Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD ...comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.
Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology. Intracranial volume (ICV) and volumes of the nucleus ...accumbens, amygdala, caudate nucleus, hippocampus, and putamen are smaller in people with ADHD compared with healthy individuals. The authors investigated the overlap between common genetic variation associated with ADHD risk and these brain volume measures to identify underlying biological processes contributing to the disorder.
The authors combined genome-wide association results from the largest available studies of ADHD (N=55,374) and brain volumes (N=11,221-24,704), using a set of complementary methods to investigate overlap at the level of global common variant genetic architecture and at the single variant level.
Analyses revealed a significant negative genetic correlation between ADHD and ICV (r
=-0.22). Meta-analysis of single variants revealed two significant loci of interest associated with both ADHD risk and ICV; four additional loci were identified for ADHD and volumes of the amygdala, caudate nucleus, and putamen. Exploratory gene-based and gene-set analyses in the ADHD-ICV meta-analytic data showed association with variation in neurite outgrowth-related genes.
This is the first genome-wide study to show significant genetic overlap between brain volume measures and ADHD, both on the global and the single variant level. Variants linked to smaller ICV were associated with increased ADHD risk. These findings can help us develop new hypotheses about biological mechanisms by which brain structure alterations may be involved in ADHD disease etiology.
Abstract Genome‐wide association studies (GWAS) have provided valuable insights into the genetic basis of neuropsychiatric disorders and highlighted their complexity. Careful consideration of the ...polygenicity and complex genetic architecture could aid in the understanding of the underlying brain mechanisms. We introduce an innovative approach to polygenic scoring, utilizing imaging‐derived phenotypes (IDPs) to predict a clinical phenotype. We leveraged IDP GWAS data from the UK Biobank, to create polygenic imaging‐derived scores (PIDSs). As a proof‐of‐concept, we assessed genetic variations in brain structure between individuals with ADHD and unaffected controls across three NeuroIMAGE waves ( n = 954). Out of the 94 PIDS, 72 exhibited significant associations with their corresponding IDPs in an independent sample. Notably, several global measures, including cerebellum white matter, cerebellum cortex, and cerebral white matter, displayed substantial variance explained for their respective IDPs, ranging from 3% to 5.7%. Conversely, the associations between each IDP and the clinical ADHD phenotype were relatively weak. These findings highlight the growing power of GWAS in structural neuroimaging traits, enabling the construction of polygenic scores that accurately reflect the underlying polygenic architecture. However, to establish robust connections between PIDS and behavioral or clinical traits such as ADHD, larger samples are needed. Our novel approach to polygenic risk scoring offers a valuable tool for researchers in the field of psychiatric genetics.
Externalizing behavior in its more extreme form is often considered a problem to the individual, their families, teachers, and society as a whole. Several brain structures have been linked to ...externalizing behavior and such associations may arise if the (co)development of externalizing behavior and brain structures share the same genetic and/or environmental factor(s). We assessed externalizing behavior with the Child Behavior Checklist and Youth Self Report, and the brain volumes and white matter integrity (fractional anisotropy FA and mean diffusivity MD) with magnetic resonance imaging in the BrainSCALE cohort, which consisted of twins and their older siblings from 112 families measured longitudinally at ages 10, 13, and 18 years for the twins. Genetic covariance modeling based on the classical twin design, extended to also include siblings of twins, showed that genes influence externalizing behavior and changes therein (
up to 88%). More pronounced externalizing behavior was associated with higher FA (observed correlation
up to +0.20) and lower MD (
up to -0.20), with sizeable genetic correlations (FA
up to +0.42; MD
up to -0.33). The cortical gray matter (CGM;
up to -0.20) and cerebral white matter (CWM;
up to +0.20) volume were phenotypically but not genetically associated with externalizing behavior. These results suggest a potential mediating role for global brain structures in the display of externalizing behavior during adolescence that are both partially explained by the influence of the same genetic factor.
