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PubMed2003

Behaviour in children with language development disorders.

OBJECTIVE: The objective of the study was to explore the univariate and multivariate differences in behavioural problems among children with disorders in expressive or mixed receptive-expressive language development and children with unimpaired language development. METHOD: Ninety-four children with language development disorders (LDD) between the ages of 4 and 6 years and 94 children (matched by age and sex) without disorders of language development were compared concerning behavioural problems, as measured by the German version of the Child Behavior Checklist/4-18. RESULTS: Thirty-two children (34%) with LDD showed behavioural problems in the clinical range, whereas only 6 control subjects (6%) had scores in this range. Univariate group comparisons between patients and control subjects showed significant differences in all 8 syndromes and the scale "other problems," with patients having higher scores. Multivariate stepwise discriminant analysis showed a significant discriminant function by the scales "other problems," "social problems," "anxious-depressed," "thought problems," "attention problems," and "delinquent problems." CONCLUSIONS: In general, our results agree with several studies that report that children with speech and language disorders are at special risk for developing behavioural problems. Neurodevelopmental immaturity may be one factor underlying both the disorder in language development and the behavioural problems.

Age Factors↗

PubMed2000

The neurodevelopmental hypothesis of schizophrenia: following a trail of evidence from cradle to grave.

This is a critical review of the literature related to the neurodevelopmental hypothesis of schizophrenia which posits that the illness is related to abnormal brain development. The review focuses on data deriving from clinical studies, and it is organized according to the life phase from which the data were collected: conception and birth, infancy and childhood up to the onset of the illness, after illness onset, and postmortem. The neurodevelopmental hypothesis is supported by several pieces of evidence, including increased frequency of obstetric complications in patients with schizophrenia: the presence of minor physical anomalies; the presence of neurological, cognitive, and behavioral dysfunction long before illness onset; a course and outcome of the illness itself that is incompatible in most cases with a degenerative illness; the stability of brain structural measures over time; and the absence of postmortem evidence of neurodegeneration. A historical perspective on how this research accumulated and a section addressing important areas of future investigation are also provided. We conclude that schizophrenia is certainly not a degenerative brain disorder, and that it is likely that a brain insult in utero or at birth plays a role in its expression. Current evidence cannot completely exclude the role of environmental variables after birth. In addition, it is possible that other psychiatric disorders may also have a neurodevelopmental component.

Adolescent↗

PubMed2025

rbfox1 LoF mutants show disrupted bdnf/trkb2 and crhb/nr3c2 expression and increased cortisol levels during development coupled with signs of allostatic overload in adulthood.

Mutations in the RBFOX1 gene are associated with psychiatric disorders but how RBFOX1 influences psychiatric disorder vulnerability remains unclear. Recent studies showed that RBFOX proteins mediate the alternative splicing of PAC1, a critical HPA axis activator. Further, RBFOX1 dysfunction is linked to dysregulation of BDNF/TRKB, a pathway promoting neuroplasticity, neuronal survival, and stress resilience. Hence, RBFOX1 dysfunction may increase psychiatric disorder vulnerability via HPA axis dysregulation, leading to disrupted development and allostatic overload. To test this hypothesis, we generated a zebrafish rbfox1 loss of function (LoF) line and examined behavioural and molecular effects during development. We found that rbfox1 LoF mutants exhibited hyperactivity, impulsivity and heightened arousal, alongside alterations in proliferation - traits associated with neurodevelopmental and stress-related disorders. In adults, loss of rbfox1 function led to decreased fertility and survival, consistent with allostatic overload. At the molecular level, at larval stages rbfox1 mutants showed increased cortisol levels and disrupted expression of key stress-related genes (bdnf, trkb2, pac1a-hop, crhb, nr3c2). Pharmacological intervention targeting TRKB restored crhb and nr3c2 gene expression and hyperactive and hyperarousal behaviours. In adults, dysregulation of crhb, nr3c2 and bdnf/trkb2 genes was only seen following acute stress exposure. Our findings reveal a fundamental role for RBFOX1 in integrating stress responses through its regulation of BDNF/TRKB and neuroendocrine signalling.

Journal Article↗

PubMed2002

Expression of Oct-6, a POU III domain transcription factor, in schizophrenia.

