A multi-omics study of brain tissue transcription and DNA methylation revealing the genetic pathogenesis of ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is a chronic psychiatric disease that often affects a patient's whole life. Research has found that genetics plays an important role in the development of ADHD. However, there is still a lack of knowledge about the tissue-specific causal effects of biological processes beyond gene expression, such as alternative splicing (AS) and DNA methylation (DNAm), on ADHD. In this paper, a multi-omics study was conducted to investigate the causal effects of the transcription and the DNAm on ADHD, by integrating ADHD genome-wide association data with quantitative trait loci data of gene expression, AS, and DNAm across 14 different brain tissues. The causal effects were estimated using four different two-sample Mendelian randomization methods. Finally, we also prioritized the expression of 866 genes showing significant causal effects, including COMMD5, ENSG00000271904, HYAL3, etc., within at least one brain tissue. We prioritized 966 unique genes that have statistically significant causal AS events, within at least one of the 14 different brain tissues. These genes include PPP1R16A, GGT7, TREM2, etc. Furthermore, through mediation analysis, 106 regulatory pathways were inferred where DNAm influences ADHD through gene expression or AS processes. Our research findings provide guidance for future experimental studies on the molecular mechanisms of ADHD development, and also put forward valuable knowledge for the prevention, diagnosis, and treatment of ADHD.

Cumulative Effects of Resting-State Connectivity Across All Brain Networks Significantly Correlate with Attention-Deficit Hyperactivity Disorder Symptoms.

Identification of replicable neuroimaging correlates of attention-deficit hyperactivity disorder (ADHD) has been hindered by small sample sizes, small effects, and heterogeneity of methods. Given evidence that ADHD is associated with alterations in widely distributed brain networks and the small effects of individual brain features, a whole-brain perspective focusing on cumulative effects is warranted. The use of large, multisite samples is crucial for improving reproducibility and clinical utility of brain-wide MRI association studies. To address this, a polyneuro risk score (PNRS) representing cumulative, brain-wide, ADHD-associated resting-state functional connectivity was constructed and validated using data from the Adolescent Brain Cognitive Development (ABCD, N = 5,543, 51.5% female) study, and was further tested in the independent Oregon-ADHD-1000 case-control cohort (N = 553, 37.4% female). The ADHD PNRS was significantly associated with ADHD symptoms in both cohorts after accounting for relevant covariates (p < 0.001). The most predictive PNRS involved all brain networks, though the strongest effects were concentrated among the default mode and cingulo-opercular networks. In the longitudinal Oregon-ADHD-1000, non-ADHD youth had significantly lower PNRS (Cohen's d = -0.318, robust p = 5.5 × 10-4) than those with persistent ADHD (age 7-19). The PNRS, however, did not mediate polygenic risk for ADHD. Brain-wide connectivity was robustly associated with ADHD symptoms in two independent cohorts, providing further evidence of widespread dysconnectivity in ADHD. Evaluation in enriched samples demonstrates the promise of the PNRS approach for improving reproducibility in neuroimaging studies and unraveling the complex relationships between brain connectivity and behavioral disorders.

ADGRL1 haploinsufficiency causes a variable spectrum of neurodevelopmental disorders in humans and alters synaptic activity and behavior in a mouse model.

ADGRL1 (latrophilin 1), a well-characterized adhesion G protein-coupled receptor, has been implicated in synaptic development, maturation, and activity. However, the role of ADGRL1 in human disease has been elusive. Here, we describe ten individuals with variable neurodevelopmental features including developmental delay, intellectual disability, attention deficit hyperactivity and autism spectrum disorders, and epilepsy, all heterozygous for variants in ADGRL1. In vitro, human ADGRL1 variants expressed in neuroblastoma cells showed faulty ligand-induced regulation of intracellular Ca2+ influx, consistent with haploinsufficiency. In vivo, Adgrl1 was knocked out in mice and studied on two genetic backgrounds. On a non-permissive background, mice carrying a heterozygous Adgrl1 null allele exhibited neurological and developmental abnormalities, while homozygous mice were non-viable. On a permissive background, knockout animals were also born at sub-Mendelian ratios, but many Adgrl1 null mice survived gestation and reached adulthood. Adgrl1-/- mice demonstrated stereotypic behaviors, sexual dysfunction, bimodal extremes of locomotion, augmented startle reflex, and attenuated pre-pulse inhibition, which responded to risperidone. Ex vivo synaptic preparations displayed increased spontaneous exocytosis of dopamine, acetylcholine, and glutamate, but Adgrl1-/- neurons formed synapses in vitro poorly. Overall, our findings demonstrate that ADGRL1 haploinsufficiency leads to consistent developmental, neurological, and behavioral abnormalities in mice and humans.

