Examining Differences in the Genetic and Functional Architecture of Attention-Deficit/Hyperactivity Disorder Diagnosed in Childhood and Adulthood.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with diagnostic criteria requiring symptoms to begin in childhood. We investigated whether individuals diagnosed as children differ from those diagnosed in adulthood with respect to shared and unique architecture at the genome-wide and gene expression level of analysis. Methods: We used genomic structural equation modeling (SEM) to investigate differences in genetic correlations (rg) of childhood-diagnosed (ncases = 14,878) and adulthood-diagnosed (ncases = 6961) ADHD with 98 behavioral, psychiatric, cognitive, and health outcomes. We went on to apply transcriptome-wide SEM to identify functional annotations and patterns of gene expression associated with genetic risk sharing or divergence across the ADHD subgroups. Results: Compared with the childhood subgroup, adulthood-diagnosed ADHD exhibited a significantly larger negative rg with educational attainment, the noncognitive skills of educational attainment, and age at first sexual intercourse. We observed a larger positive rg for adulthood-diagnosed ADHD with major depression, suicidal ideation, and a latent internalizing factor. At the gene expression level, transcriptome-wide SEM analyses revealed 22 genes that were significantly associated with shared genetic risk across the subtypes that reflected a mixture of coding and noncoding genes and included 15 novel genes relative to the ADHD subgroups. Conclusions: This study demonstrated that ADHD diagnosed later in life shows much stronger genetic overlap with internalizing disorders and related traits. This may indicate the potential clinical relevance of distinguishing these subgroups or increased misdiagnosis for those diagnosed later in life. Top transcriptome-wide SEM results implicated genes related to neuronal function and clinical characteristics (e.g., sleep).

It is unclear whether individuals who are diagnosed with attention-deficit/hyperactivity disorder (ADHD) as children differ from those who are diagnosed in adulthood with respect to their genetic architecture. We found that adulthood-diagnosed ADHD is much more genetically similar than ADHD diagnosed in childhood to disorders in the internalizing space, such as depression and suicidality. Differences between the distinct age groups at diagnosis highlight the importance of distinguishing these subgroups in a clinical and treatment setting.

Stimulus shapes strategy: Effects of stimulus characteristics and individual differences in academic achievement on the neural mechanisms engaged during the N-back task.

This fMRI study of 126 youth explored whether the neural mechanisms underlying the N-back task, commonly used to examine executive control over the contents of working memory, are associated with individual differences in academic achievement in reading and math. Moreover, the study explored whether these relationships occur regardless of the nature of the stimulus being manipulated in working memory (letters, numbers, nonsense shapes) or whether these relationships are specific to achievement domain and stimulus type (i.e., letters for reading and numbers for math). The results indicated that higher academic achievement in each of reading and math was associated with greater activation of dorsolateral prefrontal cortex in the N-back task regardless of stimulus type (i.e., did not differ for letters and numbers), suggesting that at least some aspects of the neural mechanisms underlying these academic domains are executive in nature. In addition, regardless of level of academic achievement, prefrontal regions were engaged to a greater degree for letters than numbers than nonsense shapes. In contrast, nonsense shapes yielded greater hippocampal activation than letters and numbers. Potential reasons for this pattern of findings are discussed.

The Rosetta Phenotype Harmonization Method Facilitates Finding a Relationship Quantitative Trait Locus for a Complex Cognitive Trait.

Genetics researchers increasingly combine data across many sources to increase power and to conduct analyses that cross multiple individual studies. However, there is often a lack of alignment on outcome measures when the same constructs are examined across studies. This inhibits comparison across individual studies and may impact the findings from meta-analysis. Using a well-characterized genotypic (brain-derived neurotrophic factor: BDNF) and phenotypic constructs (working memory and reading comprehension), we employ an approach called Rosetta, which allows for the simultaneous examination of primary studies that employ related but incompletely overlapping data. We examined four studies of BDNF, working memory, and reading comprehension with a combined sample size of 1711 participants. Although the correlation between working memory and reading comprehension over all participants was high, as expected (ρ = 0.45), the correlation between working memory and reading comprehension was attenuated in the BDNF Met/Met genotype group (ρ = 0.18, n.s.) but not in the Val/Val (ρ = 0.44) or Val/Met (ρ = 0.41) groups. These findings indicate that Met/Met carriers may be a unique and robustly defined subgroup in terms of memory and reading comprehension. This study demonstrates the utility of the Rosetta method when examining complex phenotypes across multiple studies, including psychiatric genetic studies, as shown here, and also for the mega-analysis of cohorts generally.