OBJECTIVE: Oct-6, a POU-III domain transcription factor, is expressed in embryonic stem cells and Schwann cells and in neuronal subpopulations during early mammalian development, but its relevance to disorders of cerebral development in humans is untested. This study evaluated the expression of Oct-6 in schizophrenia, a disorder that has been linked with neurodevelopmental abnormalities. METHOD: Immunohistochemistry was used to examine Oct-6 expression in the temporal lobe in postmortem tissue from 10 subjects with schizophrenia and 10 matched comparison subjects. Western blot analysis was used to study Oct-6 expression in the frontal and temporal cortex in tissue from an additional three schizophrenic and three matched comparison subjects and in the frontal lobe only in tissue from an additional 10 schizophrenic and 10 matched comparison subjects. RESULTS: Extensive Oct-6 immunoreactivity was present in the temporal lobe in all 10 schizophrenic subjects, while very little or no expression was found in the comparison subjects. In schizophrenic subjects, Oct-6 immunoreactivity was found in a subset of cells in the pyramidal cell layer of the hippocampus and in the granule cell layer of the dentate gyrus. Oct-6 staining was predominantly localized in the cytoplasm. Western blot analysis confirmed the presence of Oct-6 in the frontal and temporal cortex in schizophrenic subjects but not in comparison subjects. CONCLUSIONS: The presence of Oct-6 expression in the schizophrenic subjects but not in the comparison subjects suggests that Oct-6 may provide a marker for the neuropathology associated with schizophrenia. Further, it may provide a clue to the neurodevelopmental basis of the disease and could be a reliable means to examine the developmental brain abnormalities described in this disorder.

Adult↗

PubMed1990

Autistic disorder in Sotos syndrome: a case report.

A case study of a child with Sotos syndrome, normal intelligence, and autistic disorder is presented. Initial descriptions of Sotos syndrome included severe to mild mental retardation. More recent studies indicate language and learning disabilities with normal intelligence. Our patient met criteria for a diagnosis of autistic disorder. Sotos syndrome is another genetic and neurodevelopmental syndrome that can be associated with autistic as well as communication and language disorders.

Autistic Disorder↗

PubMed2001

Molecular foundation of anxiety disorders.

Genetic epidemiology has assembled convincing evidence that anxiety and related disorders are influenced by genetic factors and that the genetic component is highly complex, polygenic, and epistatic. Although several genes which may contribute to the genetic variance of anxiety-related traits or modify the phenotypic expression of pathologic anxiety are currently under investigation, molecular genetics has so far failed to identify a genomic variation that can consistently contribute susceptibility of anxiety disorders. Investigation of gene-gene and gene-environment interactions in humans and nonhuman primates as well as gene inactivation studies in mice further intensify the identification of genes that are essential for development and adult plasticity of the brain related to complex anxiety responses. Because the modes of inheritance of anxiety disorders are complex, it has been concluded that multiple genes of small effect, in interaction with each other and with nongenetic neurodevelopmental events, produce vulnerability to the disorder. Future research directions will take advantage of the completion of the sequencing the human and mouse genome coinciding with the revolution in bioinformatics. More than 1.4 million single nucleotide polymorphisms (SNPs) in the human genome have been identified. This collection should allow the initiation of genome-wide linkage disequilibrium mapping of the genes influencing anxiety in the human population. Integration of these emerging tools and technologies for genetic analysis will provide the groundwork for an advanced stage of gene identification and functional studies in anxiety and related disorders.

Animals↗

PubMed2006

Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males.

PURPOSE: Mutations in the MECP2 gene are associated with Rett syndrome, an X-linked mental retardation disorder in females. Mutations also cause variable neurodevelopmental phenotypes in rare affected males. Recent clinical testing for MECP2 gene rearrangements revealed that entire MECP2 gene duplication occurs in some males manifesting a progressive neurodevelopmental syndrome. METHODS: Clinical testing through quantitative DNA methods and chromosomal microarray analysis in our laboratories identified seven male patients with increased MECP2 gene copy number. RESULTS: Duplication of the entire MECP2 gene was found in six patients, and MECP2 triplication was found in one patient with the most severe phenotype. The Xq28 duplications observed in these males are unique and vary in size from approximately 200 kb to 2.2 Mb. Three of the mothers who were tested were asymptomatic duplication carriers with skewed X-inactivation. In silico analysis of the Xq28 flanking region showed numerous low-copy repeats with potential roles in recombination. CONCLUSIONS: These collective data suggest that increased MECP2 gene copy number is mainly responsible for the neurodevelopmental phenotypes in these males. These findings underscore the allelic and phenotypic heterogeneity associated with the MECP2 gene and highlight the value of molecular analysis for patient diagnosis, family members at risk, and genetic counseling.