Resolving heterogeneity in schizophrenia, bipolar I disorder, and attention-deficit/hyperactivity disorder through individualized structural covariance network analysis.

Disruptions in large-scale brain connectivity are hypothesized to contribute to psychiatric disorders, including schizophrenia, bipolar I disorder, and attention-deficit/hyperactivity disorder. However, high inter-individual variation among patients with psychiatric disorders hinders achievement of unified findings. To this end, we adopted a newly proposed method to resolve heterogeneity of differential structural covariance network in schizophrenia, bipolar I disorder, and attention-deficit/hyperactivity disorder. This method could infer individualized structural covariance aberrance by assessing the deviation from healthy controls. T1-weighted anatomical images of 114 patients with psychiatric disorders (schizophrenia: n = 37; bipolar I disorder: n = 37; attention-deficit/hyperactivity disorder: n = 37) and 110 healthy controls were analyzed to obtain individualized differential structural covariance network. Patients exhibited tremendous heterogeneity in profiles of individualized differential structural covariance network. Despite notable heterogeneity, patients with the same disorder shared altered edges at network level. Moreover, individualized differential structural covariance network uncovered two distinct psychiatric subtypes with opposite differences in structural covariance edges, that were otherwise obscured when patients were merged, compared with healthy controls. These results provide new insights into heterogeneity and have implications for the nosology in psychiatric disorders.

Pain hypersensitivity in a pharmacological mouse model of attention-deficit/hyperactivity disorder.

Clinical evidence suggests that pain hypersensitivity develops in patients with attention-deficit/hyperactivity disorder (ADHD). However, the mechanisms and neural circuits involved in these interactions remain unknown because of the paucity of studies in animal models. We previously validated a mouse model of ADHD obtained by neonatal 6-hydroxydopamine (6-OHDA) injection. Here, we have demonstrated that 6-OHDA mice exhibit a marked sensitization to thermal and mechanical stimuli, suggesting that phenotypes associated with ADHD include increased nociception. Moreover, sensitization to pathological inflammatory stimulus is amplified in 6-OHDA mice as compared to shams. In this ADHD model, spinal dorsal horn neuron hyperexcitability was observed. Furthermore, ADHD-related hyperactivity and anxiety, but not inattention and impulsivity, are worsened in persistent inflammatory conditions. By combining in vivo electrophysiology, optogenetics, and behavioral analyses, we demonstrated that anterior cingulate cortex (ACC) hyperactivity alters the ACC-posterior insula circuit and triggers changes in spinal networks that underlie nociceptive sensitization. Altogether, our results point to shared mechanisms underlying the comorbidity between ADHD and nociceptive sensitization. This interaction reinforces nociceptive sensitization and hyperactivity, suggesting that overlapping ACC circuits may be targeted to develop better treatments.

A systematic review on the application of machine learning models in psychometric questionnaires for the diagnosis of attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder is one of the most prevalent neurodevelopmental disorders worldwide. Recent studies show that machine learning has great potential for the diagnosis of attention deficit hyperactivity disorder. The aim of the present article is to systematically review the scientific literature on machine learning studies for the diagnosis of attention deficit hyperactivity disorder, focusing on psychometric questionnaire tools. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were adopted. The review protocol was registered in the PROSPERO database. A search was conducted in three databases-Web of Science Core Collection, Scopus and Pubmed-with the aim of identifying studies that apply ML techniques to support the diagnosis of attention deficit hyperactivity disorder. A total of 17 empirical studies were found that met the established inclusion criteria. The results showed that machine learning can be used to increase the accuracy of attention deficit hyperactivity disorder diagnosis. Machine learning techniques are useful and effective strategies that can complement traditional diagnostics in patients with attention deficit hyperactivity disorder.

