Showing papers by "Stephen V. Faraone published in 2017"
Radboud University Nijmegen1, University of Southern California2, University Medical Center Groningen3, QIMR Berghofer Medical Research Institute4, Utrecht University5, National Institutes of Health6, Harvard University7, Broad Institute8, University of Bergen9, Region Zealand10, Cincinnati Children's Hospital Medical Center11, University of California, Irvine12, University of California, San Diego13, University of Würzburg14, University of Tübingen15, Trinity College, Dublin16, New York University17, King's College London18, Heidelberg University19, Federal University of Rio de Janeiro20, University of California, Los Angeles21, MIND Institute22, Nathan Kline Institute for Psychiatric Research23, Otto-von-Guericke University Magdeburg24, Maastricht University25, Goethe University Frankfurt26, Haukeland University Hospital27, Beth Israel Deaconess Medical Center28, VU University Amsterdam29, Autonomous University of Barcelona30, State University of New York Upstate Medical University31
TL;DR: Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes.
749 citations
Aarhus University1, Harvard University2, Karolinska Institutet3, Stockholm County Council4, Broad Institute5, Statens Serum Institut6, University of California, Los Angeles7, Charité8, Oslo University Hospital9, University of Toronto10, VU University Amsterdam11, University of Barcelona12, Radboud University Nijmegen13, Yale University14, Children's Hospital of Philadelphia15, University of Pennsylvania16, King's College London17, Cardiff University18, University of Würzburg19, University of Queensland20, Goethe University Frankfurt21, Universidade Federal do Rio Grande do Sul22, Icahn School of Medicine at Mount Sinai23, University of North Carolina at Chapel Hill24, Emory University25, University of Copenhagen26, State University of New York Upstate Medical University27
TL;DR: The hypothesis that clinical diagnosis of ADHD is an extreme expression of one or more continuous heritable traits is supported, supported by additional analyses of a self-reported ADHD sample and a study of quantitative measures of ADHD symptoms in the population.
Abstract: Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of school-age children and 25% of adults Common genetic variants contribute substantially to ADHD susceptibility, but no individual variants have been robustly associated with ADHD We report a genome-wide association meta-analysis of 20,183 ADHD cases and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, revealing new and important information on the underlying biology of ADHD Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes, as well as around brain-expressed regulatory marks These findings, based on clinical interviews and/or medical records are supported by additional analyses of a self-reported ADHD sample and a study of quantitative measures of ADHD symptoms in the population Meta-analyzing these data with our primary scan yielded a total of 16 genome-wide significant loci The results support the hypothesis that clinical diagnosis of ADHD is an extreme expression of one or more continuous heritable traits
230 citations
TL;DR: A novel machine-learning algorithm designed to create screening scales with optimal integer weights and limited numbers of screening questions was applied to the pooled data to create a DSM-5 version of the ASRS screening scale, which is short, easily scored, detects the vast majority of general population cases at a threshold that also has high specificity and PPV, and could be used as a screening tool in specialty treatment settings.
Abstract: Importance Recognition that adult attention-deficit/hyperactivity disorder (ADHD) is common, seriously impairing, and usually undiagnosed has led to the development of adult ADHD screening scales for use in community, workplace, and primary care settings. However, these scales are all calibrated to DSM-IV criteria, which are narrower than the recently developed DSM-5 criteria. Objectives To update for DSM-5 criteria and improve the operating characteristics of the widely used World Health Organization Adult ADHD Self-Report Scale (ASRS) for screening. Design, Setting, and Participants Probability subsamples of participants in 2 general population surveys (2001-2003 household survey [n = 119] and 2004-2005 managed care subscriber survey [n = 218]) who completed the full 29-question self-report ASRS, with both subsamples over-sampling ASRS-screened positives, were blindly administered a semistructured research diagnostic interview for DSM-5 adult ADHD. In 2016, the Risk-Calibrated Supersparse Linear Integer Model, a novel machine-learning algorithm designed to create screening scales with optimal integer weights and limited numbers of screening questions, was applied to the pooled data to create a DSM-5 version of the ASRS screening scale. The accuracy of the new scale was then confirmed in an independent 2011-2012 clinical sample of patients seeking evaluation at the New York University Langone Medical Center Adult ADHD Program (NYU Langone) and 2015-2016 primary care controls (n = 300). Data analysis was conducted from April 4, 2016, to September 22, 2016. Main Outcomes and Measures The sensitivity, specificity, area under the curve (AUC), and positive predictive value (PPV) of the revised ASRS. Results Of the total 637 participants, 44 (37.0%) household survey respondents, 51 (23.4%) managed care respondents, and 173 (57.7%) NYU Langone respondents met DSM-5 criteria for adult ADHD in the semistructured diagnostic interview. Of the respondents who met DSM-5 criteria for adult ADHD, 123 were male (45.9%); mean (SD) age was 33.1 (11.4) years. A 6-question screening scale was found to be optimal in distinguishing cases from noncases in the first 2 samples. Operating characteristics were excellent at the diagnostic threshold in the weighted (to the 8.2% DSM-5 /Adult ADHD Clinical Diagnostic Scale population prevalence) data (sensitivity, 91.4%; specificity, 96.0%; AUC, 0.94; PPV, 67.3%). Operating characteristics were similar despite a much higher prevalence (57.7%) when the scale was applied to the NYU Langone clinical sample (sensitivity, 91.9%; specificity, 74.0%; AUC, 0.83; PPV, 82.8%). Conclusions and Relevance The new ADHD screening scale is short, easily scored, detects the vast majority of general population cases at a threshold that also has high specificity and PPV, and could be used as a screening tool in specialty treatment settings.