Processing Speed is Related to the General Psychopathology Factor in Youth.

The relationship between the p factor and cognition in youth has largely focused on general cognition (IQ) and executive functions (EF). Another cognitive construct, processing speed (PS), is dissociable from IQ and EF, but has received less research attention despite being related to many different mental health symptoms. The present sample included 795 youth, ages 11-16 from the Colorado Learning Disabilities Research Center (CLDRC) sample. Confirmatory factor analyses tested multiple p factor models, with the primary model being a second-order, multi-reporter p factor. We then tested the correlation between the p factor and a latent PS factor. There was a significant, negative correlation between the p factor and PS (r(87) = -0.42, p < .001), indicating that slower processing speed is associated with higher general mental health symptoms. This association is stronger than previously reported associations with IQ or EF. This finding was robust across models that used different raters (youth and caregiver) and modeling approaches (second-order vs. bifactor). Our findings indicate that PS is related to general psychopathology symptoms. This research points to processing speed as an important transdiagnostic construct that warrants further exploration across development.

ADHD and Psychological Need Fulfillment in College Students.

OBJECTIVE: Self-determination theory suggests that the satisfaction and frustration of basic psychological needs-autonomy, competence, relatedness-are uniquely associated with overall well-being. Undergraduates with attention-deficit/hyperactivity disorder (ADHD) experience more academic-related impairment and are less likely to graduate. Thus, well-being is important to understand and aim to improve in these students. METHOD: Students at four universities (N = 2,197) completed a survey and reported previous diagnoses, ADHD symptoms, and psychological need satisfaction and frustration. Group differences were explored via t-tests; associations were explored via structural equation modeling. RESULTS: The ADHD group reported lower satisfaction and higher frustration across all psychological needs. Inattention and hyperactivity/impulsivity were uniquely associated with aspects of need fulfillment beyond the impact of comorbid symptoms. Sex differences emerged such that women with ADHD had the lowest overall need satisfaction. CONCLUSIONS: Addressing need fulfillment, both satisfaction and frustration, in interventions with undergraduates with clinical/subclinical levels of ADHD may optimize treatment effectiveness.

Attention-Deficit/Hyperactivity Disorder and Academic Functioning: Reading, Writing, and Math Abilities in a Community Sample of Youth with and without ADHD.

Previous studies have shown that Attention-Deficit/Hyperactivity disorder (ADHD) is marked by impairments in academic functioning in reading, writing, and mathematics. Yet, virtually no studies have examined academic functioning in terms of both basic skills (e.g., word recognition, handwriting/spelling, arithmetic calculations) and more complex advanced skills (e.g., reading comprehension, writing composition, and mathematical problem-solving) within the same sample. In the present study, 518 children with ADHD were compared to a control group of 851 children without ADHD (ages 8-18) and assessed on a comprehensive battery of reading, writing, and math assessments. It was hypothesized that ADHD diagnostic status would uniquely predict performance on advanced skill measures even after controlling for performance on basic skills in that academic domain. ADHD status was associated with worse performance across all academic tests. Results also indicated that ADHD independently predicted performance for measures of writing composition and one measure of reading comprehension, even after controlling for performance on basic skills in those domains. However, ADHD did not independently predict mathematical problem-solving performance. These findings add to the literature on ADHD and academic functioning and indicate that inattention may weaken skills necessary for effective reading comprehension and writing composition.

Mathematics Difficulties and Psychopathology in School-Age Children.