Structural brain alterations in autism spectrum disorder (ASD) are heterogeneous, with limited effect sizes overall. In this study, we aimed to identify subgroups in ASD, based on neuroanatomical ...profiles; we hypothesized that the effect sizes for case/control differences would be increased in the newly defined subgroups. Analyzing a large data set from the ENIGMA‐ASD working group (n = 2661), we applied exploratory factor analysis (EFA) to seven subcortical volumes of individuals with and without ASD to uncover the underlying organization of subcortical structures. Based on earlier findings and data availability, we focused on three age groups: boys (<=14 years), male adolescents (15–22 years), and adult men (> = 22 years). The resulting factor scores were used in a community detection (CD) analysis to cluster participants into subgroups. Three factors were found in each subsample; the factor structure in adult men differed from that in boys and male adolescents. From these factors, CD uncovered four distinct communities in boys and three communities in adolescents and adult men, irrespective of ASD diagnosis. The effect sizes for case/control comparisons were more pronounced than in the combined sample, for some communities. A significant group difference in ADOS scores between communities was observed in boys and male adolescents with ASD. We succeeded in stratifying participants into more homogeneous subgroups based on subcortical brain volumes. This stratification enhanced our ability to observe case/control differences in subcortical brain volumes in ASD, and may help to explain the heterogeneity of previous findings in ASD.
Lay summary
Structural brain alterations in ASD are heterogeneous, with overall limited effect sizes. Here we aimed to identify subgroups in ASD based on neuroimaging measures. We tested whether the effect sizes for case/control differences would be increased in the newly defined subgroups.
Based on neuroanatomical profiles, we succeeded in stratifying our participants into more homogeneous subgroups. The effect sizes of case/control differences were more pronounced in some subgroups than those in the whole sample.
Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder (NDD). In this narrative review, we summarize recent advances in quantitative and ...molecular genetic research from the past 5-10 years. Combined with large-scale international collaboration, these advances have resulted in fast-paced progress in understanding the etiology of ADHD and how genetic risk factors map on to clinical heterogeneity. Studies are converging on a number of key insights. First, ADHD is a highly polygenic NDD with a complex genetic architecture encompassing risk variants across the spectrum of allelic frequencies, which are implicated in neurobiological processes. Second, genetic studies strongly suggest that ADHD diagnosis shares a large proportion of genetic risks with continuously distributed traits of ADHD in the population, with shared genetic risks also seen across development and sex. Third, ADHD genetic risks are shared with those implicated in many other neurodevelopmental, psychiatric and somatic phenotypes. As sample sizes and the diversity of genetic studies continue to increase through international collaborative efforts, we anticipate further success with gene discovery, characterization of how the ADHD phenotype relates to other human traits and growing potential to use genomic risk factors for understanding clinical trajectories and for precision medicine approaches.
Attention‐deficit/hyperactivity disorder (ADHD) symptoms are continuously distributed in the general population, where both genetic and environmental factors play roles. Stressful life events (SLEs) ...have been associated with ADHD diagnosis, but the relationship between ADHD genetic liability, SLEs, and ADHD symptoms in healthy individuals is less clear. Using a sample of 1,531 healthy adults (average age 26.9 years; 55.8% female), we investigated relationships between ADHD polygenic risk scores (ADHD‐PRSs), SLEs, and ADHD symptoms in a general population sample. Confirming earlier findings in an overlapping sample, all SLE‐measures assessed (lifetime SLEs, recent SLEs, and childhood trauma (CT)) were significantly correlated with total ADHD, inattention (IA), and hyperactivity‐impulsivity (HI) scores (r2 range = .08–.15; all p < .005). ADHD‐PRSs was associated with HI (R2best‐fit = .37%), lifetime SLEs (R2best‐fit = .56%), and CT (R2best‐fit = .40%). Mediation analyses showed that lifetime SLEs partially mediated the association between ADHD‐PRSs and HI (indirect effect: β = 68.6, bias corrected accelerated 95% confident interval (BCa95%CI) 11.9, 131.0, p = .016, proportion mediated (PM) =19.5%), with strongest effects contributed by CT (β = 34.4, BCa95%CI 0.4, 76.5, p = .040, PM = 9.8%). On the other hand, HI partially mediated the association between the ADHD‐PRSs and lifetime SLEs (β = 42.9, BCa95%CI 7.3, 83.9, p = .014, PM = 18.8%). Our study observed a complex relationship of genetic and environmental risk factors contributing to ADHD symptoms in the healthy adult population.