196 citations
VU University Amsterdam1, VU University Medical Center2, QIMR Berghofer Medical Research Institute3, Åbo Akademi University4, University of Gothenburg5, University of Turku6, University of Helsinki7, University of Eastern Finland8, National Institutes of Health9, Erasmus University Rotterdam10, Medical Research Council11, Michigan State University12, University College London13, Washington University in St. Louis14, Florida State University15, King Abdulaziz University16, Emory University17, Yale University18, Veterans Health Administration19, University of Pennsylvania20, Boston University21, University of Cambridge22, Karolinska Institutet23, Virginia Commonwealth University24, Karabük University25, State University of New York Upstate Medical University26
TL;DR: The Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.
Abstract: Importance Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. Objectives To estimate the single-nucleotide polymorphism–based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. Design, Setting, and Participants Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). Main Outcome and Measures This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges. Results The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1:rs2764450, chromosome 11:rs11215217; 7772 male individuals, chromosome X,rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R2 = 0.0017 in the most optimal model,P = 0.03). Significant inverse genetic correlation of ASB with educational attainment (r = –0.52,P = .005) was detected. Conclusions and Relevance The Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.
137 citations
Radboud University Nijmegen1, University of Würzburg2, Harvard University3, University College London4, University of Southampton5, University of California, San Diego6, Karolinska Institutet7, University of Gothenburg8, Oslo University Hospital9, Goethe University Frankfurt10, University of Bergen11, State University of New York Upstate Medical University12
TL;DR: The single nucleotide polymorphism-based genetic correlation between ADHD and BPD is substantial, significant, and consistent with the existence of genetic overlap between ADHDand BPD, with potential differential genetic mechanisms involved in early and later BPD onset.
101 citations
TL;DR: Despite the robust presentation of ADHD, a significant majority of ASD youth with ADHD failed to receive appropriate ADHD treatment and a high rate of comorbidity with ADHD was observed in psychiatrically referred youth with ASD.
Abstract: Objective: To compare the clinical presentation of ADHD between youth with autism spectrum disorder (ASD) and ADHD and a sample of youth with ADHD only. Method: A psychiatrically referred sample of...
96 citations
TL;DR: Results show that executive dysfunction is as central as DSM‐5 symptoms to adult ADHD, while emotional dyscontrol is more distinct but nonetheless part of the combined presentation of adult ADHD.
Abstract: Although DSM-5 stipulates that symptoms of attention-deficit hyperactivity disorder (ADHD) are the same for adults as children, clinical observations suggest that adults have more diverse deficits than children in higher-level executive functioning and emotional control. Previous psychometric analyses to evaluate these observations have been limited in ways addressed in the current study, which analyzes the structure of an expanded set of adult ADHD symptoms in three pooled US samples: a national household sample, a sample of health plan members, and a sample of adults referred for evaluation at an adult ADHD clinic. Exploratory factor analysis found four factors representing executive dysfunction/inattention (including, but not limited to, all the DSM-5 inattentive symptoms, with non-DSM symptoms having factor loadings comparable to those of DSM symptoms), hyperactivity, impulsivity, and emotional dyscontrol. Empirically-derived multivariate symptom profiles were broadly consistent with the DSM-5 inattentive-only, hyperactive/impulsive-only, and combined presentations, but with inattention including executive dysfunction/inattention and hyperactivity-only limited to hyperactivity without high symptoms of impulsivity. These results show that executive dysfunction is as central as DSM-5 symptoms to adult ADHD, while emotional dyscontrol is more distinct but nonetheless part of the combined presentation of adult ADHD.