This study investigated the relationship between mathematics difficulties and psychopathology in a large community sample (N = 881) of youth (8-18 years of age) in the United States. The primary aims of the study were to (a) test the associations between mathematics difficulties and specific components of internalizing, externalizing, attention, and social problems; (b) examine potential age and gender differences; and (c) investigate the longitudinal relationship between mathematics and psychopathology using 5-year follow-up data. Results indicated that individuals with mathematics difficulties exhibited elevations in most dimensions of psychopathology, including anxiety, depression, externalizing behaviors, attention problems, and social problems. Furthermore, mathematics impairment was associated with internalizing problems, rule-breaking behaviors, inattention, and social problems even after controlling for comorbid reading difficulties. Results suggested that the associations between mathematics and psychopathology are generally similar in males and females. Finally, preliminary longitudinal evidence suggested that initial mathematics difficulties predicted elevations of conduct disorder, rule-breaking behavior, inattention, hyperactivity, and social problems at follow-up, with several of these associations remaining significant even after controlling for initial reading. In contrast, there was no significant association between initial mathematics ability and internalizing symptoms at follow-up, demonstrating some amelioration of internalizing symptoms over time.

Compounding Effects of Domain-General Cognitive Weaknesses and Word Reading Difficulties on Anxiety Symptoms in Youth.

This study examined whether domain-general cognitive weaknesses in processing speed (PS) or executive functioning (EF) moderate the relation between word reading scores and anxiety such that lower word reading scores in combination with lower cognitive scores are associated with higher anxiety symptoms. The sample consisted of 755 youth ages 8-16 who were recruited as part of the Colorado Learning Disabilities Research Center twins study. Lower scores on PS (R2 = .007, p = .014), EF (R2 = .009, p = .006), and word reading (R2 = .006-.008, p = .010-.032) were associated with higher anxiety scores. In addition, the word reading × cognitive interactions were significant such that lower scores on PS (R2 = .010, p = .005) or EF (R2 = .013, p = .010) combined with lower word reading were associated with higher-than-expected anxiety symptoms. Results suggest that weaknesses in PS, EF, and word reading are modestly associated with higher anxiety symptoms, and these anxiety symptoms may be compounded in youth with both PS or EF weaknesses and word reading difficulties. These findings can guide assessment approaches for identifying youth with word reading challenges who may be at increased risk for anxiety.

Report of a Work Group on Sluggish Cognitive Tempo: Key Research Directions and a Consensus Change in Terminology to Cognitive Disengagement Syndrome.

OBJECTIVE: The aim of this work was 2-fold: (1) to evaluate current knowledge and identify key directions in the study of sluggish cognitive tempo (SCT); and (2) to arrive at a consensus change in terminology for the construct that reflects the current science and may be more acceptable to researchers, clinicians, caregivers, and patients. METHOD: An international Work Group was convened that, in early 2021, compiled an online archive of all research studies on SCT and summarized the current state of knowledge, noted methodological issues, and highlighted future directions, and met virtually on 10 occasions in 2021 to discuss these topics and terminology. RESULTS: Major progress has been made over the last decade in advancing our understanding of SCT across the following domains of inquiry: construct measurement and stability; genetic, environmental, pathophysiologic, and neuropsychological correlates; comorbid conditions; functional impairments; and psychosocial and medication interventions. Findings across these domains are summarized, and potential avenues to pursue in the next generation of SCT-related research are proposed. Following repeated discussions on terminology, the Work Group selected "cognitive disengagement syndrome" (CDS) to replace "SCT" as the name for this construct. This term was deemed to best satisfy considerations that should apply when selecting terms for a condition or syndrome, as it does not overlap with established terms for other constructs, is not offensive, and reflects the current state of the science. CONCLUSION: It is evident that CDS (SCT) has reached the threshold of recognition as a distinct syndrome. Much work remains to further clarify its nature (eg, transdiagnostic factor, separate disorder, diagnostic specifier), etiologies, demographic factors, relations to other psychopathologies, and linkages to specific domains of functional impairment. Investigators are needed with interests and expertise spanning basic, clinical, and translational research to advance our understanding and to improve the lives of individuals with this unique syndrome.

Discovery of 42 genome-wide significant loci associated with dyslexia.

Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia.

The Angular Gyrus as a Hub for Modulation of Language-related Cortex by Distinct Prefrontal Executive Control Regions.