Adolescent↗

PubMed1989

Toe walking. A marker for language disorders in the developmentally disabled.

Toe walking unassociated with an autistic disorder or cerebral palsy generally has been considered a normal infant gait. The incidence of toe walking in various diagnostic subgroups of 799 developmentally disabled children presenting to a tertiary-level multidisciplinary assessment clinic was reviewed to investigate the authors' clinical impression that toe walking may be a marker for language dysfunction. Toe walking was found to be more frequent in those diagnostic subgroups with more severe language disorders. Toe walking also correlated with lower IQ scores (p less than 0.0001). The sensitivities, specificities, predictive validities and odds ratios all supported the hypothesized association between toe walking and language disorders. Further prospective studies of the neurodevelopmental outcome of children with toe walking are needed to determine whether this behavior can identify children at risk for language disorders.

Autistic Disorder↗

PubMed2024

Obesity: exploring its connection to brain function through genetic and genomic perspectives.

Obesity represents an escalating global health burden with profound medical and economic impacts. The conventional perspective on obesity revolves around its classification as a "pure" metabolic disorder, marked by an imbalance between calorie consumption and energy expenditure. Present knowledge, however, recognizes the intricate interaction of rare or frequent genetic factors that favor the development of obesity, together with the emergence of neurodevelopmental and mental abnormalities, phenotypes that are modulated by environmental factors such as lifestyle. Thirty years of human genetic research has unveiled >20 genes, causing severe early-onset monogenic obesity and ~1000 loci associated with common polygenic obesity, most of those expressed in the brain, depicting obesity as a neurological and mental condition. Therefore, obesity's association with brain function should be better recognized. In this context, this review seeks to broaden the current perspective by elucidating the genetic determinants that contribute to both obesity and neurodevelopmental and mental dysfunctions. We conduct a detailed examination of recent genetic findings, correlating them with clinical and behavioral phenotypes associated with obesity. This includes how polygenic obesity, influenced by a myriad of genetic variants, impacts brain regions associated with addiction and reward, differentiating it from monogenic forms. The continuum between non-syndromic and syndromic monogenic obesity, with evidence from neurodevelopmental and cognitive assessments, is also addressed. Current therapeutic approaches that target these genetic mechanisms, yielding improved clinical outcomes and cognitive advantages, are discussed. To sum up, this review corroborates the genetic underpinnings of obesity, affirming its classification as a neurological disorder that may have broader implications for neurodevelopmental and mental conditions. It highlights the promising intersection of genetics, genomics, and neurobiology as a foundation for developing tailored medical approaches to treat obesity and its related neurological aspects.

Humans↗

PubMed2026

Abnormal ClC-3/TMEM9-mediated endosomal ion transport in CLCN3-associated neurodevelopmental disease.

Endolysosomal abnormalities are particularly detrimental to the nervous system and have been implicated in neuropsychiatric disorders. Key regulators of the lysosomal and endosomal luminal ion homeostasis are CLC chloride/proton exchangers. We report 15 individuals carrying variants in CLCN3, encoding a ubiquitous endosomal 2Cl-/H+ exchanger, and provide updated clinical information for 5 previously reported individuals. Subjects displayed a broad spectrum of neuropsychiatric symptoms, including developmental delay, intellectual disability, and epilepsy. To reveal the pathogenic mechanism, we investigated ClC-3 variants-mediated ion transport and its regulation by the recently discovered inhibitory beta subunit TMEM9. 12/20 missense variants exhibited altered properties and fell into two classes: those affecting the region binding inhibitory TMEM9 carboxy-termini, and those that broaden the voltage range over which ClC-3 conducts ions. Surprisingly, the latter variants also attenuated TMEM9-mediated inhibition. Both classes produced a toxic gain-of-function, as evident from endolysosomal vacuolization by mutant ClC-3/TMEM9 overexpression. Our results expand the genetic and clinical spectrum of CLCN3-related disease, provide a solid basis for genetic counseling, and uncover an unexpected link between gating-associated conformational changes and inhibition by TMEM9.

Chloride Channels↗

PubMed2001

Autism spectrum disorders: update of evaluation and treatment.