71 citations
TL;DR: It is proposed that ASD may feature decoupling between certain circulating signaling proteins and the transcriptional cascades which they typically elicit within circulating immune cells (lower in ASD samples).
Abstract: Blood-based microarray studies comparing individuals affected with autism spectrum disorder (ASD) and typically developing individuals help characterize differences in circulating immune cell functions and offer potential biomarker signal. We sought to combine the subject-level data from previously published studies by mega-analysis to increase the statistical power. We identified studies that compared ex vivo blood or lymphocytes from ASD-affected individuals and unrelated comparison subjects using Affymetrix or Illumina array platforms. Raw microarray data and clinical meta-data were obtained from seven studies, totaling 626 affected and 447 comparison subjects. Microarray data were processed using uniform methods. Covariate-controlled mixed-effect linear models were used to identify gene transcripts and co-expression network modules that were significantly associated with diagnostic status. Permutation-based gene-set analysis was used to identify functionally related sets of genes that were over- and under-expressed among ASD samples. Our results were consistent with diminished interferon-, EGF-, PDGF-, PI3K-AKT-mTOR-, and RAS-MAPK-signaling cascades, and increased ribosomal translation and NK-cell related activity in ASD. We explored evidence for sex-differences in the ASD-related transcriptomic signature. We also demonstrated that machine-learning classifiers using blood transcriptome data perform with moderate accuracy when data are combined across studies. Comparing our results with those from blood-based studies of protein biomarkers (e.g., cytokines and trophic factors), we propose that ASD may feature decoupling between certain circulating signaling proteins (higher in ASD samples) and the transcriptional cascades which they typically elicit within circulating immune cells (lower in ASD samples). These findings provide insight into ASD-related transcriptional differences in circulating immune cells. © 2016 Wiley Periodicals, Inc.
57 citations
TL;DR: Investigation of the effect of comorbid ODD on cerebral volume and cortical thickness in ADHD found ADHD+ODD and ADHD-only were associated with volumetric reductions in brain areas crucial for attention, (working) memory, and decision-making.
46 citations
TL;DR: Results showed that better working memory predicted lower ADHD symptom severity, and less reaction time variability predicted better overall functioning, and the role of neurocognitive functioning in the long term outcome of ADHD behavior is discussed.
Abstract: Although a broad array of neurocognitive dysfunctions are associated with ADHD, it is unknown whether these dysfunctions play a role in the course of ADHD symptoms. The present longitudinal study investigated whether neurocognitive functions assessed at study-entry (mean age = 11.5 years, SD = 2.7) predicted ADHD symptom severity and overall functioning 6 years later (mean age = 17.4 years, 82.6 % = male) in a carefully phenotyped large sample of 226 Caucasian participants from 182 families diagnosed with ADHD-combined type. Outcome measures were dimensional measures of ADHD symptom severity and the Kiddie-Global Assessment Scale (K-GAS) for overall functioning. Predictors were derived from component scores for 8 domains of neurocognitive functioning: working memory, motor inhibition, cognitive inhibition, reaction time variability, timing, information processing speed, motor control, intelligence. Effects of age, gender, and pharmacological treatment were considered. Results showed that better working memory predicted lower ADHD symptom severity (R 2 = 3.0 %), and less reaction time variability predicted better overall functioning (higher K-GAS-score, R 2 = 5.6 %). Predictors were still significant with baseline behavior included in the models. The role of neurocognitive functioning in the long term outcome of ADHD behavior is discussed.
44 citations
TL;DR: Individuals with ADHD are significantly more likely to become teenage parents compared with individuals without ADHD, and it might be appropriate to target this group with an intervention program that includes sexual education and contraceptive counseling.
Abstract: Objective Prior studies have established that attention-deficit/hyperactivity disorder (ADHD) is associated with risky sexual behavior, but it remains unknown whether individuals with ADHD also are more likely to become parents while being teenagers. This aspect is clinically relevant because teenage parenthood is associated with adverse outcomes for parents and children. Therefore, the main aim of this study was to investigate whether individuals with ADHD would be more likely to become teenage parents compared with individuals without ADHD. Method This is a historical prospective cohort study based on nationwide data from Danish registers. The cohort consisted of all individuals (N = 2,698,052) born in Denmark from January 1, 1960 through December 31, 2001. The association between ADHD (n = 27,479 cases) and parenthood (first child) in age intervals of 12 to 16, 17 to 19, 20 to 24, 25 to 29, 30 to 34, 35 to 39, and 40 years and above was investigated by Poisson regression and expressed as incidence rate ratios (IRRs) with accompanying 95% CIs. IRRs can be interpreted as relative risks. Results Compared with individuals without ADHD, those with ADHD were significantly more likely to become parents at 12 to 16 years of age (IRR for females 3.62, 95% CI 2.14–6.13; IRR for males 2.30, 95% CI 1.27–4.17) and at 17 to 19 years of age (IRR for females 1.94, 95% CI 1.62–2.33; IRR for males 2.27, 95% CI 1.90–2.70). Conclusion Individuals with ADHD are significantly more likely to become teenage parents compared with individuals without ADHD. Therefore, it might be appropriate to target this group with an intervention program that includes sexual education and contraceptive counseling.
