Endophenotype For Attention Deficit Hyperactivity Disorder Research Articles

Toward an endophenotype for ADHD: Exploring the duration mismatch negativity in drug-free children with ADHD

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent disorders in children that is considered to affect early stages of information processes. Inefficient processing of temporal information, which is a vital auditory processing skill suggests itself as a potential candidate for investigating ADHD deficits. The Research Domain Criteria (RDoC), a neuroscience-based research framework, has been introduced to study mental illness without relying on pre-established diagnostic categories. In this regard, Mismatch Negativity (MMN) has been considered an ideal electrophysiological marker for investigating ADHD deficits. This study investigates alterations in the amplitude and latency of the MMN component in response to changes in the duration and Inter-Stimulus Interval (ISI) of basic sound stimuli within an oddball task. The MMN paradigm was employed to examine duration deviations in ADHD (n = 25, 84% male, mean age: 7.3 years, SD = 2.01) compared to Control group of typically developing (TD) children (n = 25, 72% male, mean age: 7.2 years, SD = 1.92). Participants with ADHD were introduced from an accredited psychiatrist. TD children were recruited from social media and online forms. Both groups were matched in terms of gender, age and IQ. The psychological tests conducted in this study included Conners’ Parent Rating Scale (CPRS), Gilliam Autism Rating Scale|Third Edition (Gars3), Sensory profile questionnaire and Edinburgh Handedness inventory. Our findings revealed reduced MMN amplitudes in response to two blocks of duration and ISI-based deviations in ADHD children. To elaborate in greater detail, at Fz, in Duration and ISI block, respectively, the ADHD group showed an amplitude of −1.2097 ± 0.2938 and −0.8553 ± 0.4423, while the normal group showed an amplitude of −1.8325 ± 0.3689 and −2.0855 ± 0.3802. Additionally, at Cz, the ADHD group exhibited a shorter amplitude (-1.2515 ± 0.3261 and −0.9367 ± 0.3432) compared to the normal group (−2.1319 ± 0.4445 and −2.7561 ± 0.4883), in the duration and ISI blocks, respectively. Furthermore, children with ADHD display longer MMN latencies in both experimental blocks, suggesting atypical responses. To provide more detail, at Fz, the ADHD group displayed MMN latencies of 239.68 ± 5.059 and 226.88 ± 4.885 in the Duration and ISI blocks, respectively, whereas the normal group showed MMN latencies of 228.56 ± 6.584 and 213.56 ± 4.153. Similarly, at Cz, the ADHD group exhibited longer MMN latencies (234.40 ± 5.741 and 231.44 ± 5.464) compared to the normal group (227.52 ± 6.710 and 218.00 ± 5.261) in the Duration and ISI blocks, respectively. Our findings were interpreted in the context of the internal clock model, which involves the pace of an internal pacemaker regulated by dopamine (DA) levels. The convergence of MMN and auditory timing abnormalities within the RDoC framework suggests their potential as endophenotypes for ADHD, highlighting the significance of sensory processing in understanding the disorder.

Novel genetic loci of inhibitory control in ADHD and healthy children and genetic correlations with ADHD

Cumulative evidence has showed the deficits of inhibitory control in patients with attention deficit hyperactivity disorder (ADHD), which is considered as an endophenotype of ADHD. Genetic study of inhibitory control could advance gene discovery and further facilitate the understanding of ADHD genetic basis, but the studies were limited in both the general population and ADHD patients. To reveal genetic risk variants of inhibitory control and its potential genetic relationship with ADHD, we conducted genome-wide association studies (GWAS) on inhibitory control using three datasets, which included 783 and 957 ADHD patients and 1350 healthy children. Subsequently, we employed polygenic risk scores (PRS) to explore the association of inhibitory control with ADHD and related psychiatric disorders. Firstly, we identified three significant loci for inhibitory control in the healthy dataset, two loci in the case dataset, and one locus in the meta-analysis of three datasets. Besides, we found more risk genes and variants by applying transcriptome-wide association study (TWAS) and conditional FDR method. Then, we constructed a network by connecting the genes identified in our study, leading to the identification of several vital genes. Lastly, we identified a potential relationship between inhibitory control and ADHD and autism by PRS analysis and found the direct and mediated contribution of the identified genetic loci on ADHD symptoms by mediation analysis. In conclusion, we revealed some genetic risk variants associated with inhibitory control and elucidated the benefit of inhibitory control as an endophenotype, providing valuable insights into the mechanisms underlying ADHD.

