated with disrupted youth behavior and functioning across mental health diagnoses. The identification of skill deficits are important for effective treatment planning, particularly for personalized interventions. While there are multiple ways to assess these skills, parent/caregiver reports represent an important information source. To date, no single, brief measure has been developed that gathers parent/caregiver ratings across this range of constructs. We have developed a short caregiver-report questionnaire (the Thinking Skills Inventory; TSI), to screen for skill deficits. Here, we examine the reliability and validity of this rating scale in 384 youth who were consecutively referred for neuropsychiatric evaluation. A primary caregiver completed the TSI as well as other established measures. Exploratory and confirmatory factor analyses support five subscales on the TSI: Attention and Working Memory, Language and Communication, Emotion Regulation, Cognitive Flexibility, and Social Thinking Skills. The subscales showed moderate to high internal consistency (Cronbach's alphas range from 0.84 to 0.91). Correlations with established caregiver-report measures confirm their convergent and discriminant validity, and associations with multiple clinical diagnoses and cross-diagnostic aggressive behavior further support the utility of the scale for our intended purpose. In sum, this free, brief measure is a valid and reliable way to identify variation in skill domains relevant to a range of psychopathology. The TSI may be useful in youth mental health settings to assist with treatment planning and to inform referral for further evaluation.

BACKGROUND: Relying on diagnostic categories of neuropsychiatric illness obscures the complexity of these disorders. Capturing multiple dimensional measures of neuropathology could facilitate clinical and neurobiological investigation of cognitive and behavioral phenotypes. METHODS: We developed a natural language processing (NLP)-based approach to extract five symptom dimensions, based on the NIMH Research Domain Criteria (RDoC) definitions, from narrative clinical notes. Estimates of RDoC loading (eRDoC) were derived from a cohort of 3,619 individuals with 4,623 hospital admissions. We applied this tool to a large corpus of psychiatric inpatient admission and discharge notes (2010–2015), and using the same cohort examined face validity, predictive validity, and convergent validity with gold standard annotations. RESULTS: In mixed effects models adjusted for sociodemographic and clinical features, greater negative and positive symptom domains were associated with shorter stay (β=−0.88; p=0.001 and β=−1.22; p

Background A recent genome-wide association analysis has identified specific susceptibility variants and a substantial polygenic component for Attention-Deficit/Hyperactivity Disorder (ADHD). Given that emerging risk variants are unlikely to track precisely with conventional diagnoses, whether these discoveries will have utility in clinical settings for improved diagnostics and risk stratification requires further study. Our overall goal is to establish the relevance of emerging psychiatric genetics findings to youth clinical samples. In the current study, we aimed to 1) confirm the convergent validity of ADHD polygenic risk with ADHD-related phenotypes in youth presenting for neuropsychiatric evaluation; and 2) determine the extent to which ADHD polygenic risk associates with phenotypes beyond ADHD that putatively share its underlying liability and have implications for functional outcome. Methods Participants were 470 youth, ages 7 to 18, consecutively referred for neuropsychiatric evaluation and genotyped on the Illumina Infinium PsychArray Beadchip. Diagnoses made subsequent to study enrollment reflected a range of psychopathology and comorbidity. We determined the burden of ADHD-related common variants in these patients at different significance thresholds from the ADHD PGC-iPSYCH meta-analysis. We then associated this polygenic risk with clinical phenotypes. First, we conducted univariate analyses relating ADHD polygenic risks scores (PRSs) to ADHD diagnoses (none/borderline/full) and symptoms, cognition, and dimensional ratings of aggression and mania. Second, we stratified youth by low, medium, and high ADHD polygenic burden and used a mixed modeling approach to determine whether risk strata associated with distinct multivariate clinical profiles. Third, we determined phenotypically distinct latent classes in these and other youth (N~900) based on eight dimensional measures of psychopathology and examined whether the ADHD-PRS discriminated among them. Results The ADHD-PRS predicted the ADHD diagnosis at seven discovery sample thresholds after correction for potential confounds and multiple testing. The strongest association occurred at discovery sample p Discussion In a multi-diagnostic clinical sample, ADHD polygenic risk showed convergent validity with ADHD phenotypes. Genotype- and phenotype-first analyses also indicated that ADHD polygenic burden associates with traits reflecting cognition and behavioral and emotional dysregulation that extend beyond ADHD and that have implications for functional outcome.