TL;DR: Evidence is provided that nearly all of the comorbidity between ADHD and ID can be attributed to genetic factors, which has implications for diagnostic practice.
Abstract: Objective Although many studies document an association between attention-deficit/hyperactivity disorder (ADHD) and intellectual disability (ID), little is known about the etiology of this comorbidity and how it should be addressed in clinical settings. We sought to clarify this issue. Method All individuals born in Sweden between 1987 and 2006 (n = 2,049,587) were identified using the Medical Birth Register (MBR). From this we selected 7 cohorts of relatives: 1,899,654 parent–offspring pairs, 4,180 monozygotic twin pairs, 12,655 dizygotic twin pairs, 914,848 full sibling pairs, 136,962 maternal half-sibling pairs, 134,502 paternal half-sibling pairs, and 2,790,164 full cousin pairs. We used within-individual and within-family analyses to assess the association between ADHD and ID. Results Individuals with ID were at increased risk for ADHD compared to those without ID, and relatives of participants with ID were at increased risk of ADHD compared with relatives of those without ID. The magnitude of this association was positively associated with the fraction of the genome shared by the relative pair and was lower for severe compared with mild and moderate ID. Model-fitting analyses demonstrated that 91% of the correlation between the liabilities of ADHD and ID was attributable to genetic factors. Conclusion These data provide evidence that nearly all of the comorbidity between ADHD and ID can be attributed to genetic factors, which has implications for diagnostic practice.
TL;DR: Among adults with ADHD and EFDs, adjunct treatment with memantine to osmotic release oral system-methylphenidate (OROS-MPH) was associated with improvements in selective areas of executive functioning, supporting the need for further research.
Abstract: Objective: To evaluate the efficacy and safety of memantine hydrochloride as an adjunct to stimulant pharmacotherapy for treating executive function deficits (EFDs) in adults with ADHD. Method: This was a 12-week, double-blind, placebo-controlled, randomized clinical trial of memantine added to open-label treatment with stimulant medication. Because of the small sample size, we considered a standardized mean difference (equivalent to effect size) of ≥0.5 and odds ratios ≥2 as indicators of trend improvements. Results: Twelve participants received memantine and 14 received a placebo. Trend improvements favoring memantine were observed on Behavior Rating Inventory of Executive Functions–Adult Inhibition and Self-Monitor subscales when compared with Placebo. No significant changes were noted on the Cambridge Neuropsychological Test Automated Battery. Conclusion: Among adults with ADHD and EFDs, adjunct treatment with memantine to osmotic release oral system-methylphenidate (OROS-MPH) was associated with impr...
University of North Carolina at Chapel Hill1, Oslo University Hospital2, Aarhus University3, King's College London4, University of Basel5, Indiana University6, State University of New York Upstate Medical University7, Yale University8, University of Florida9, University of California, San Diego10, Harvard University11, Cardiff University12
TL;DR: The emerging findings suggest that the PGC is entering into a phase of accelerated translation of genetic discoveries to impact psychiatric practice within a precision medicine framework.
Abstract: The Psychiatric Genomics Consortium (PGC) is the largest consortium in the history of psychiatry. In the past decade, this global effort has delivered a rapidly increasing flow of new knowledge about the fundamental basis of common psychiatric disorders, particularly given its dedication to rapid progress and open science. The PGC has recently commenced a program of research designed to deliver “actionable” findings - genomic results that (a) reveal the fundamental biology, (b) inform clinical practice, and (c) deliver new therapeutic targets. This is the central idea of the PGC: to convert the family history risk factor into biologically, clinically, and therapeutically meaningful insights. The emerging findings suggest that we are entering into a phase of accelerated translation of genetic discoveries to impact psychiatric practice within a precision medicine framework.
TL;DR: The predictive features of the ‘OR’ and ‘AND’ rules are useful in evaluating approaches to better integrating information from parent and teacher informants relative to a gold-standard ADHD diagnosis in pediatric populations.
