Polygenic association between attention-deficit/hyperactivity disorder liability and cognitive impairments.

BACKGROUND: A 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). METHODS: The 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. RESULTS: When combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, ß = 0.088, p = 0.02) but not for CE (R2 = 0.011, ß = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10). CONCLUSIONS: We 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.

Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets.

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.

Neuropsychological Profile of an Adolescent Female With Ectodermal Dysplasia With Hypohidrosis.

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.

The Shared Genetic Basis of Educational Attainment and Cerebral Cortical Morphology.

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.

Characteristics of child psychiatric outpatients with slow processing speed and potential mechanisms of academic impact.

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 < 85) and seven neuropsychiatric diagnostic groups. In 492 of these youth, we also related slow PS to eight psychopathology symptom dimensions. Finally, we modeled the relationship between PS, other cognitive functions and academic achievement. Data are from the Longitudinal Study of Genetic Influences on Cognition. Analyses included one-sample t tests, ANOVA, logistic regression, mixed modeling, and structural equation modeling (SEM), controlling for age, sex, and medication. Compared to normative data, all clinical groups showed PS decrements. Compared to referred youth without full diagnoses and accounting for other psychopathology, risk for slow PS was elevated in youth with autism spectrum disorder (OR = 1.8), psychotic disorders (OR = 3.4) and ADHD-inattentive type (OR = 1.6). Having multiple comorbidities also increased risk for slow PS. Among dimensions, inattention (OR = 1.5) associated with slow PS but did not fully explain the association with autism or psychosis. In SEM, PS had direct effects on academic achievement and indirect effects through working memory. Findings extend evidence that PS relates to multiple aspects of child psychopathology and associates with academic achievement in child psychiatric outpatients.

Slow Processing Speed and Sluggish Cognitive Tempo in Pediatric Attention-Deficit/Hyperactivity Disorder: Evidence for Differentiation of Functional Correlates.

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.

Characteristics of Child Psychiatric Outpatients at Highest Risk for Suicidal Thoughts and Behaviors.

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.

Cross-Disorder Cognitive Impairments in Youth Referred for Neuropsychiatric Evaluation.

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).

Cryptic and complex chromosomal aberrations in early-onset neuropsychiatric disorders.

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.

Extending the 'cross-disorder' relevance of executive functions to dimensional neuropsychiatric traits in youth.

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.

Editorial: Can Improving Youth Mental Health Reduce Mortality?

It is well established that mental health conditions, including substance use disorders, are associated with premature mortality. A meta-analysis1 has demonstrated that this association holds across a range of diagnoses. Although the effect is stronger for schizophrenia, depression and anxiety contribute to more deaths overall because of their high prevalence rates. Moreover, more than two-thirds of associated deaths were explained by natural causes.1 The next logical questions, then, are as follows: which mechanisms underlie this association, and can they can be mitigated? In the current issue of JAACAP, Clark et al.2 aim to tie mental health symptoms and substance use to the acceleration of biological aging.

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.

Editors' Best of 2023.

There is, in the content of the Journal, an embarrassment of riches, and picking a "best" seems to demand a certain qualification: is the "best" the most interesting, most surprising, most educational, most important, most provocative, most enjoyable? How to choose? We are hardly unbiased and can admit to a special affection for the ones that we and the authors worked hardest on, modifying version after version into shape. Acknowledging these biases, here are the 2023 articles that we think deserve your attention or at least a second read.

Behavior ratings of executive functions index multiple domains of psychopathology and school functioning in child psychiatric outpatients.

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.

Youth Team Sports Participation Associates With Reduced Dimensional Psychopathology Through Interaction With Biological Risk Factors.