Working memory and reaction time variability mediate the relationship between polygenic risk and ADHD traits in a general population sample

Endophenotypes are heritable and quantifiable traits indexing genetic liability for a disorder. Here, we examined three potential endophenotypes, working memory function, response inhibition, and reaction time variability, for attention-deficit hyperactivity disorder (ADHD) measured as a dimensional latent trait in a large general population sample derived from the Adolescent Brain Cognitive DevelopmentSM Study. The genetic risk for ADHD was estimated using polygenic risk scores (PRS) whereas ADHD traits were quantified as a dimensional continuum using Bartlett factor score estimates, derived from Attention Problems items from the Child Behaviour Checklist and Effortful Control items from the Early Adolescent Temperament Questionnaire-Revised. The three candidate cognitive endophenotypes were quantified using task-based performance measures. Higher ADHD PRSs were associated with higher ADHD traits, as well as poorer working memory performance and increased reaction time variability. Lower working memory performance, poorer response inhibition, and increased reaction time variability were associated with more pronounced ADHD traits. Working memory and reaction time variability partially statistically mediated the relationship between ADHD PRS and ADHD traits, explaining 14% and 16% of the association, respectively. The mediation effect was specific to the genetic risk for ADHD and did not generalise to genetic risk for four other major psychiatric disorders. Together, these findings provide robust evidence from a large general population sample that working memory and reaction time variability can be considered endophenotypes for ADHD that mediate the relationship between ADHD PRS and ADHD traits.

Impulsive and Omission Errors: Potential Temporal Processing Endophenotypes in ADHD.

Temporal processing (TP) is associated with functions such as perception, verbal skills, temporal perspective, and future planning, and is intercorrelated with working memory, attention, and inhibitory control, which are highly impaired in individuals with attention deficit hyperactivity disorder (ADHD). Here we evaluate TP measures as potential endophenotypes in Caribbean families ascertained from probands affected by ADHD. A total of 232 individuals were recruited and clinically evaluated using an extensive battery of neuropsychological tasks and reaction time (RT)-based task paradigms. Further, the heritability (genetic variance underpinning phenotype) was estimated as a measure of the genetics apportionment. A predictive framework for ADHD diagnosis was derived using these tasks. We found that individuals with ADHD differed from controls in neuropsychological tasks assessing mental control, visual-verbal memory, verbal fluency, verbal, and semantic fluency. In addition, TP measures such as RT, errors, and variability were also affected in individuals with ADHD. Moreover, we determined that only omission and commission errors had significant heritability. In conclusion, we have disentangled omission and commission errors as possible TP endophenotypes in ADHD, which can be suitable to assess the neurobiological and genetic basis of ADHD. A predictive model using these endophenotypes led to remarkable sensitivity, specificity, precision and classification rate for ADHD diagnosis, and may be a useful tool for patients’ diagnosis, follow-up, and longitudinal assessment in the clinical setting.

ADGRL3, FGF1 and DRD4: Linkage and Association with Working Memory and Perceptual Organization Candidate Endophenotypes in ADHD.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable neurobehavioral disorder that affects children worldwide, with detrimental long-term consequences in affected individuals. ADHD-affected patients display visual–motor and visuospatial abilities and skills that depart from those exhibited by non-affected individuals and struggle with perceptual organization, which might partially explain impulsive responses. Endophenotypes (quantifiable or dimensional constructs that are closely related to the root cause of the disease) might provide a more powerful and objective framework for dissecting the underlying neurobiology of ADHD than that of categories offered by the syndromic classification. In here, we explore the potential presence of the linkage and association of single-nucleotide polymorphisms (SNPs), harbored in genes implicated in the etiology of ADHD (ADGRL3, DRD4, and FGF1), with cognitive endophenotypes related to working memory and perceptual organization in 113 nuclear families. These families were ascertained from a geographical area of the Caribbean coast, in the north of Colombia, where the community is characterized by its ethnic diversity and differential gene pool. We found a significant association and linkage of markers ADGRL3-rs1565902, DRD4-rs916457 and FGF1-rs2282794 to neuropsychological tasks outlining working memory and perceptual organization such as performance in the digits forward and backward, arithmetic, similarities, the completion of figures and the assembly of objects. Our results provide strong support to understand ADHD as a combination of working memory and perceptual organization deficits and highlight the importance of the genetic background shaping the neurobiology, clinical complexity, and physiopathology of ADHD. Further, this study supplements new information regarding an ethnically diverse community with a vast African American contribution, where ADHD studies are scarce.