Abstract: Objective: To review the literature evaluating the psychometric properties of parent and teacher informants relative to a gold-standard ADHD diagnosis in pediatric populations.Method: We included studies that included both a parent and teacher informant, a gold-standard diagnosis, and diagnostic accuracy metrics. Potential confounds were evaluated. We also assessed the ‘OR’ and the ‘AND’ rules for combining informant reports.Results: Eight articles met inclusion criteria. The diagnostic accuracy for predicting gold standard ADHD diagnoses did not differ between parents and teachers. Sample size, sample type, participant drop-out, participant age, participant gender, geographic area of the study, and date of study publication were assessed as potential confounds.Conclusion: Parent and teachers both yielded moderate to good diagnostic accuracy for ADHD diagnoses. Parent reports were statistically indistinguishable from those of teachers. The predictive features of the ‘OR’ and ‘AND’ rules are useful...
TL;DR: The results indicate that individuals with 22q11DS who develop positive prodromal symptoms demonstrate differential longitudinal trajectories of cortical thickness in some regions of the frontal lobe, and suggest that the pruning stage associated with adolescent brain development may be disrupted.
TL;DR: This study analyzes genome-wide common variants from the Psychiatric Genomics Consortium and iPSYCH Project and Swedish population-registry data to find strong genetic correlation for ADHD across sex and no mean difference in polygenic burden across sex.
Abstract: Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is 2-7 times more common in males than females. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. We analyzed genome-wide common variants from the Psychiatric Genomics Consortium and iPSYCH Project (20,183 cases, 35,191 controls) and Swedish population-registry data (N=77,905 cases, N=1,874,637 population controls). We find strong genetic correlation for ADHD across sex and no mean difference in polygenic burden across sex. In contrast, siblings of female probands are at an increased risk of ADHD, compared to siblings of male probands. The results also suggest that females with ADHD are at especially high risk of comorbid developmental conditions. Overall, this study supports a greater familial burden of risk in females with ADHD and some clinical and etiological heterogeneity. However, autosomal common variants largely do not explain the sex bias in ADHD prevalence.
TL;DR: It is concluded that random forest regression may be used to investigate how multiple genetic and environmental factors jointly contribute to ADHD, and is able to implicate novel SNPs of interest, interacting with stress exposure, and may explain inconsistent findings in ADHD genetics.
Abstract: Identifying genetic variants contributing to attention-deficit/hyperactivity disorder (ADHD) is complicated by the involvement of numerous common genetic variants with small effects, interacting with each other as well as with environmental factors, such as stress exposure. Random forest regression is well suited to explore this complexity, as it allows for the analysis of many predictors simultaneously, taking into account any higher-order interactions among them. Using random forest regression, we predicted ADHD severity, measured by Conners' Parent Rating Scales, from 686 adolescents and young adults (of which 281 were diagnosed with ADHD). The analysis included 17 374 single-nucleotide polymorphisms (SNPs) across 29 genes previously linked to hypothalamic-pituitary-adrenal (HPA) axis activity, together with information on exposure to 24 individual long-term difficulties or stressful life events. The model explained 12.5% of variance in ADHD severity. The most important SNP, which also showed the strongest interaction with stress exposure, was located in a region regulating the expression of telomerase reverse transcriptase (TERT). Other high-ranking SNPs were found in or near NPSR1, ESR1, GABRA6, PER3, NR3C2 and DRD4. Chronic stressors were more influential than single, severe, life events. Top hits were partly shared with conduct problems. We conclude that random forest regression may be used to investigate how multiple genetic and environmental factors jointly contribute to ADHD. It is able to implicate novel SNPs of interest, interacting with stress exposure, and may explain inconsistent findings in ADHD genetics. This exploratory approach may be best combined with more hypothesis-driven research; top predictors and their interactions with one another should be replicated in independent samples.
TL;DR: Attention-deficit/hyperactivity disorder and overweight/obesity share familial risk factors, which are not limited to those causing overweight/OBesity through the mediation of ADHD, and future research aiming at identifying family-wide environmental risk factors as well as common pleiotropic genetic variants contributing to both traits is warranted.
Abstract: Background
Despite meta-analytic evidence for the association between attention-deficit/hyperactivity disorder (ADHD) and overweight/obesity, the mechanisms underlying the association are yet to be fully understood.
Methods
By linking multiple Swedish national and regional registers, we identified 472,735 index males born during 1973–1992, with information on body weight and height directly measured before they were conscripted for military service. We further identified 523,237 full siblings born during 1973–2002 for the index males. All individuals were followed up from their third birthday to December 31, 2009 for ADHD diagnosis. Logistic regression models were used to estimate the association between overweight/obesity in index males and ADHD in their full siblings.
