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Attention-deficit/hyperactivity (ADHD) and autism spectrum (ASD) disorders are commonly co-occurring conditions characterized by neurocognitive impairments. Few studies have directly compared neurocognitive profiles in ADHD and ASD and fewer still have controlled for comorbidity of ADHD and ASD. All direct comparisons have been in clinic samples, leaving the question of generalizability of results unaddressed. We compared neurocognitive performance in clinically ascertained ASD (n = 261) and ADHD (n = 423) cases and controls (n = 162), 6.0–17.9 years of age. We also compared ASD (n = 190) and ADHD (n = 926) cases ascertained in the community with controls (n = 14,842) of similar age. Using the stop-signal task (SST), we measured response inhibition (stop-signal reaction time–SSRT), sustained attention (defined as reaction time variability–RTV), and reaction time (RT). We controlled for comorbidity using ADHD and ASD trait scores and categorically-defined ADHD. Compared with controls, both clinic ADHD and ASD had significantly longer SSRT and RTV than controls and did not differ from each other. ADHD traits accounted for neurocognitive impairment in ASD, but not vice versa. There were no group differences for RT. Similar patterns of neurocognitive impairment were observed in the community sample. In the largest direct comparison of ADHD and ASD to date, we found impaired response inhibition and sustained attention in both disorders. However, neurocognitive impairment in ASD was almost completely accounted for by comorbid ADHD. Results generalized in the community sample indicating that referral bias alone did not drive results. Response inhibition and sustained attention likely play a role in ADHD and ASD.

Executive functions (EF) deficits are hypothesized to be a core contributor to hoarding symptoms. EF have been studied in adult hoarding populations, but studies in youth are lacking. The current study compared multiple EF subdomains between youth with obsessive-compulsive disorder (OCD) and youth with OCD and hoarding symptoms. Forty youth (8–18 years old) with a primary diagnosis of OCD were recruited. Participants were divided by hoarding severity on the Child Saving Inventory (CSI) into either the “hoarding group” (upper 33.3%) or the “low-hoarding group” (lower 66.7%). Groups were compared on EF tasks of cognitive flexibility, decision-making, and inhibitory control. Youth in the hoarding group exhibited significantly higher cognitive flexibility and lowered perseveration than the low-hoarding group. Hoarding and low-hoarding groups did not differ in any other EF subdomain. Hoarding symptoms in youth with OCD were not associated with deficits in EF subdomains; instead, youth who hoard exhibited higher cognitive flexibility compared to youth with low hoarding symptoms.

Hoarding Disorder (HD) is a mental disorder characterized by persistent difficulties discarding or parting with possessions, often resulting in cluttered living spaces, distress, and impairment. Its etiology is largely unknown, but twin studies suggest that it is moderately heritable. In this study, we pooled phenotypic and genomic data from seven international cohorts (N = 27,651 individuals) and conducted a genome wide association study (GWAS) meta-analysis of parent- or self-reported hoarding symptoms (HS). We followed up the results with gene-based and gene-set analyses, as well as leave-one-out HS polygenic risk score (PRS) analyses. To examine a possible genetic association between hoarding symptoms and other phenotypes we conducted cross-trait PRS analyses. Though we did not report any genome-wide significant SNPs, we report heritability estimates for the twin-cohorts between 26–48%, and a SNP-heritability of 11% for an unrelated sub-cohort. Cross-trait PRS analyses showed that the genetic risk for schizophrenia and autism spectrum disorder were significantly associated with hoarding symptoms. We also found suggestive evidence for an association with educational attainment. There were no significant associations with other phenotypes previously linked to HD, such as obsessive-compulsive disorder, depression, anxiety, or attention-deficit hyperactivity disorder. To conclude, we found that HS are heritable, confirming and extending previous twin studies but we had limited power to detect any genome-wide significant loci. Much larger samples will be needed to further extend these findings and reach a “gene discovery zone”. To move the field forward, future research should not only include genetic analyses of quantitative hoarding traits in larger samples, but also in samples of individuals meeting strict diagnostic criteria for HD, and more ethnically diverse samples.