Social and non-social gaze cueing in autism spectrum disorder, attention-deficit/hyperactivity disorder and a comorbid group

Recent trends in literature, along with the changes to the Diagnostic and Statistical Manual (DSM), make it imperative to study Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) together, in order to better understand potential aetiological commonalities between these highly comorbid disorders. The present study examines social cueing, a highly studied construct in ASD, and intra-subject variability (ISV), a potential endophenotype of ADHD, in four groups of typically developing (TD), ADHD, ASD- (ASD without ADHD), ASD+ (ASD with ADHD) participants (N = 85) aged 10–13 years. Results showed that social cueing is intact in the ‘pure’ ASD group when task expectations are clear. The ADHD group showed faster saccadic reaction times, no increased ISV and a pattern of viewing comparable to the TD group. However, the ASD + group showed a differences in processing style and ISV. A secondary analysis gives evidence of non-additive effects of the ASD and ADHD factors.

Improving neurocognitive testing using computational psychiatry—A systematic review for ADHD.

Computational models, in conjunction with (neuro)cognitive tests, are increasingly used to understand the cognitive characteristics of participants with attention-deficit/hyperactivity disorder (ADHD). We reviewed 50 studies from a broad range of cognitive tests for ADHD to synthesize findings and to summarize the new insights provided by three commonly applied computational models (i.e., diffusion decision models, absolute accumulator models, ex-Gaussian distribution models). Four areas are discussed to improve the utility of (neuro)cognitive testing for ADHD: (a) the requirements for appropriate application of the computational models; (b) the consideration of sample characteristics and neurophysiological measures; (c) the integration of findings from cognitive psychology into the literature of cognitive testing to reconcile mixed evidence; and (d) future directions for the study of ADHD endophenotypes. We illustrate how computational models refine our understanding of cognitive concepts (slow processing speed, inhibition failures) presumed to characterize ADHD. We also show that considering sample characteristics and integrating findings from computational models and neurophysiological measures provide evidence for ADHD endophenotype-specific cognitive characteristics. However, studying the cognitive characteristics of ADHD endophenotypes often lies beyond the scope of existing research for three reasons: some cognitive tests lack sensitivity to detect clinical characteristics; analysis methods do not allow the study of subtle cognitive differences; and the precategorization of participants restricts the study of symptom severity on a continuous spectrum. We provide recommendations for cognitive testing, computational modeling, and integrating electrophysiological measures to produce more valuable tools in research and clinical practice (above and beyond the research domain of ADHD). (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Adult glut3 homozygous null mice survive to demonstrate neural excitability and altered neurobehavioral responses reminiscent of neurodevelopmental disorders

Since GLUT3 is vital for fueling neurotransmission, we examined in-vivo the adult phenotype carrying the conditional homozygous glut3 gene mutation (KO) in glutamate-excitatory neurons. These KO mice demonstrated sex-specific differences in brain and body weights (p = 0.0001 and p = 0.01 each) with reduced GLUT3 protein in cerebral cortices and brain stem (p = 0.005). In patch clamp studies the glut3 KO mice displayed a shorter latency to and enhanced paroxysmal activity (p = 0.01 and p = 0.015 each) in pyramidal neurons upon application of a GABAA antagonist, supporting hyperexcitability. Further, associated changes in neurobehavior consisted of reduced latency to fall in the rotorod motor test related to incoordination, increased distance traveled in total and periphery versus center in open field testing suggesting hyperactivity with anxiety (p = 0.0013 in male, p = 0.045 in female), reduced time freezing reminiscent of disrupted contextual fear conditioning (p = 0.0033), decreased time in target quadrant seen with spatial cognitive memory water maze testing (p = 0.034), and enhanced sociability particularly for novelty reflecting a lack of inhibition/impulsivity (p = 0.038). Some of these features were equally pronounced in males and females (cognitive) while others were seen in females (anxiety and impulsivity). We conclude that GLUT3 in adult glutamate-excitatory neurons is essential for maintaining neurotransmitory equipoise regulating excitation with maintenance of motor coordination and activity, cognition, spatial memory and normal fear for both contextual events and novelty with tempered sociability. While sex-specificity was forthcoming for some of these behaviors, our findings collectively suggest that loss-of-function glut3 gene mutations or polymorphisms may underlie an endophenotype of attention deficit-hyperactivity disorder.