It has become clear in recent years that reading, while relying on domain-specific language processing regions, also involves regions that implement executive processes more broadly. Such executive control is generally considered to be implemented by prefrontal regions, which exert control via connectivity that allows them to modulate processing in target brain regions. The present study examined whether three previously identified and distinct executive control regions in the pFC [Wang, K., Banich, M. T., Reineberg, A. E., Leopold, D. R., Willcutt, E. G., Cutting, L. E., et al. Left posterior prefrontal regions support domain-general executive processes needed for both reading and math. Journal of Neuropsychology, 14, 467-495, 2020] show similar patterns of functional connectivity (FC) during a reading comprehension task as compared with a symbol identification condition. Our FC results in a sample of adolescents (n = 120) suggest all three regions commonly show associations with activity in "classic" left hemisphere reading areas, including the angular and supramarginal gyri, yet each exhibits differential connectivity as well. In particular, precentral regions show differential FC to parietal portions of the dorsal language stream, the inferior frontal junction shows differential FC to middle temporal regions of the right hemisphere and other regions involved in semantic processing, and portions of the inferior frontal gyrus show differential FC to an extensive set of right hemisphere prefrontal regions. These results suggest that prefrontal control over language-related regions occurs in a coordinated yet discrete manner.

Heritability and Clinical Characteristics of Neuropsychological Profiles in Youth With and Without Elevated ADHD Symptoms.

OBJECTIVE: In the last decade, there has been an increase in research that aims to parse heterogeneity in attention deficit hyperactivity disorder (ADHD). The current study tests heritability of latent class neuropsychological subtypes. METHOD: Latent class analysis was used to derive subtypes in a sample of school-age twins (N = 2,564) enriched for elevated ADHD symptoms. RESULTS: Five neuropsychological profiles replicated across twin 1 and twin 2 datasets. Latent class membership was heritable overall, but heritability varied by profile and was lower than heritability of ADHD status. Variability in neuropsychological performance across domains was the strongest predictor of elevated ADHD symptoms. Neuropsychological profiles showed distinct associations with age, psychiatric symptoms and reading ability. CONCLUSION: Neuropsychological profiles are associated with unique neurocognitive presentations, but are not strong candidate endophenotypes for ADHD diagnosis.

Modeling the Speeded Determinants of Adolescents' Academic and Attentional Functioning.

The current study utilized a large, unselected sample of adolescent twins to examine whether processing speed (PS) is an important shared predictor that accounts for covariance among reading, math, ADHD, and rapid naming (RN). The best fitting model included correlated but distinguishable latent measures of PS, RN, reading, math, inattention, hyperactivity/impulsivity, and academic fluency. PS was a shared predictor across all outcomes, while RN was uniquely associated with reading, fluency, and (albeit weakly) math. The results add to a growing literature suggesting that PS and RN may be important components of comprehensive neuropsychological models of academics, ADHD, and their covariation.

In Search of Cognitive Promotive and Protective Factors for Word Reading.

This study examined whether strong cognitive skills (i.e. vocabulary, rapid naming, verbal working memory [VWM], and processing speed [PS]) contributed to resilience in single-word reading skills in children at risk for reading difficulties because of low phonological awareness scores (PA). Promotive factors were identified by main effects and protective factors through PA x cognition interactions. This study included 1,807 children ages 8-16. As predicted, all cognitive skills were significantly related to reading, consistent with promotive effects. A significant, but small effect PA x vocabulary interaction (R2 change=.002, p=.00038) was detected but its form was not consistent with a classic protective effect. Rather, the PA x vocabulary interaction was consistent with a "skill-enhancement" pattern, such that children with strong PA and vocabulary skills had better than expected reading. This study provides a framework for reading resilience research and directs attention to promotive mechanisms underlying reading success.

Unique considerations in the assessment of ADHD in college students.