Background: Physical activity is associated with mental health benefits in youth. Here, we used causal inference and triangulation with 2 levels of biology to substantiate relationships between sports participation and dimensional psychopathology in youths. Methods: Baseline data from the Adolescent Brain Cognitive Development (ABCD) Study, which recruited children from 9 to 10 years of age across the United States, were included in multilevel regression models to assess relationships between lifetime participation in team sports (TS), individual sports, and nonsports activities and Child Behavior Checklist (CBCL) scores. We calculated polygenic risk scores for 8 psychiatric disorders to assess interactions with sports exposure on CBCL scores among European descendants. Following rigorous quality control, FreeSurfer-extracted brain magnetic resonance imaging structural data were examined for mediation of CBCL-activities relationships. Results: Among those with complete data (N = 10,411), causal estimates using inverse probability weighting associated lifetime TS exposure with a 1.05-point reduction in CBCL total (95% CI, -1.54 to -0.56, p < .0001) a relationship that was specific to TS and strengthened with more years of exposure. Associations of attention-deficit/hyperactivity disorder polygenic loading with CBCL total weakened in European children with TS exposure (n = 4041; beta = -0.93, SE = 0.38, p = .013). Furthermore, TS participation and lower CBCL each associated with increased subcortical volumes (n = 8197). Subcortical volume mediated 5.5% of TS effects on CBCL total. Conclusions: Our findings support prior associations of TS participation with lower psychopathology in youths through additional studies that demonstrate specificity, dose response, and coherence across 2 levels of biology. Longitudinal studies that further clarify causal relationships may justify interventional studies of TS for high-risk youth.

Differences in cognitive and academic performance during the COVID-19 pandemic in child psychiatric outpatients.

This study examined the impact of the COVID-19 pandemic on cognitive and academic functioning in 574 youth presenting for outpatient clinical neuropsychiatric evaluations. We extended the prior literature by (a) determining the extent to which academic difficulties documented in population and community samples also occurred in child psychiatric outpatients; (b) evaluating the impact of the pandemic on neuropsychological functions relevant to academic performance (overall cognition, executive functions, and graphomotor skill); and (c) investigating the moderating impact of attention deficit hyperactivity disorder (ADHD) diagnosis. We compared cross-sectional scores on standardized measures for groups of youth evaluated at three time periods related to the COVID-19 pandemic: (a) prior to onset (PRIOR; N = 198), (b) during Year 1 (Y1; N = 149), and (c) during Year 2 (Y2; N = 227). Relative to overall cognitive ability, math scores were lower in Y1 and Y2 and reading scores were lower in Y2. Additionally, relative to overall cognitive ability, youth showed lower working memory in Y1 and lower processing speed in Y1 and Y2. Graphomotor skill and parent-rated executive functions (EF) did not vary significantly across the three time periods. ADHD status did not moderate psychometric test scores but did moderate parent-rated EF. These data suggest that the COVID-19 pandemic has negatively impacted academic and executive functions in child psychiatry outpatients. More research is needed to understand the long-term implications for development. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Editors' Best of 2022.

There is, in the content of the Journal, an embarrassment of riches, and picking a "best" seems to demand a certain qualification: is the "best" the most interesting, most surprising, most educational, most important, most provocative, most enjoyable? How to choose? We are hardly unbiased and can admit to a special affection for the ones that we and the authors worked hardest on, hammering version after version into shape. Acknowledging these biases, here are the 2022 articles that we think deserve your attention or at least a second read.

Uncovering and mitigating bias in large, automated MRI analyses of brain development.

Large, population-based MRI studies of adolescents promise transformational insights into neurodevelopment and mental illness risk 1,2. However, MRI studies of youth are especially susceptible to motion and other artifacts 3,4. These artifacts may go undetected by automated quality control (QC) methods that are preferred in high-throughput imaging studies, 5 and 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.

Genetic patterning for child psychopathology is distinct from that for adults and implicates fetal cerebellar development.

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.

Editors' Note: Third Annual Report Regarding JAACAP's Antiracist Journey.

In 2020, we wrote to you of our dedication and vision for JAACAP "to be antiracist at every level."1 Over the last 3 years, we have pursued initiatives "to reshape the Journal to pursue this vision."2,3 In this article, we provide an update on these goals and initiatives (Figure 1). With the launching of our new open access journal, JAACAP Open,4 in late 2022, we now extend these initiatives to both scientific journals in the JAACAP family and aspire to be a leader among mental health journals in our intentional pursuit of antiracist policies and practices.