Computational Modeling of Attentional Impairments in Disruptive Mood Dysregulation and Attention-Deficit/Hyperactivity Disorder

Computational models provide information about cognitive components underlying behavior. When applied to psychopathology-relevant processes, they offer additional insight to observed differences in behavioral performance. Drift diffusion models have been successfully applied to investigate processing efficiency during binary choice tasks. Using these models, we examine the association between psychopathology (irritability and inattention/hyperactivity) and processing efficiency under different attentional demands. A total of 187 youths with attention-deficit/hyperactivity disorder (ADHD), disruptive mood dysregulation disorder (DMDD), both disorders, or no major psychopathology (age, mean ± SD, 13.09 ± 2.55 y, 34% female) completed an Eriksen Flanker task. Of these, 87 youths provided complete data on dimensional measures of the core symptom of DMDD (irritability) and those of ADHD (inattention and hyperactivity). In a categorical diagnosis-based analysis (n= 187), we found significant interactive effects among ADHD, DMDD, and task condition on processing efficiency, whereby changes in processing efficiency between conflict and nonconflict conditions were larger in youths without psychopathology compared with patients. Analysis of symptom severity (n= 87) across diagnoses similarly revealed an interaction between symptom dimensions and task condition on processing efficiency. Irritability moderated the magnitude of association between inattention symptoms and difference in processing efficiency between conflict and nonconflict conditions. Adapting processing efficiency to cognitive demands may represent a shared cognitive endophenotype for both ADHD and DMDD. Highly irritable and/or inattentive youth may have difficulty adjusting processing efficiency to changing task demands, possibly reflecting impairments in cognitive flexibility.

Look duration at the face as a developmental endophenotype: elucidating pathways to autism and ADHD.

Identifying developmental endophenotypes on the pathway between genetics and behavior is critical to uncovering the mechanisms underlying neurodevelopmental conditions. In this proof-of-principle study, we explored whether early disruptions in visual attention are a unique or shared candidate endophenotype of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). We calculated the duration of the longest look (i.e., peak look) to faces in an array-based eye-tracking task for 335 14-month-old infants with and without first-degree relatives with ASD and/or ADHD. We leveraged parent-report and genotype data available for a proportion of these infants to evaluate the relation of looking behavior to familial (n = 285) and genetic liability (using polygenic scores, n = 185) as well as ASD and ADHD-relevant temperament traits at 2 years of age (shyness and inhibitory control, respectively, n = 272) and ASD and ADHD clinical traits at 6 years of age (n = 94).Results showed that longer peak looks at the face were associated with elevated polygenic scores for ADHD (β = 0.078, p = .023), but not ASD (β = 0.002, p = .944), and with elevated ADHD traits in mid-childhood (F(1,88) = 6.401, p = .013, $\eta _p^2$=0.068; ASD: F (1,88) = 3.218, p = .076), but not in toddlerhood (ps > 0.2). This pattern of results did not emerge when considering mean peak look duration across face and nonface stimuli. Thus, alterations in attention to faces during spontaneous visual exploration may be more consistent with a developmental endophenotype of ADHD than ASD. Our work shows that dissecting paths to neurodevelopmental conditions requires longitudinal data incorporating polygenic contribution, early neurocognitive function, and clinical phenotypic variation.

EEG spectral power, but not theta/beta ratio, is a neuromarker for adult ADHD.