Results
Siblings of index males with overweight/obesity had increased risk for ADHD (overweight: OR = 1.14, 95% CI = 1.05–1.24; obesity: OR = 1.42, 95% CI = 1.24–1.63), compared with siblings of index males with normal weight. The results were adjusted for birth year of the index male and sex of the sibling. After further adjustment for ADHD status of the index male, the familial coaggregation remained significant (overweight: OR = 1.13, 95% CI = 1.04–1.22; obesity: OR = 1.38, 95% CI = 1.21–1.57). The results were similar across sex of the siblings.
Conclusions
Attention-deficit/hyperactivity disorder and overweight/obesity share familial risk factors, which are not limited to those causing overweight/obesity through the mediation of ADHD. Future research aiming at identifying family-wide environmental risk factors as well as common pleiotropic genetic variants contributing to both traits is warranted.
TL;DR: A network discovery approach was applied to assess specific functional networks associated with reward processing in participants with attention‐deficit/hyperactivity disorder (ADHD) and found deficiencies within these circuits were associated with psychopathology.
Abstract: Introduction Reward processing is a key aspect of cognitive control processes, putatively instantiated by mesolimbic and mesocortical brain circuits. Deficient signaling within these circuits has been associated with psychopathology. We applied a network discovery approach to assess specific functional networks associated with reward processing in participants with attention-deficit/hyperactivity disorder (ADHD). Methods To describe task-related processes in terms of integrated functional networks, we applied independent component analysis (ICA) to task response maps of 60 healthy participants who performed a monetary incentive delay (MID) task. The resulting components were interpreted on the basis of their similarity with group-level task responses as well as their similarity with brain networks derived from resting state fMRI analyses. ADHD-related effects on network characteristics including functional connectivity and communication between networks were examined in an independent sample comprising 150 participants with ADHD and 48 healthy controls. Results We identified 23 components to be associated with 4 large-scale functional networks: the default-mode, visual, executive control, and salience networks. The salience network showed a specific association with reward processing as well as the highest degree of within-network integration. ADHD was associated with decreased functional connectivity between the salience and executive control networks as well as with peripheral brain regions. Conclusions Reward processing as measured with the MID task involves one reward-specific and three general functional networks. Participants with ADHD exhibited alterations in connectivity of both the salience and executive control networks and associated brain regions during task performance. Hum Brain Mapp 38:2359-2369, 2017. © 2017 Wiley Periodicals, Inc.
TL;DR: The study of IC adds a semi-independent, sensitive measure of cortical morphology that relates to the underlying cytoarchitecture and may aid understanding of normal brain development and deviations from it.
Abstract: Adolescence is a period of significant brain changes; however, the effects of age and sex on cortical development are yet to be fully characterized. Here, we utilized innovative intrinsic curvature (IC) analysis, along with the traditional cortical measures [cortical thickness (CT), local gyrification index (LGI), and surface area (SA)], to investigate how these indices (1) relate to each other and (2) depend on age and sex in adolescent cortical development. T1-weighted magnetic resonance images from 218 healthy volunteers (age range 8.3–29.2 years, M[SD] = 16.5[3.4]) were collected at two sites and processed with FreeSurfer and Caret software packages. Surface indices were extracted per cortex area (frontal, parietal, occipital, temporal, insula, and cingulate). Correlation analyses between the surface indices were conducted and age curves were modelled using generalized additive mixed-effect models. IC showed region-specific associations with LGI, SA, and CT, as did CT with LGI. SA was positively associated with LGI in all regions and CT in none. CT and LGI, but not SA, were inversely associated with age in all regions. IC was inversely associated with age in all but the occipital region. For all regions, males had larger cortical SA than females. Males also had larger LGI in all regions and larger IC of the frontal area; however, these effects were accounted for by sex differences in SA. There were no age-by-sex interactions. The study of IC adds a semi-independent, sensitive measure of cortical morphology that relates to the underlying cytoarchitecture and may aid understanding of normal brain development and deviations from it.
Karolinska Institutet1, University of Amsterdam2, University of Fribourg3, Columbia University4, National Drug and Alcohol Research Centre5, Eötvös Loránd University6, Semmelweis University7, University of Bordeaux8, State University of New York Upstate Medical University9, Curtin University10, University Medical Center Groningen11
TL;DR: The findings suggest that the increased rate of adult ADHD in SUD patients with CTE is not the consequence of a negative effect of CTE on the persistence of childhood ADHD into adulthood, but a direct expression of the high rate of childhood hyperactivity in Sud patients withCTE.
TL;DR: 5 novel loci associated with ADHD are identified and evidence for a shared genetic basis between ADHD and EA is provided, which could aid understanding of the genetic risk architecture of ADHD and its relation to EA.