Autistic spectrum disorders are a group of neurodevelopmental conditions that are increasingly capturing the attention of clinicians and investigators. New insights from genetics and neuropathophysiology of autism will increasingly inform treatment. Presently, individualized treatment approaches typically include a mix of behavioral and, occasionally, pharmacotherapeutic strategies. Concerning the latter, exquisite sensitivity to medication is not uncommon in some children with autism.

Antipsychotic Agents↗

PubMedDate not supplied

[Neurodevelopmental hypothesis in schizophrenia].

The hypothesis for a neurodevelopmental basis to the underlying physiopathological disorder leading to schizophrenia has been proposed by many investigators for more than two decades. This hypothesis is supported by -several lines of evidence. Pregnancy and delivery complications, particularly those with known or presumed impact on fetal neurologic development, result in increased risk for psychotic disorders. Other possible etiologic candidates include viral infections. Minor physical anomalies, manifesting as slight anatomical defects of the head, hair, eyes, mouth, hands and feet, as dematoglyphic fluctuating asymmetries, are due to some injury occurring during the first or second trimester of fetal life, and are more common among patients with schizophrenia and in their unaffected siblings than in the general population. But a major Issue in a such neurodevelopmental model theory is the delayed onset of the schizophrenic disorder. Although early signs and prodromal symptoms can be defined retrospectively in patients who have developed schizophrenia, they do have to be confirmed as early predictors in prospective and longitudinal studies. Abnormalities in brain development and maturation seem to begin prenatally, but may continue throughout childhood and the observed changes during these periods must have -consequences for the neuronal circuitry and connectivity. Advances in brain imaging have now led to the identification of a great number of brain abnormalities in schizophrenia. The most consistently replicated structural anomaly present in the brains of patients with chronic schizophrenia is ventricular enlargement. These findings also include medial temporal lobe structures (which include the amygdala, hippocampus, and parahippocampal gyrus), and neocortical temporal lobe regions (superior temporal gyrus). There is also some evidence for frontal lobe abnormalities, particularly prefrontal gray matter and orbitofrontal regions. Similarly, there are findings for parietal lobe abnormalities (particularly of the inferior parietal lobule which includes both supramarginal and angular gyri) and subcortical abnormalities (basal ganglia, corpus callosum, and thalamus) but more equivocal evidence for cerebellar abnormalities. However, it is possible that the brain structural abnormalities observed in schizophrenia are not only due to neurodevelopmental anomalies, but also to an alteration in cortical plasticity and maturation processes that occurs over the long course of the disease. The genetic predisposition for schizophrenia has been confirmed in many studies. It is utterly disappointing that molecular genetic approaches have so far not yielded conclusive evidence for vulnerability or protection genes in schizophrenia. Future studies will likely benefit from: 1) studying more homogeneous patient groups, 2) studying high risk populations such as biological relatives of patients with schizophrenia, 3) using longitudinal and prospective methodological design in order to confirm the predictive validity of neurodevelopmental clues found in patients with schizophrenia, 4) applying newer strategies such as composite phenotypes of developmental origin, in combination with new genetic methods.

Amygdala↗

PubMed2006

Psychopathology in tuberous sclerosis: an overview and findings in a population-based sample of adults with tuberous sclerosis.

BACKGROUND: Tuberous sclerosis (TS) is a multi- system disorder with complex genetics. The neurodevelopmental manifestations of TS are responsible for considerable morbidity. The prevalence of epilepsy and intellectual disabilities among individuals with TS have been well described. Ours is the first study that explores the prevalence and pattern of psychopathology in a population-based sample of adults with TS. METHODS: Sixty subjects were identified through a capture-recapture analysis of TS. Information was gathered as to seizure history, cognitive functioning (WISC-III) and psychopathology (SADS-L, SAPPA). Lifetime psychopathology was categorized according to Research Diagnostic Criteria. The overall pattern of mental illness (MI) was examined as well as how this varied with IQ and seizure history. RESULTS: Twenty-four (40.0%) subjects had a history of MI. The most common diagnosis was that of an affective disorder [18 (30.0%)], the majority of which were major depressive episodes. Alcoholism [4 (6.7%)] and anxiety disorders [3 (5.0%)] were the next most common diagnoses. Two (3.3%) subjects had had a tic disorder. Only one individual had a diagnosis of schizophrenia. MI was found in 75.0% of those with a history of epilepsy and 37.5% of those without epilepsy. MI was significantly more prevalent in those with a full-scale IQ above 70. CONCLUSIONS: A significant proportion of adult with TS experience MI. MI was significantly more [corrected] prevalent in subjects with a full-scale IQ above 70. Reasons for such a finding are explored, and related methodological considerations for future research outlined.