Adults with attention-deficit/hyperactivity disorder (ADHD) have been described as having altered resting-state electroencephalographic (EEG) spectral power and theta/beta ratio (TBR). However, a recent review (Pulini et al. 2018) identified methodological errors in neuroimaging, including EEG, ADHD classification studies. Therefore, the specific EEG neuromarkers of adult ADHD remain to be identified, as do the EEG characteristics that mediate between genes and behaviour (mediational endophenotypes). Resting-state eyes-open and eyes-closed EEG was measured from 38 adults with ADHD, 45 first-degree relatives of people with ADHD and 51 unrelated controls. A machine learning classification analysis using penalized logistic regression (Elastic Net) examined if EEG spectral power (1-45Hz) and TBR could classify participants into ADHD, first-degree relatives and/or control groups. Random-label permutation was used to quantify any bias in the analysis. Eyes-open absolute and relative EEG power distinguished ADHD from control participants (area under receiver operating characteristic=0.71-0.77). The best predictors of ADHD status were increased power in delta, theta and low-alpha over centro-parietal regions, and in frontal low-beta and parietal mid-beta. TBR did not successfully classify ADHD status. Elevated eyes-open power in delta, theta, low-alpha and low-beta distinguished first-degree relatives from controls (area under receiver operating characteristic=0.68-0.72), suggesting that these features may be a mediational endophenotype for adult ADHD. Resting-state EEG spectral power may be a neuromarker and mediational endophenotype of adult ADHD. These results did not support TBR as a diagnostic neuromarker for ADHD. It is possible that TBR is a characteristic of childhood ADHD.

The key role of daytime sleepiness in cognitive functioning of adults with attention deficit hyperactivity disorder

Adults with attention deficit hyperactivity disorder (ADHD) frequently suffer from sleep problems and report high levels of daytime sleepiness compared to neurotypical controls, which has detrimental effect on quality of life. We evaluated daytime sleepiness in adults with ADHD compared to neurotypical controls using an observer-rated sleepiness protocol during the Sustained Attention Response Task as well as electroencephalogram (EEG) slowing, a quantitative electroencephalographic measure collected during a short period of wakeful rest. We found that adults with ADHD were significantly sleepier than neurotypical controls during the cognitive task and that this on-task sleepiness contributed to cognitive performance deficits usually attributed to symptoms of ADHD. EEG slowing predicted severity of ADHD symptoms and diagnostic status, and was also related to daytime sleepiness. Frontal EEG slowing as well as increased frontal delta were especially prominent in adults with ADHD. We have validated and adapted an objective observer-rated measure for assessing on-task sleepiness that will contribute to future sleep research in psychology and psychiatry. These findings indicate that the cognitive performance deficits routinely attributed to ADHD and often conceptualized as cognitive endophenotypes of ADHD are largely due to on-task sleepiness and not exclusively due to ADHD symptom severity. Daytime sleepiness plays a major role in cognitive functioning of adults with ADHD.

Increased Functional Segregation Related to the Salience Network in Unaffected Siblings of Youths With Attention-Deficit/Hyperactivity Disorder

Although there are frequent reports of shared neurofunctional and neurostructural alterations among probands with attention-deficit/hyperactivity disorder (ADHD) and their unaffected siblings, there is little knowledge regarding whether abnormalities in the resting-state functional connectivity of ADHD probands is also expressed in unaffected siblings, or whether this unaffected (but at-risk) cohort manifests distinct patterns. We used a multivariate connectome-wide association study examining intrinsic functional connectivity with resting-state functional magnetic resonance imaging (MRI) in a sample (aged 8-17 years) of medication-naive ADHD probands (n= 56), their unaffected siblings (n= 55), and typically developing (TD) youths (n= 106). ADHD probands showed, relative to TD youths, increased connectivity between the default-mode network (DMN) and task-positive networks. Relative to ADHD and TD groups, respectively, unaffected siblings showed increased connectivity within the salience network and reduced connectivity between the DMN and salience network. No shared alterations in functional connectivity among ADHD probands and their unaffected siblings were identified. These findings were largely confirmed by complementary pairwise connectomic comparisons. However, the main connectivity differences between ADHD and unaffected siblings were not replicated in a tightly age- and sex-matched subsample (20 proband-sibling pairs and 60 TD youths). Our findings suggest that increased functional segregation related to the attention networks, especially the salience (ventral attention) system, may be a potential feature of at-risk siblings who remain unaffected by ADHD expression. Further replications are needed in other larger and sex-matched samples. Structural and Functional Connectivity of Frontostriatal and Frontoparietal Networks as Endophenotypes of ADHD; https://clinicaltrials.gov/; NCT01682915.