Abstract: Background Attention-Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental condition that affects about 5% of children and adolescents worldwide. Despite its high heritability little is known about underlying genetic factors. Among other things ADHD is tightly associated with educational failure. However, potential genetic overlap between ADHD and educational attainment has not been examined in detail so far. Exploiting epidemiological similarity between ADHD and educational attainment we aimed to improve discovery of ADHD-associated genetic factors and investigated genetic overlap between these phenotypes. Methods We used ADHD data from the PGC (2064 trios, 896 cases, 2455 controls) and educational attainment data from the SSGAC (N=328917). To investigate polygenic overlap between ADHD and educational attainment we constructed fold-enrichment plots and conditional QQ plots in both directions: conditioning ADHD on educational attainment and vice versa. To explore the nature of the polygenic overlap and test a hypothesis that investigated traits correlate genetically we calculated correlations between z-scores of ADHD and educational attainment variants for nested strata of variants, representing subsets of SNPs with increasing significance of p-values in one of the traits. Additionally we supported this hypothesis by estimating genetic correlation between ADHD and educational attainment using LD score regression. We applied condFDR/conjFDR method to identify specific loci associated with ADHD and loci associated with both ADHD and educational attainment simultaneously. Consistency of effect directions for top association signals detected in our condFDR/conjFDR analyses was tested in the independent GWAS of ADHD symptoms from EAGLE consortium (N=17666). Results Using condFDR/conjFDR method we identified five novel loci associated with ADHD, three of these being shared between ADHD and educational attainment. Leading variants for four of five identified regions are located in introns of protein coding genes: KDM4A, MEF2C, PINK1, RUNX1T1, while the remaining one is an intergenic SNP on chromosome 2 at 2p24. Four of five loci have opposite directions of effect in ADHD and educational attainment and consistent directions of effect in the independent GWAS of ADHD symptoms from the EAGLE consortium. A hypothesis of polygenic overlap between ADHD and educational attainment was supported by significant genetic correlation (rg=-0.403, p=7.90E-8), consistent pleiotropic enrichment in conditional QQ plots, >10-fold mutual enrichment of SNPs associated with both traits and growing negative correlation of association z-scores for the nested SNP strata with increasing significance in both phenotypes. Discussion We found five novel loci associated with ADHD and provided evidence for a shared genetic basis between ADHD and educational attainment, implicating three genetic loci in this overlap. Four of five identified loci showed consistent effects in the independent data set of ADHD symptoms, and inverse correlation with educational attainment. The latter is in line with prior epidemiological and genetic studies. We belive that altogether these findings provide new insights into the relationship between ADHD and educational attainment, suggesting shared molecular genetic mechanisms. Further research is required to clarify the biological effects of the identified genetic variants and how these may influence educational attainment and ADHD pathogenesis.
Radboud University Nijmegen1, Harvard University2, Aarhus University3, University of North Carolina at Chapel Hill4, Erasmus University Rotterdam5, University of Toronto6, King's College London7, Broad Institute8, Karolinska Institutet9, QIMR Berghofer Medical Research Institute10, State University of New York Upstate Medical University11
TL;DR: A significant negative genetic correlation between ADHD and intracranial volume (ICV) is discovered and new hypotheses about biological mechanisms involved in ADHD etiology are suggested and the need to study additional brain parameters is highlighted.
Abstract: Attention-Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology, where genetic risk is hypothesized to be mediated by alterations in structure and function of diverse brain networks. We tested one aspect of this hypothesis by investigating the genetic overlap between ADHD (n=55,374) and (mainly subcortical) brain volumes (n=11,221-24,704), using the largest publicly available studies. At the level of common variant genetic architecture, we discovered a significant negative genetic correlation between ADHD and intracranial volume (ICV). Meta-analysis of individual variants found significant loci associated with both ADHD risk and ICV; additional loci were identified for ADHD and amygdala, caudate nucleus, and putamen volumes. Gene-set analysis in the ADHD-ICV meta-analytic data showed significant association with variation in neurite outgrowth-related genes. In summary, our results suggest new hypotheses about biological mechanisms involved in ADHD etiology and highlight the need to study additional brain parameters.
TL;DR: Rates of alcohol and drug use in the past year were significantly lower in the clinical trial compared with untreated and treated naturalistic ADHD comparators, and similar to rates in non-ADHD comparators.