Adult↗

PubMed2004

Refractory atypical absence seizures in rat: a two hit model.

Medically refractory seizure disorders in children usually have malignant neurodevelopmental outcomes and often are associated with the presence of congenital cortical dysplasias in the brain. To date, there are no animal models of these disorders by which to test hypotheses of pathogenesis or to screen novel drugs for antiepileptic activity. In rats, treatment with the antimitotic agent methylazoxymethanol acetate (MAM) on gestational day (G) 15 produces a neuronal migration disorder similar to the cortical dysplasias seen in human brain. We sought to produce chronic, recurrent, medically refractory seizures by administration of the cholesterol biosynthesis inhibitor AY-9944 (AY) during postnatal development in rats exposed prenatally to MAM. Prenatal MAM and postnatal AY treatments resulted in spontaneous, recurrent atypical absence seizures that were characterized by bilaterally synchronous slow spike-and-wave discharges (SWD) with a frequency of 6 Hz. The MAM-AY-induced seizures were refractory to ethosuximide, sodium valproate, and the GABABR antagonist CGP 35348, and were exacerbated by carbamazepine. Histological examination of brains from MAM-treated rats showed hippocampal heterotopias, in addition to atrophy and abnormalities of cortical lamination. The MAM-AY-treated rat represents a reproducible model of refractory atypical absence seizures in children with brain dysgenesis.

Animals↗

PubMed2026

Prenatal BPA exposure perturbs RNA-binding protein-mediated splicing regulation and synaptogenesis in the developing cerebellum in a sex-dependent manner.

BACKGROUND: Autism spectrum disorder (ASD) is a pervasive neurodevelopmental condition characterized by social communication deficits, exhibiting a male bias in prevalence. Emerging evidence suggests that prenatal exposure to bisphenol A (BPA) may perturb neurodevelopmental trajectories relevant to ASD. While the cerebellum is increasingly recognized as a brain region implicated in ASD pathophysiology, the impact of gestational BPA exposure on its post-transcriptional alternative splicing machinery remains fundamentally undefined. METHODS: Here, we investigated sex-dependent effects of prenatal BPA exposure on the alternative splicing landscape of the neonatal rat cerebellum. We utilized RNA-seq to profile differential alternative splicing (DAS) events. Ingenuity Pathway Analysis (IPA) was used to predict biological functions and canonical pathways, and to construct the interactome network of DAS genes. To explore candidate upstream regulatory mechanisms, we performed in silico molecular docking and used high-resolution melting (HRM) qRT-PCR to validate selected splicing events. Furthermore, we assessed in vitro cellular phenotypes in primary cerebellar neurons by measuring MTS-based viability and Syn1/Psd95 puncta colocalization. RESULTS: Prenatal BPA exposure was associated with widespread DAS in genes enriched for ASD-relevant pathways in the neonatal rat cerebellum. To our knowledge, this study is the first to report molecular docking analyses predicting favorable interactions between BPA and several candidate RNA-binding proteins (RBPs), including CPEB1, RALYL, HNRNPDL, and ACO1. Our findings support a model in which BPA may perturb RBP-associated splicing regulation, including altered splicing of chromatin regulators such as Ccar1 in males. These molecular and cellular findings were accompanied by sex-stratified differences in neuronal viability and synaptic puncta measurements. BPA exposure was associated with an increased MTS viability signal in male primary cerebellar neurons, together with significant reductions in Psd95 and Syn1 puncta density, whereas female neurons showed significantly increased synaptic puncta colocalization together with reduced viability. CONCLUSIONS: In this study, we propose that prenatal BPA may be relevant to ASD-related neurodevelopmental pathways through sex-dependent changes in RBP-associated alternative splicing, including altered splicing of Ccar1 in males, together with distinct cellular outcomes. Together, these findings identify the developing cerebellum as a sensitive target of prenatal BPA exposure and highlight alternative splicing as a candidate pathway relevant to ASD biology.