Shared alterations in resting-state brain connectivity in adults with attention-deficit/hyperactivity disorder and their unaffected first-degree relatives.

Attention-deficit/hyperactivity disorder (ADHD) is a developmental condition that often persists into adulthood with extensive negative consequences on quality of life. Despite emerging evidence indicating the genetic basis of ADHD, investigations into the familial expression of latent neurocognitive traits remain limited. In a group of adult ADHD probands (n = 20), their unaffected first-degree relatives (n = 20) and typically developing control participants (n = 20), we assessed endophenotypic alterations in the default mode network (DMN) connectivity during resting-state functional magnetic resonance imaging in relation to cognitive performance and clinical symptoms. In an external validation step, we also examined the dimensional nature of this neurocognitive trait in a sample of unrelated healthy young adults (n = 100) from the Human Connectome Project (HCP). The results illustrated reduced anti-correlations between the posterior cingulate cortex/precuneus and right middle frontal gyrus that was shared between adult ADHD probands and their first-degree relatives, but not with healthy controls. The observed connectivity alterations were linked to higher ADHD symptoms that was mediated by performance in a sustained attention task. Moreover, this brain-based neurocognitive trait dimensionally explained ADHD symptom variability in the HCP sample. Alterations in the default mode connectivity may represent a dimensional endophenotype of ADHD, hence a significant aspect of the neuropathophysiology of this disorder. As such, brain network organisation can potentially be employed as an important neurocognitive trait to enhance statistical power of genetic studies in ADHD and as a surrogate efficacy endpoint in the development of novel pharmaceuticals.

54 - GENETIC STUDY FOR THE NEUROPSYCHOLOGICAL FUNCTION IN ATTENTION DEFICIT HYPERACTIVITY DISORDER

Attention deficit hyperactivity disorder (ADHD) is a common psychiatric disorder with high prevalence. Candidate gene association studies have identified several genes contributing to the development of ADHD. However, these genes only interpreted 4.3% of the average heritability. Several genome-wide association studies (GWAS) of ADHD have been performed, but none of them got genome-wide significant result. One reason for the lack of significant genetic result is that ADHD is a heterogeneous disorder. Endophenotypes as the intermediate phenotypes between genes and phenotypes have been widely used in psychiatric disorders. Many neuropsychological features have been suggested to be endophenotypes of ADHD. Exploration of the genetic basis of the disease related neuropsychological traits would provide clues for the understanding of the genetic basis of the disease and further facilitate the differentiation of disease and precision prevention, diagnosis and treatment. We had identified one significant locus near MICALL2 gene for inhibitory control in ADHD by using a two-stage Genome-Wide Association Study for the Word Interference Time (WIT) in the Stroop task (PMID: 28416812). The down expression of the homologous gene of MICALL2 led to hyperactive-impulsive-like behavior in zebrafish. In our new experimental study, we further tested the numbers/ activity of neurons in zebrafish with MICALL2b gene knockdown by using real-time quantitative PCR, in situ hybridization, as well as neuroD transgenic zebrafish and th transgenic zebrafish. The result showed that the catecholaminergic activity were increased at 24 hours, 48 hours and 3 days of the embryonic development and the noradrenergic activity was increased at 3 days of the embryonic development after the reduction of MICALL2b gene expression. At 3 days post fertilization, the activity of catecholaminergic neuron was tend to increase in the transgenic zebrafish. The neurobiological changes of the zebrafish with decreased MICALL2b gene function further validated the contribution of MICALL2 to ADHD. In addition, we tested the cognitive flexibility of ADHD patients using Trail-Make Test, and performed genome-wide association study for the shifting time in 785 ADHD patients. The top SNP is located in gene DLGAP1 (P = 5.08E-07), which was validated in several other cognitive flexibility related traits, ADHD symptoms and several other psychiatric disorders. Gene-level analysis showed the most significant gene is CADPS2, which also interacted with several well-known psychiatric disorder related genes, including BDNF, DRD2, NRG3. Pathway enrichment analysis for the potential SNPs with P<e-4 highlighted the ‘adenylatecyclaseactivity’ pathway and an involved gene ADCY2. Enrichment analysis for the enhancer region in 127 different tissues/cell types showed the potential SNPs with P<e-4 were enriched in neural system related tissues/cell types. Our result showed using the neuropsychological traits could advance the genetic discovery of ADHD. The identified genes and pathways would help understand the relationship between ADHD and the neuropsychological function, and the underlying genetic basis.