Background Evidence that different neuropsychiatric conditions share genetic liability has increased interest in phenotypes with ‘cross-disorder’ relevance, as they may contribute to revised models of psychopathology. Cognition is a promising construct for study; yet, evidence that the same cognitive functions are impaired across different forms of psychopathology comes primarily from separate studies of individual categorical diagnoses versus controls. Given growing support for dimensional models that cut across traditional diagnostic boundaries, we aimed to determine, within a single cohort, whether performance on measures of executive functions (EFs) predicted dimensions of different psychopathological conditions known to share genetic liability. Methods Data are from 393 participants, ages 8–17, consecutively enrolled in the Longitudinal Study of Genetic Influences on Cognition (LOGIC). This project is conducting deep phenotyping and genomic analyses in youth referred for neuropsychiatric evaluation. Using structural equation modeling, we examined whether EFs predicted variation in core dimensions of the autism spectrum disorder, bipolar illness, and schizophrenia (including social responsiveness, mania/emotion regulation, and positive symptoms of psychosis, respectively). Results We modeled three cognitive factors (working memory, shifting, and executive processing speed) that loaded on a second-order EF factor. The EF factor predicted variation in our three target traits, but not in a negative control (somatization). Moreover, this EF factor was primarily associated with the overlapping (rather than unique) variance across the three outcome measures, suggesting that it related to a general increase in psychopathology symptoms across those dimensions. Conclusions Findings extend support for the relevance of cognition to neuropsychiatric conditions that share underlying genetic risk. They suggest that higher-order cognition, including EFs, relates to the dimensional spectrum of each of these disorders and not just the clinical diagnoses. Moreover, results have implications for bottom-up models linking genes, cognition, and a general psychopathology liability.

Unbiased genomewide association studies of tens of thousands of individuals are transforming our understanding of the origins and structure of psychopathology across the lifespan. Together with findings from epidemiology and cognitive neuroscience, these recent molecular genetic studies underscore the importance of studying phenotypes across as well as within conventional psychiatric diagnoses in order to construct a more pathophysiologically grounded taxonomy from the bottom up. Such efforts, promoted by NIMH's Research Domain Criteria (RDoC) framework, are critical to developing more accurate models of the risk mechanisms that are shared and distinct across various psychopathologic outcomes. In turn, these models could reveal new treatment targets and early intervention opportunities. In their article in the 2015 JCPP Annual Research Review, Scerif and Baker remind us that bottom-up insights into psychiatric illness might also be gained by examining specific genetic disorders that often fall within the purview of pediatrics and neurology. These authors note high rates of symptoms of attention-deficit hyperactivity disorder (ADHD) in syndromes with known and often monogenic genetic causes (e.g. Fragile X) and suggest that studying the ADHD-like phenomena in these conditions may provide insight into ADHD itself. This commentary highlights themes from Scerif and Baker's review that overlap with the core tenets of RDoC and notes their significance for advancing our understanding of ADHD in the coming years. It concludes by suggesting ways in which further attention to the RDoC framework could also enhance Scerif and Baker's agenda.

Contains fulltext : 169834.pdf (Publisher’s version ) (Open Access) Contains fulltext : 169834pos.pdf (Author’s version postprint ) (Open Access) BACKGROUND: Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis. METHODS: In this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0.0156. FINDINGS: Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohen's d=-0.15), amygdala (d=-0.19), caudate (d=-0.11), hippocampus (d=-0.11), putamen (d=-0.14), and intracranial volume (d=-0.10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0.95) and thalamus (p=0.39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (21 years): in the accumbens (Cohen's d=-0.19 vs -0.10), amygdala (d=-0.18 vs -0.14), caudate (d=-0.13 vs -0.07), hippocampus (d=-0.12 vs -0.06), putamen (d=-0.18 vs -0.08), and intracranial volume (d=-0.14 vs 0.01). There was no difference between children and adults for the pallidum (p=0.79) or thalamus (p=0.89). Case-control differences in adults were non-significant (all p>0.03). Psychostimulant medication use (all p>0.15) or symptom scores (all p>0.02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0.5). INTERPRETATION: With the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes. FUNDING: National Institutes of Health. 10 p.

Structural variation (SV) is a significant component of the genetic etiology of both neurodevelopmental and psychiatric disorders; however, routine guidelines for clinical genetic screening have been established only in the former category. Genome-wide chromosomal microarray (CMA) can detect genomic imbalances such as copy-number variants (CNVs), but balanced chromosomal abnormalities (BCAs) still require karyotyping for clinical detection. Moreover, submicroscopic BCAs and subarray threshold CNVs are intractable, or cryptic, to both CMA and karyotyping. Here, we performed whole-genome sequencing using large-insert jumping libraries to delineate both cytogenetically visible and cryptic SVs in a single test among 30 clinically referred youth representing a range of severe neuropsychiatric conditions. We detected 96 SVs per person on average that passed filtering criteria above our highest-confidence resolution (6,305 bp) and an additional 111 SVs per genome below this resolution. These SVs rearranged 3.8 Mb of genomic sequence and resulted in 42 putative loss-of-function (LoF) or gain-of-function mutations per person. We estimate that 80% of the LoF variants were cryptic to clinical CMA. We found myriad complex and cryptic rearrangements, including a “paired” duplication (360 kb, 169 kb) that flanks a 5.25 Mb inversion that appears in 7 additional cases from clinical CNV data among 47,562 individuals. Following convergent genomic profiling of these independent clinical CNV data, we interpreted three SVs to be of potential clinical significance. These data indicate that sequence-based delineation of the full SV mutational spectrum warrants exploration in youth referred for neuropsychiatric evaluation and clinical diagnostic SV screening more broadly.