Animals↗

PubMedDate not supplied

Are schizophrenic men at higher risk for developmental deficits than schizophrenic women? Implications for adult neuropsychological functions.

This study tested the hypothesis that schizophrenic men would be at a greater risk than schizophrenic women for exhibiting a history of developmental problems in childhood and would exhibit more neuropsychological deficits as adults. The study was a secondary analysis of data that were collected in 1981-83. The sample consisted of 49 DSM-III schizophrenic patients (57% male/43% female), who were generally in the early stages of the disorder. All subjects received a neurodevelopmental and clinical/diagnostic interview and a neuropsychological battery of tests, including measures of intelligence, abstract reasoning, memory, sustained attention, executive function, language skills, and motor ability. Latent class analysis was used to identify gender differences in subclasses of schizophrenia. The groups were then compared on neuropsychological function. Results indicated that schizophrenics with histories of early developmental problems exhibited significantly more neuropsychological dysfunction as adults than did other schizophrenics, and they were more likely to be men. Impairment in this group was evident in the areas of verbal ability, attention, abstraction, motor function, and verbal and nonverbal learning and memory, with verbal tasks being relatively more impaired.

Adult↗

PubMed1999

Meta-analysis of brain size in bipolar disorder.

A recent meta-analysis concluded that patients with schizophrenia have reduced cerebral volume, and this finding has been used to implicate neurodevelopmental events in the etiology of this disorder. Since bipolar-disorder patients and schizophrenia patients have some similar brain abnormalities, it was of interest to meta-analytically review the literature on brain size in bipolar disorder. Only seven studies met the inclusion/exclusion criteria for our meta-analysis, but none reported the brain size differences between the bipolar patients and the controls to be statistically significant. The composite effect size was a negligible 0.04 (95% CI: -0.17 to 0.25) and statistically not significantly different from 0.0 (no effect). Thus, it appears that bipolar disorder is not associated with the same cerebral volume reductions noted in schizophrenia. Implications for hypotheses regarding the etiology of the two disorders are discussed.

Bipolar Disorder↗

PubMed2026

Shared genetic architecture between ADHD and intelligence varies across ADHD subtypes.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental condition frequently accompanied by cognitive difficulties. Although previous genetic studies have demonstrated substantial overlap between ADHD and intelligence, most have treated ADHD as a single phenotype. However, whether this shared genetic architecture differs across ADHD subtypes remains unclear. METHODS: We conducted a genome-wide cross-trait analysis integrating large-scale genome-wide association study (GWAS) datasets of overall ADHD, its subtypes-childhood ADHD, persistent ADHD, and late-diagnosed ADHD-and intelligence (total N > 300,000). Genome-wide genetic correlations, polygenic overlap, local genetic correlations, and variant-level associations between ADHD phenotypes and intelligence were evaluated to characterize their shared genetic architecture. Shared variants were identified through cross-trait enrichment analyses and subsequently mapped to genes for functional annotation and gene-set enrichment. Bidirectional associations were evaluated using two-sample Mendelian randomization with sensitivity analyses. Additional GWAS datasets were used to validate the robustness of shared loci by assessing the consistency of effect directions. RESULTS: All ADHD phenotypes showed significant negative genetic correlations with intelligence (rg ranging from -0.3442 to -0.4205). Despite these modest genome-wide correlations, cross-trait analyses revealed substantial genetic overlap, including polygenic overlap, local genetic correlations, and variant-level associations. We identified 184 loci jointly associated with ADHD traits and intelligence, including 64 novel loci, whereas no shared loci were detected for persistent ADHD under the current analysis. Functional annotation revealed biologically distinct enrichment patterns across subtypes: childhood ADHD loci were linked to early neurodevelopmental processes, while late-diagnosed ADHD loci were enriched in synapse-related and neuronal signaling pathways. Mendelian randomization analyses suggested bidirectional associations, with stronger evidence supporting a directional association from intelligence to ADHD risk. Furthermore, these shared loci showed largely consistent effect directions across additional GWAS datasets, providing support for the robustness of the findings. CONCLUSIONS: The shared genetic architecture between ADHD and intelligence varies across ADHD subtypes, highlighting distinct biological pathways underlying cognitive heterogeneity in ADHD. These findings suggest that the relationship between ADHD liability and general cognitive ability is not uniform across ADHD subtypes and may inform future research on risk stratification and early identification in child and adolescent psychiatry.

Humans↗