The circadian system: A neglected player in neurodevelopmental disorders.

Patients with neurodevelopmental disorders, such as autism spectrum disorder, often display abnormal circadian rhythms. The role of the circadian system in these disorders has gained considerable attention over the last decades. Yet, it remains largely unknown how these disruptions occur and to what extent they contribute to the disorders' development. In this review, we examine circadian system dysregulation as observed in patients and animal models of neurodevelopmental disorders. Second, we explore whether circadian rhythm disruptions constitute a risk factor for neurodevelopmental disorders from studies in humans and model organisms. Lastly, we focus on the impact of psychiatric medications on circadian rhythms and the potential benefits of chronotherapy. The literature reveals that patients with neurodevelopmental disorders display altered sleep-wake cycles and melatonin rhythms/levels in a heterogeneous manner, and model organisms used to study these disorders appear to support that circadian dysfunction may be an inherent characteristic of neurodevelopmental disorders. Furthermore, the pre-clinical and clinical evidence indicates that circadian disruption at the environmental and genetic levels may contribute to the behavioural changes observed in these disorders. Finally, studies suggest that psychiatric medications, particularly those prescribed for attention-deficit/hyperactivity disorder and schizophrenia, can have direct effects on the circadian system and that chronotherapy may be leveraged to offset some of these side effects. This review highlights that circadian system dysfunction is likely a core pathological feature of neurodevelopmental disorders and that further research is required to elucidate this relationship.

Gray matter volume associations in youth with ADHD features of inattention and hyperactivity/impulsivity.

BACKGROUND: Prior research has shown smaller cortical and subcortical gray matter volumes among individuals with attention-deficit/hyperactivity disorder (ADHD). However, neuroimaging studies often do not differentiate between inattention and hyperactivity/impulsivity, which are distinct core features of ADHD. The present study uses an approach to disentangle overlapping variance to examine the neurostructural heterogeneity of inattention and hyperactivity/impulsivity dimensions. METHODS: We analyzed data from 10,692 9- to 10-year-old children from the Adolescent Brain Cognitive Development (ABCD) Study. Confirmatory factor analysis was used to derive factors representing inattentive and hyperactive/impulsive traits. We employed structural equation modeling to examine these factors' associations with gray matter volume while controlling for the shared variance between factors. RESULTS: Greater endorsement of inattentive traits was associated with smaller bilateral caudal anterior cingulate and left parahippocampal volumes. Greater endorsement of hyperactivity/impulsivity traits was associated with smaller bilateral caudate and left parahippocampal volumes. The results were similar when accounting for socioeconomic status, medication, and in-scanner motion. The magnitude of these findings increased when accounting for overall volume and intracranial volume, supporting a focal effect in our results. CONCLUSIONS: Inattentive and hyperactivity/impulsivity traits show common volume deficits in regions associated with visuospatial processing and memory while at the same time showing dissociable differences, with inattention showing differences in areas associated with attention and emotion regulation and hyperactivity/impulsivity associated with volume differences in motor activity regions. Uncovering such biological underpinnings within the broader disorder of ADHD allows us to refine our understanding of ADHD presentations.

Common and distinct cortical thickness alterations in youth with autism spectrum disorder and attention-deficit/hyperactivity disorder.