Abstract: Objective: The purpose of this study was to examine the impact of stimulant treatment on risk for alcohol and illicit drug use in adolescents with ADHD. Method: Analysis of data derived from a prospective open-label treatment study of adolescent ADHD (n = 115, 76% male), and a historical, naturalistic sample of ADHD (n = 44, 68% male) and non-ADHD youth (n = 52, 73% male) of similar age and sex. Treatment consisted of extended-release methylphenidate in the clinical trial or naturalistic stimulant treatment. Self-report of alcohol and drug use was derived from a modified version of the Drug Use Screening Inventory. Results: Rates of alcohol and drug use in the past year were significantly lower in the clinical trial compared with untreated and treated naturalistic ADHD comparators, and similar to rates in non-ADHD comparators. Conclusion: Well-monitored stimulant treatment may reduce the risk for alcohol and substance use in adolescent ADHD.
TL;DR: Maternal smoking during pregnancy was found to increase the risk for smoking and a wide range of adverse psychiatric, cognitive, and functional outcomes in youth.
Abstract: Objective: This study examined whether exposure to maternal smoking during pregnancy in children with and without ADHD is associated with smoking in offspring and whether this association is selective to ADHD children. Method: Ninety-six exposed and 400 unexposed participants were derived from two longitudinal studies of boys and girls with and without ADHD. Maternal smoking during pregnancy was defined by interviews with participants’ mothers. Results: A significant association was observed between exposure to maternal smoking in pregnancy and cigarette smoking in offspring (p = .02). Exposed offspring were also more likely to have higher rates of major depression (p = .04), bipolar disorder (p = .04), and conduct disorder (p = .04), and lower IQ (p = .01), lower Global Assessment of Functioning (GAF) score (p = .02), and more impaired Social Adjustment Inventory for Children and Adolescents (SAICA) scores versus unexposed offspring, adjusting for social class. Conclusion: Maternal smoking during pregnan...
TL;DR: Higher IQ score was most strongly related to fewer attention problems, with more rater discrepancy in the high v. average IQ range, and attention problems in highly intelligent children are exceptional and affect school performance; they are therefore a reason for clinical concern.
Abstract: BackgroundHigh intelligence may be associated with positive (adaptive, desired) outcomes, but may also come with disadvantages.AimsTo contribute empirically to the debate concerning whether a trade-off in IQ scores exists in relation to attention-deficit hyperactivity disorder (ADHD) and related problems, suggesting that high intelligence - like low intelligence - increases the risk of ADHD.MethodCurves of the relation between IQ score and ADHD problems were fitted to questionnaire data (parent, teacher, self-report} in a population-based study of 2221 children and adolescents aged 10-12 years. Externalising and internalising problems were included for comparison purposes.ResultsHigher IQ score was most strongly related to fewer attention problems, with more rater discrepancy in the high v. average IQ range. Attention problems - but only minimally hyperactivity/impulsivity problems - predicted functional impairment at school, also in the higher IQ range.ConclusionsAttention problems in highly intelligent children are exceptional and affect school performance; they are therefore a reason for clinical concern.
TL;DR: The results suggest that RTN4R, a relatively under‐studied gene at the 22q11 locus, constitutes a susceptibility gene for psychosis in individuals with this syndrome through its alteration of the architecture of the brain.
Abstract: 22q11.2 deletion syndrome is a neurogenetic disorder resulting in the deletion of over 40 genes. Up to 40% of individuals with 22q11.2DS develop schizophrenia, though little is known about the underlying mechanisms. We hypothesized that allelic variation in functional polymorphisms in seven genes unique to the deleted region would affect lobar brain volumes, which would predict risk for psychosis in youth with 22q11.2DS. Participants included 56 individuals (30 males) with 22q11.2DS. Anatomic MR images were collected and processed using Freesurfer. Participants were genotyped for 10 SNPs in the COMT, DGCR8, GNB1L, PIK4CA, PRODH, RTN4R, and ZDHHC8 genes. All subjects were assessed for ultra high risk symptoms of psychosis. Allelic variation of the rs701428 SNP of RTN4R was significantly associated with volumetric differences in gray matter of the lingual gyrus and cuneus of the occipital lobe. Moreover, occipital gray matter volumes were robustly associated with ultra high risk symptoms of psychosis in the presence of the G allele of rs701428. Our results suggest that RTN4R, a relatively under-studied gene at the 22q11 locus, constitutes a susceptibility gene for psychosis in individuals with this syndrome through its alteration of the architecture of the brain. © 2017 Wiley Periodicals, Inc.
TL;DR: LDX is effective in treating adult ADHD and has a smooth drug effect throughout the day with limited symptom rebound and the AMSES and AMRS are valid and reliable measures.
Abstract: Objectives: (a) Evaluate the efficacy and duration of effect of lisdexamfetamine dimesylate (LDX) in adult ADHD. (b) Assess the reliability and validity of the Adult ADHD Medication Smoothness of E...