This study investigated the genetic components of ADHD and ASD by examining the cross‐disorder trait of emotion recognition problems. The genetic burden for ADHD and ASD on previously identified ...emotion recognition factors (speed and accuracy of visual and auditory emotion recognition) and classes (Class 1: Average visual, impulsive auditory; Class 2: Average‐strong visual & auditory; Class 3: Impulsive & imprecise visual, average auditory; Class 4: Weak visual & auditory) was assessed using ASD and ADHD polygenic risk scores (PRS). Our sample contained 552 participants: 74 with ADHD, 85 with ASD, 60 with ASD + ADHD, 177 unaffected siblings of ADHD or ASD probands, and 156 controls. ADHD‐ and ASD‐PRS, calculated from the latest ADHD and ASD GWAS meta‐analyses, were analyzed across these emotion recognition factors and classes using linear mixed models. Unexpectedly, the analysis of emotion recognition factors showed higher ASD‐PRS to be associated with faster visual emotion recognition. The categorical analysis of emotion recognition classes showed ASD‐PRS to be reduced in Class 3 compared to the other classes (p value threshold pT = 1, p = .021). A dimensional analysis identified a high ADHD‐PRS reduced the probability of being assigned to the Class 1 or Class 3 (pT = .05, p = .028 and p = .044, respectively). Though these nominally significant results did not pass FDR correction, they potentially indicate different indirect causative chains from genetics via emotion recognition to ADHD and ASD, which need to be verified in future research.
Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder (ADHD). However, a considerable interindividual variability ...exists in clinical outcome. Thus, we performed a genome-wide association study of MPH efficacy in 173 ADHD paediatric patients. Although no variant reached genome-wide significance, the set of genes containing single-nucleotide polymorphisms (SNPs) nominally associated with MPH response (P < 0.05) was significantly enriched for candidates previously studied in ADHD or treatment outcome. We prioritised the nominally significant SNPs by functional annotation and expression quantitative trait loci (eQTL) analysis in human brain, and we identified 33 SNPs tagging cis-eQTL in 32 different loci (referred to as eSNPs and eGenes, respectively). Pathway enrichment analyses revealed an over-representation of genes involved in nervous system development and function among the eGenes. Categories related to neurological diseases, psychological disorders and behaviour were also significantly enriched. We subsequently meta-analysed the association with clinical outcome for the 33 eSNPs across the discovery sample and an independent cohort of 189 ADHD adult patients (target sample) and we detected 15 suggestive signals. Following this comprehensive strategy, our results provide a better understanding of the molecular mechanisms implicated in MPH treatment effects and suggest promising candidates that may encourage future studies.
The dense co‐occurrence of psychiatric disorders questions the categorical classification tradition and motivates efforts to establish dimensional constructs with neurobiological foundations that ...transcend diagnostic boundaries. In this study, we examined the genetic liability for eight major psychiatric disorder phenotypes under both a disorder‐specific and a transdiagnostic framework. The study sample (n = 513) was deeply phenotyped, consisting of 452 patients from tertiary care with mood disorders, anxiety disorders (ANX), attention‐deficit/hyperactivity disorder (ADHD), autism spectrum disorders, and/or substance use disorders (SUD) and 61 unaffected comparison individuals. We computed subject‐specific polygenic risk score (PRS) profiles and assessed their associations with psychiatric diagnoses, comorbidity status, as well as cross‐disorder behavioral dimensions derived from a rich battery of psychopathology assessments. High PRSs for depression were unselectively associated with the diagnosis of SUD, ADHD, ANX, and mood disorders (p < 1e‐4). In the dimensional approach, four distinct functional domains were uncovered, namely the negative valence, social, cognitive, and regulatory systems, closely matching the major functional domains proposed by the Research Domain Criteria (RDoC) framework. Critically, the genetic predisposition for depression was selectively reflected in the functional aspect of negative valence systems (R2 = 0.041, p = 5e‐4) but not others. This study adds evidence to the ongoing discussion about the misalignment between current psychiatric nosology and the underlying psychiatric genetic etiology and underscores the effectiveness of the dimensional approach in both the functional characterization of psychiatric patients and the delineation of the genetic liability for psychiatric disorders.
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