BACKGROUND: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental disorders with overlapping behavioral features and genetic etiology. While brain cortical thickness (CTh) alterations have been reported in ASD and ADHD separately, the degree to which ASD and ADHD are associated with common and distinct patterns of CTh changes is unclear. METHODS: We searched PubMed, Web of Science, Embase, and Science Direct from inception to 8 December 2023 and included studies of cortical thickness comparing youth (age less than 18) with ASD or ADHD with typically developing controls (TDC). We conducted a comparative meta-analysis of vertex-based studies to identify common and distinct CTh alterations in ASD and ADHD. RESULTS: Twelve ASD datasets involving 458 individuals with ASD and 10 ADHD datasets involving 383 individuals with ADHD were included in the analysis. Compared to TDC, ASD showed increased CTh in bilateral superior frontal gyrus, left middle temporal gyrus, and right superior parietal lobule (SPL) and decreased CTh in right temporoparietal junction (TPJ). ADHD showed decreased CTh in bilateral precentral gyri, right postcentral gyrus, and right TPJ relative to TDC. Conjunction analysis showed both disorders shared reduced TPJ CTh located in default mode network (DMN). Comparative analyses indicated ASD had greater CTh in right SPL and TPJ located in dorsal attention network and thinner CTh in right TPJ located in ventral attention network than ADHD. CONCLUSIONS: These results suggest shared thinner TPJ located in DMN is an overlapping neurobiological feature of ASD and ADHD. This alteration together with SPL alterations might be related to altered biological motion processing in ASD, while abnormalities in sensorimotor systems may contribute to behavioral control problems in ADHD. The disorder-specific thinner TPJ located in disparate attention networks provides novel insight into distinct symptoms of attentional deficits associated with the two neurodevelopmental disorders. TRIAL REGISTRATION: PROSPERO CRD42022370620. Registered on November 9, 2022.

Diffusion kurtosis imaging reveals abnormal gray matter and white matter development in some brain regions of children with attention-deficit/hyperactivity disorder.

In this study, we explored the application of diffusion kurtosis imaging (DKI) technology in the brains of children with attention-deficit/hyperactivity disorder (ADHD). Seventy-two children with ADHD and 79 age- and sex-matched healthy controls were included in the study. All children were examined by means of 3D T1-weighted image, DKI, and conventional sequence scanning. The volume and DKI parameters of each brain region were obtained by software postprocessing (GE ADW 4.6 workstation) and compared between the two groups of children to determine the imaging characteristics of children with ADHD. The result showed the total brain volume was lower in children with ADHD than in healthy children (p < .05). The gray and white matter volumes in the frontal lobe, temporal lobe, hippocampus, caudate nucleus, putamen, globus pallidus, and other brain regions were lower in children with ADHD than in healthy children (p < .05). The axial kurtosis (Ka), mean kurtosis (MK), fractional anisotropy (FA), and radial kurtosis(Kr) values in the frontal lobe, temporal lobe, and caudate nucleus of children with ADHD were lower than those of healthy children, while the mean diffusivity(MD) and fractional anisotropy of kurtosis (FAK) values were higher than those of healthy children (p < .05). Additionally, the Ka, MK, FA, and Kr values in the frontal lobe, caudate nucleus, and temporal lobe could be used to distinguish children with ADHD (AUC > .05, p < .05). In conclusion, DKI showed abnormal gray matter and white matter development in some brain regions of children with ADHD.

Attention deficits linked with proclivity to explore while foraging.

All mobile organisms forage for resources, choosing how and when to search for new opportunities by comparing current returns with the average for the environment. In humans, nomadic lifestyles favouring exploration have been associated with genetic mutations implicated in attention deficit hyperactivity disorder (ADHD), inviting the hypothesis that this condition may impact foraging decisions in the general population. Here we tested this pre-registered hypothesis by examining how human participants collected resources in an online foraging task. On every trial, participants chose either to continue to collect rewards from a depleting patch of resources or to replenish the patch. Participants also completed a well-validated ADHD self-report screening assessment at the end of sessions. Participants departed resource patches sooner when travel times between patches were shorter than when they were longer, as predicted by optimal foraging theory. Participants whose scores on the ADHD scale crossed the threshold for a positive screen departed patches significantly sooner than participants who did not meet this criterion. Participants meeting this threshold for ADHD also achieved higher reward rates than individuals who did not. Our findings suggest that ADHD attributes may confer foraging advantages in some environments and invite the possibility that this condition may reflect an adaptation favouring exploration over exploitation.

Rising Trends of Childhood Attention-Deficit/Hyperactivity Disorder in a Large Integrated Healthcare Delivery System in Southern California, 2010-2021.