SA5 - GAENETICS OF WORKING MEMORY AND VIGILANCE EDOPHENOTYPES IN ADHD

Background Joint genetic analysis of correlated endophenotypes markedly enhances insight into the relationships among them and the shared and distinct genetic influences on phenotypically related complex traits. In addition, identifying pleiotropic effects among endophenotypes can help improve our biological understanding of the genetic architecture of a complex disease, namely childhood Attention Deficit Hyperactivity Disorder (ADHD). Cognitive functions, in particular aspects of executive functioning, have long been proposed as endophenotypes for ADHD, in some cases with distinct components of ADHD emphasized (hyperactivity and inattention-disorganization). This study identifies and characterizes the individual and shared genetic variants associated with two major cognitive endophenotypes—Working Memory (WM) and arousal — in relation to both ADHD sub-dimensions. Methods Composite scores for working memory and arousal were created on the basis of a latent variable model using multiple laboratory-obtained measures of each construct. Inattention and hyperactivity were defined on the basis of a composite of parental and teacher ratings. A confirmatory factor model fit well, supporting the internal validity of the composite scores. Subjects included 656 unrelated community recruited volunteer children ranging 7 to 13 years old (n=435 ADHD, 221 non-ADHD). SNPs included in our analysis (n=193,657) were from a polygenic risk score (PGS) computed using the reported discovery sample of 20,183 ADHD cases and 35,191 controls from the Psychiatric Genetics Consortium. A linear regression analysis accounting for age, sex and population stratification was used to test for association to each endophenotype. Pleiotropic relationships were identified using linear regression analysis accounting for the correlation among all four phenotype measures. A likelihood ratio test framework was used for inferring the number of traits associated with a genetic variant and for partitioning traits associated with the different SNPs. Results The PGS was associated with ADHD diagnosis (Nagelkerke R2=.04, p=0.0000006) and multi-indicator dimensional ADHD latent variables by parent report (beta=.196, SE=.041) and teacher report (beta=.176, SE=.040). Univariate SNP associations (p Discussion Our study provides motivation for pleiotropic effects in ADHD endophenotypes and helps begin to account for the mechanism by which cognitive endophenotypes participate in ADHD development.

Genetic variant for behavioral regulation factor of executive function and its possible brain mechanism in attention deficit hyperactivity disorder

As a childhood-onset psychiatric disorder, attention deficit hyperactivity disorder (ADHD) is complicated by phenotypic and genetic heterogeneity. Lifelong executive function deficits in ADHD are described in many literatures and have been proposed as endophenotypes of ADHD. However, its genetic basis is still elusive. In this study, we performed a genome-wide association study of executive function, rated with Behavioral Rating Inventory of Executive Function (BRIEF), in ADHD children. We identified one significant variant (rs852004, P = 2.51e-08) for the overall score of BRIEF. The association analyses for each component of executive function found this locus was more associated with inhibit and monitor components. Further principle component analysis and confirmatory factor analysis provided an ADHD-specific executive function pattern including inhibit and monitor factors. SNP rs852004 was mainly associated with the Behavioral Regulation factor. Meanwhile, we found the significant locus was associated with ADHD symptom. The Behavioral Regulation factor mediated its effect on ADHD symptom. Functional magnetic resonance imaging (fMRI) analyses further showed evidence that this variant affected the activity of inhibition control related brain regions. It provided new insights for the genetic basis of executive function in ADHD.