Evidence-based practice in psychology (EBPP) has long focused on treatment, but evidence-based psychological assessment (EBPA) is also crucial given the important role of accurate and reliable diagnostic practices in treatment planning. In terms of the diagnosis of attention-deficit/hyperactivity disorder (ADHD), EBPA practices are well-established for children, and more recently for adults, but for college students in particular there are special considerations that warrant attention. College students with symptoms of ADHD have some challenges that are unique, and thus the assessment and diagnosis of ADHD in these students is unique. The aim of this review is not to cover all EBPA strategies for diagnosing ADHD in emerging adult college students; rather, we will focus on the unique considerations at play in college ADHD assessment. These include (a) conceptual matters such as the appropriateness of the DSM-5 criteria for college students, the limitations of our understanding of ADHD this population because of a lack of diversity in research studies, and the issue of late-identified ADHD; and (b) practical matters, such as specific documentation needs, how to gather and interpret self- and other-report of symptoms, how to assess impairment, and alternate explanations for ADHD-like symptoms in college students.

Sluggish Cognitive Tempo and Neuropsychological Functioning.

Sluggish cognitive tempo (SCT) is marked by impairments across social, emotional, and academic functioning, but few studies have examined the association between SCT and neuropsychological functioning. The present study examined the associations between SCT and measures of processing speed, executive function, attention, and reaction time. From a larger sample of 8,238 children and adolescents, a subsample of 928 children were overselected for symptoms of SCT or attention-deficit/hyperactivity disorder (ADHD) and compared to a matched control sample of 652 individuals without elevations of ADHD or SCT (age range = 5.9-15.4 years). Multiple regression analyses revealed that symptoms of SCT were independently associated with deficits in nearly all domains assessed by a battery of neuropsychological assessments, including slower processing speed, poorer working memory, decreased inhibition, poorer vigilance, and increased reaction time. Further, weaknesses in all five of these domains remained significant even after symptoms of ADHD-inattention, anxiety, and depression were controlled. These findings add to literature that supports the validity of SCT as a symptom profile separate from ADHD-inattention symptoms.

How Specific Are Learning Disabilities?

Despite historical emphasis on "specific" learning disabilities (SLDs), academic skills are strongly correlated across the curriculum. Thus, one can ask how specific SLDs truly are. To answer this question, we used bifactor models to identify variance shared across academic domains (academic g), as well as variance unique to reading, mathematics, and writing. Participants were 686 children ages 8 to 16. Although the sample was overselected for learning disabilities, we intentionally included children across the full range of individual differences in this study in response to growing recognition that a dimensional, quantitative view of SLD is more accurate than a categorical view. Confirmatory factor analysis identified five academic domains (basic reading, reading comprehension, basic math, math problem-solving, and written expression); spelling clustered with basic reading and not writing. In the bifactor model, all measures loaded significantly on academic g. Basic reading and mathematics maintained variance distinct from academic g, consistent with the notion of SLDs in these domains. Writing did not maintain specific variance apart from academic g, and evidence for reading comprehension-specific variance was mixed. Academic g was strongly correlated with cognitive g (r = .72) but not identical to it. Implications for SLD diagnosis are discussed.

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia.

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10-6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10-13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10-43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10-22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10-12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10-4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10-7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10-29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.

Left posterior prefrontal regions support domain-general executive processes needed for both reading and math.

Substantial evidence has suggested that reading and math are supported by executive processes (EP). However, to date little is known about which portion of the neural system underpinning domain-general executive skills works to support reading and math. In this study, we aimed to answer this question using fMRI via two complementary approaches. First, imaging data were acquired whilst a sample of 231 adolescents performed each of three separate tasks designed to assess reading comprehension, numerical magnitude estimation, and EP in working memory (WM), respectively. With careful task designs and conjunction analyses, we were able to isolate cross-domain brain activity specifically related to EP, as opposed to lower-level domain-general processes (e.g., visual processing). Second, the meta-analytic tool Neurosynth was used to independently identify brain regions involved reading, math, and EP. Using a combination of forward and reverse statistical inference and conjunction analyses, we again isolated brain regions specifically supporting domain-general EP. Results from both approaches yielded overlapping activation for reading, math, and EP in the left ventrolateral prefrontal cortex, left inferior frontal junction, and left precentral gyrus. This pattern suggests that posterior regions of the prefrontal cortex, rather than more central regions such as mid-DLPFC, play a leading role in supporting domain-general EP utilized by both reading and math.