OBJECTIVE: To evaluate trends of attention-deficit/hyperactivity disorder (ADHD) diagnosis rates among children aged 5-17 years over the past decade (2010-2021) and to investigate whether there have been differences in temporal changes based on race and ethnicity, sex, or income. STUDY DESIGN: Childhood ADHD diagnosis was ascertained from electronic health records using International Classification of Diseases ninth revision (314.xx) and International Classification of Diseases tenth revision (F90.x) codes. Data were stratified by child's sex, race and ethnicity, and household income, and rates of ADHD were estimated before and after adjustment for potential confounders. RESULTS: The overall ADHD diagnosis rates increased from 3.5% in 2010 to 4.0% in 2021. ADHD diagnosis was most prevalent among White children (6.1%), then Black (4.6%), Other/multiple (3.7%), Hispanic (3.1%), and Asian/Pacific Islander (PI) (1.7%). ADHD was also highly prevalent among boys (73.3%) or family income≥$70,000 (50.0%). ADHD diagnosis increased among Black (4.2% to 5.1%), Hispanic (2.8% to 3.6%), and Asian/PI children (1.5% to 2.0%) but remained stable for White (6.2% to 6.1%) and Other/multiple race/ethnic children (3.7% to 3.7%). Increases in the prevalence among girls were also observed. CONCLUSION: The prevalence of ADHD in children has risen with the largest increases observed for Black, Hispanic, and Asian/PI children. Rates among less affluent families and girls have also been increasing, narrowing the gaps in diagnosis rates previously observed. These increases may reflect improvements in screening and provision of care among demographics where ADHD has been historically underdiagnosed.

Geographic Disparities in Availability of General and Specialized Pediatricians in the United States and Prevalence of Childhood Neurodevelopmental Disorders.

General pediatricians and those specialized in developmental-behavioral and neurodevelopmental disabilities support children with neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). We identified substantial geographic disparities in pediatrician availability (eg, urban > rural areas), as well as regions with low pediatrician access but high ASD/ADHD prevalence estimates (eg, the US Southeast).

Antihypertensive treatment during pregnancy induces long-term changes in gut microbiota and the behaviors of the attention deficit hyperactivity disorder offspring.

The pathogenesis of attention-deficit/hyperactivity disorder (ADHD) has not been fully elucidated. Gestational hypertension could double the probability of ADHD in the offspring, while the initial bacterial communication between the mother and offspring has been associated with psychiatric disorders. Thus, we hypothesize that antihypertensive treatment during pregnancy may abate the impairments in neurodevelopment of the offspring. To test this hypothesis, we chose Captopril and Labetalol, to apply to pregnant spontaneously hypertensive rat (SHR) dams and examined the outcomes in the male offspring. Our data demonstrated that maternal treatment with Captopril and Labetalol had long-lasting changes in gut microbiota and behavioral alterations, including decreased hyperactivity and increased curiosity, spatial learning and memory in the male offspring. Increased diversity and composition were identified, and some ADHD related bacteria were found to have the same change in the gut microbiota of both the dam and offspring after the treatments. LC-MS/MS and immunohistochemistry assays suggested elevated expression of brain derived neurotrophic factor (BDNF) and dopamine in the prefrontal cortex and striatum of offspring exposed to Captopril/ Labetalol, which may account for the improvement of the offspring's psychiatric functions. Therefore, our results support the beneficial long-term effects of the intervention of gestational hypertension in the prevention of ADHD.

Neurovascular dysfunction in psychiatric disorders: Underlying mechanisms and therapeutic approaches.