Working Memory and Vigilance as Multivariate Endophenotypes Related to Common Genetic Risk for Attention-Deficit/Hyperactivity Disorder

Understanding the role of endophenotypes is essential for process models of psychopathology. This study examined which candidate cognitive endophenotypes statistically mediate common variant genetic risk for attention-deficit/hyperactivity disorder (ADHD). A case-control design using community-recruited volunteer children 7 to 11 years of age (n= 656, n= 435 ADHD), of whom 514 were of homogenous European ancestry for the primary models (n= 337 ADHD, 177 non-ADHD). Children were assessed with a multi-informant, best-estimate diagnostic procedure and laboratory measures of working memory, response inhibition, executive functioning, arousal/attention, temporal information processing, and processing speed. Latent variables were created for the candidate cognitive measures and for parent- and teacher-rated ADHD dimensions. Polygenic risk scores (PGS) were computed using a discovery sample of 20,183 individuals with ADHD and 35,191 controls from the Psychiatric Genetics Consortium. Cognitive measures that survived multiple testing correction for association with the PGS were evaluated for mediation with ADHD using structural equation models. Results were essentially identical in the homogeneous European ancestry subgroup (n= 514) and in the full sample (N= 656). For the European population, the PGS was associated with ADHD diagnosis (Nagelkerke R2= 0.045; β= 0.233, SE= 0.053, p= .000011) and multi-indicator dimensional ADHD latent variables by parent report (β= 0.185, SE= 0.043) and teacher report (β= 0.165, SE= 0.042). The PGS effect was statistically mediated by working memory (indirect effect, β= 0.101, SE= 0.029, 95% CI= 0.05, 0.16, p= .00049, 43% of genetic effect accounted for) and arousal/alertness (indirect effect β= 0.115, 95% CI= 0.04, 0.20, SE= 0.041, p= .005, 49% of genetic effect accounted for). This is the first clear demonstration from molecular genetic data that working memory and arousal regulation are promising cognitive endophenotypes for ADHD with regard to mediating genetic risk from common genetic variants.

Temporal reproduction and its neuroanatomical correlates in adults with attention deficit hyperactivity disorder and their unaffected first-degree relatives.

Little is known about time perception, its putative role as cognitive endophenotype, and its neuroanatomical underpinnings in adults with attention deficit hyperactivity disorder (ADHD). Twenty adults with ADHD, 20 unaffected first-degree relatives and 20 typically developing controls matched for age and gender undertook structural magnetic resonance imaging scans. Voxel-based morphometry with DARTEL was performed to obtain regional grey-matter volumes. Temporal processing was investigated as a putative cognitive endophenotype using a temporal reproduction paradigm. General linear modelling was employed to examine the relationship between temporal reproduction performances and grey-matter volumes. ADHD participants were impaired in temporal reproduction and unaffected first-degree relatives performed in between their ADHD probands and typically developing controls. Increased grey-matter volume in the cerebellum was associated with poorer temporal reproduction performance. Adults with ADHD are impaired in time reproduction. Performances of the unaffected first-degree relatives are in between ADHD relatives and controls, suggesting that time reproduction might be a cognitive endophenotype for adult ADHD. The cerebellum is involved in time reproduction and might play a role in driving time performances.

Cognitive endophenotypes of attention deficit/hyperactivity disorder and intra-subject variability in patients with autism spectrum disorder

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) have previously been studied mainly in isolation from each other. However the two conditions may be aetiologically related and thus show overlap in aetiologically relevant functions. In order to address this question of potential aetiological overlap between ADHD and ASD, the present study set out to investigate putative endophenotypes of ADHD in N=33 typically developing (TD) children and N=28 patients with ASD that were (ASD+) or were not (ASD−) co-morbid for ADHD. With regard to both the cognitive endophenotype candidates (working memory, inhibition, temporal processing) and intra-subject variability (ISV) the pattern of abnormalities was inconsistent. Furthermore, the overall profile of ASD-TD differences was extremely similar to the pattern of differences between the ASD+ and ASD− sub-groups, suggesting that any abnormalities found were due to the comorbid ASD subgroup. This held in particular for ISV, which did not show in patients with ASD the task-general increase that is common in ADHD samples. Altogether, the present results do not support the hypothesis of aetiological overlap between ASD and ADHD.