BACKGROUND: Neurovascular interfaces, specifically the blood-brain barrier (BBB) and blood-retinal barrier (BRB), play pivotal roles in maintaining the homeostasis of the central nervous system (CNS). For a long time, these structures were seen only as a way of protection, but we currently know that they have a critical role in CNS (dys)function. Several studies have identified neurovascular alterations in early stages of brain and eye diseases, contributing to the pathophysiology of such conditions. More recently, interesting data have also highlighted the importance of neurovasculature in psychiatric disorders. METHODS: Using the PubMed database, we brought together the evidence concerning the changes in BBB and BRB under psychiatric conditions, with a focus on anxiety, major depressive disorder (MDD), attention-deficit/hyperactivity disorder (ADHD) and drug abuse, specifically related with methamphetamine (METH) and cocaine consumption. RESULTS: We summarized the main findings obtained from in vitro and animal studies, as well as clinical research that has been undertaken to identify neurovascular abnormalities upon such neuropsychiatric disorders. The drivers of barrier alterations were examined, namely the role of neuroinflammation, while reporting putative barrier-associated biomarkers of these disorders. CONCLUSION: This review underscores the critical need for a deeper understanding of BBB and BRB function in neuropsychiatric conditions and their potential as therapeutic targets while elucidating the key players involved. The innovative approaches to managing these complex disorders are also addressed while bridging the gap concerning what is currently known regarding the association between neuropsychiatric conditions and their vascular implications.

Cognitive Correlates of Risky Decision-Making in Individuals with and without ADHD: A Meta-analysis.

This meta-analytic study aims to investigate the cognitive correlates of risky decision-making in individuals with attention-deficit/hyperactivity disorder (ADHD) and typically developing (TD) individuals. A systematic analysis of existing literature was conducted, encompassing 38 studies (496 ADHD and 1493 TD). Findings revealed a consistent propensity for riskier decision-making in individuals with ADHD, supported by significant correlations with attention, cognitive flexibility, inhibitory control, time perception, and working memory. The study underscores the relevance of these cognitive functions in shaping decision-making tendencies, with nuanced patterns observed within the ADHD and TD subgroups. Individuals with ADHD often demonstrate altered patterns of correlation, reflecting the specific cognitive challenges characteristic of the disorder.

Diagnosis and pharmacological management of attention deficit hyperactivity disorder in adults with and without intellectual disability: cohort study using electronic health records.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is increasingly diagnosed in adults. People with intellectual disability have higher rates of ADHD yet there is little evidence on the presentation and pharmacological treatment of ADHD in this population or how this differs from the general population. METHODS: Retrospective cohort study using data from electronic health records. Adults with intellectual disability newly diagnosed with ADHD between 2007 and 2022 were matched to adults with ADHD without intellectual disability and their clinical features and treatments were compared. RESULTS: A total of 159 adults with ADHD and intellectual disability and 648 adults with ADHD without intellectual disability formed the dataset. Adults with intellectual disability had higher rates of psychiatric co-morbidity and spent more time under mental health services than those without intellectual disability. They were more likely to have recorded agitation, aggression, hostility, and mood instability, and less likely to have poor concentration recorded in the 12 months prior to the diagnosis of ADHD. Following diagnosis, people with intellectual disability were significantly less likely to be prescribed any medication for ADHD than controls without intellectual disability (adjusted odds ratio 0.60, 95% confidence interval 0.38-0.91), and were less likely to be prescribed stimulants (27.7% v 46.0%, p < 0.001). CONCLUSIONS: The presence of behaviors that challenge in adults with intellectual disability may indicate co-occurring ADHD. Further work to define the safety and efficacy of medication for ADHD in adults with intellectual disability is needed to understand differences in prescription rates and to avoid inequities in care outcomes.

Labour market integration among young adults diagnosed with attention-deficit/hyperactivity disorder (ADHD) at working age.

METHODS: Multiple Swedish nationwide registers were used to identify 8045 individuals, aged 20-29, with an incident diagnosis of ADHD 2006-2011. Labour market integration was conceptualized according to the core-peripheral model as a continuum from a strong (core) to a weak (peripheral) connection to the labour market. Sequence analyses categorized clusters of labour market integration, from 1 year before to 5 years after their ADHD diagnosis for individuals diagnosed with ADHD and a matched control group without ADHD. Multinomial logistic regression computed odds ratios (ORs) with 95% confidence intervals (CIs) between sociodemographic factors and comorbid disorders and the identified clusters. RESULTS: About one-fourth of the young adults diagnosed with ADHD belonged to clusters characterized by a transition to a mainly peripheral labour market position, which was approximately four-times higher compared to controls without ADHD. Foremost, those living in small cities/villages (OR 1.9; CI 1.5-2.2), those having comorbid autism-spectrum disorder (OR 13.7; CI 6.8-27.5) or schizophrenia/psychoses (OR 7.8; CI 3.8-15.9) were associated with a transition towards a peripheral labour market position throughout the study period. Those with a high educational level (OR 0.1; CI 0.1-0.1), and men (OR 0.7; CI 0.6-0.8) were less likely to have a peripheral labour market position. CONCLUSIONS: Young adults diagnosed with ADHD are four-times more likely to be in the peripheral labour market position compared to those without ADHD. To increase labour market participation, special attention is warranted to those with low educational level, those living outside big cities and those with comorbid mental disorders.

Unsupervised machine learning for identifying attention-deficit/hyperactivity disorder subtypes based on cognitive function and their implications for brain structure.

BACKGROUND: Structural anomalies in the frontal lobe and basal ganglia have been reported in patients with attention-deficit/hyperactivity disorder (ADHD). However, these findings have been not always consistent because of ADHD diversity. This study aimed to identify ADHD subtypes based on cognitive function and find their distinct brain structural characteristics. METHODS: Using the data of 656 children with ADHD from the Adolescent Brain Cognitive Development (ABCD) Study, we applied unsupervised machine learning to identify ADHD subtypes using the National Institutes of Health Toolbox Tasks. Moreover, we compared the regional brain volumes between each ADHD subtype and 6601 children without ADHD (non-ADHD). RESULTS: Hierarchical cluster analysis automatically classified ADHD into three distinct subtypes: ADHD-A (n = 212, characterized by high-order cognitive ability), ADHD-B (n = 190, characterized by low cognitive control, processing speed, and episodic memory), and ADHD-C (n = 254, characterized by strikingly low cognitive control, working memory, episodic memory, and language ability). Structural analyses revealed that the ADHD-C type had significantly smaller volumes of the left inferior temporal gyrus and right lateral orbitofrontal cortex than the non-ADHD group, and the right lateral orbitofrontal cortex volume was positively correlated with language performance in the ADHD-C type. However, the volumes of the ADHD-A and ADHD-B types were not significantly different from those of the non-ADHD group. CONCLUSIONS: These results indicate the presence of anomalies in the lateral orbitofrontal cortex associated with language deficits in the ADHD-C type. Subtype specificity may explain previous inconsistencies in brain structural anomalies reported in ADHD.

Associations between attention-deficit hyperactivity disorder genetic liability and ICD-10 medical conditions in adults: utilizing electronic health records in a Phenome-Wide Association Study.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is often comorbid with other medical conditions in adult patients. However, ADHD is extremely underdiagnosed in adults and little is known about the medical comorbidities in undiagnosed adult individuals with high ADHD liability. In this study we investigated associations between ADHD genetic liability and electronic health record (EHR)-based ICD-10 diagnoses across all diagnostic categories, in individuals without ADHD diagnosis history. METHODS: We used data from the Estonian Biobank cohort (N = 111 261) and generated polygenic risk scores (PRS) for ADHD (PRSADHD) based on the ADHD genome-wide association study. We performed a phenome-wide association study (PheWAS) to test for associations between standardized PRSADHD and 1515 EHR-based ICD-10 diagnoses in the full and sex-stratified sample. We compared the observed significant ICD-10 associations to associations with (1) ADHD diagnosis and (2) questionnaire-based high ADHD risk analyses. RESULTS: After Bonferroni correction (p = 3.3 × 10-5) we identified 80 medical conditions associated with PRSADHD. The strongest evidence was seen with chronic obstructive pulmonary disease (OR 1.15, CI 1.11-1.18), obesity (OR 1.13, CI 1.11-1.15), and type 2 diabetes (OR 1.11, CI 1.09-1.14). Sex-stratified analysis generally showed similar associations in males and females. Out of all identified associations, 40% and 78% were also observed using ADHD diagnosis or questionnaire-based ADHD, respectively, as the predictor. CONCLUSIONS: Overall our findings indicate that ADHD genetic liability is associated with an increased risk of a substantial number of medical conditions in undiagnosed individuals. These results highlight the need for timely detection and improved management of ADHD symptoms in adults.