Background Neurocognitive impairments are common in OCD, although not well studied in children and youth with the disorder. Method Using the stop-signal task (SST), we measured response inhibition (stop-signal reaction time-SSRT), sustained attention (reaction time variability-RTV), reaction time (RT), and performance monitoring (post-error slowing-PES) in OCD cases and controls from two samples of children and youth. A Clinic OCD group (n = 171, aged 7-17 years) was recruited from a specialty clinic after rigorous assessment. A typically developing (Clinic TD, n = 157) group was enlisted through advertisement. A community OCD sample (Community OCD, n = 147) and controls (Community TD n = 13,832, aged 6-17 years) were recruited at a science museum. We also identified a community group with high OCD traits without an OCD diagnosis (Community High Trait; n = 125). Results Clinic OCD participants had longer SSRT and greater RTV than Clinic TD. These effects were greater in younger OCD participants and, for SSRT, in those on medication for OCD. The Community OCD group did not differ from Controls but was similar to the Clinic OCD group in ADHD and ASD comorbidity and medication usage. The Community High Trait group had longer SSRT and atypical PES suggesting that symptom severity predicts neurocognitive function. No group differences were found in RT. Conclusions In the largest study of neurocognitive performance in children with OCD to date, we found impaired response inhibition and sustained attention in OCD participants in comparison to typically developing peers. Performance was worse in younger OCD participants. In the community sample, participants with high OCD trait scores but no OCD diagnosis had impaired response inhibition and error processing, suggesting that OCD might be under-recognized.

The comorbidity of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) diagnoses is well established. An ASD diagnosis is associated with elevated ADHD traits and symptoms, as well as strengths in attention. In the ASD literature, attentional strengths have been described as maladaptive (e.g., hyperfocus), in contrast with positive portrayals in the typically developing population (e.g., flow). The objective of this study was to (1) compare profiles of attentional strengths and weaknesses in ASD and ADHD and (2) determine whether attentional strengths in ASD are associated with impairment, poorer cognitive flexibility, and perseveration/perfectionism. In a community sample of 5,744 children and youth, 131 children were reported as having a diagnosis of ASD (mean age 10.3 years) and 346 children were reported as having a diagnosis of ADHD (mean age 10.7 years). We used the Strengths and Weaknesses of Attention-Deficit/Hyperactivity-symptoms and Normal-behaviors (SWAN) rating scale to calculate attentional and hyperactive/impulse control strength and weakness counts and scores. The Autism-Spectrum Quotient Switching factor served as a measure of cognitive flexibility. Impairment was assessed with the Columbia Impairment Scale. We used the symmetry/ordering factor on the Toronto Obsessive-Compulsive Scale as a measure of perseveration/perfectionism. No differences were found between the ADHD and ASD groups in SWAN weakness scores, symptoms, or hyperactive/impulse control strengths; however, autistic children had higher rates of attentional strengths [odds ratio: 5.7, 95% CI (2.8, 11.6), p < 0.0001]. Post-hoc pairwise testing identified four attentional strengths with significantly higher rates in ASD than in ADHD. Attentional strength scores were not associated with impairment or poor cognitive flexibility, but predicted levels of perseveration/perfectionism. The effect of attentional strengths on impairment and cognitive flexibility did not differ between autistic and Control children, but the higher perseveration/perfectionism scores seen in ASD were not found in Control children. ASD is associated with a pattern of attentional strengths that is not found in ADHD Characterizing the full range of attentional abilities in autistic children may explain variability in outcomes such as quality-of-life indicators and identify protective factors, providing targets for strength-based behavioral interventions. The clinical and etiological implications of the subgroup of autistic children with attentional strengths require further investigation.

BackgroundObsessive-compulsive disorder (OCD) is a psychiatric disorder with multiple symptom dimensions (e.g. contamination, symmetry). OCD clusters in families and decades of twin studies clearly demonstrate an important role for genetics in the etiology of the disorder.MethodsIn this review, we summarize the genetic epidemiology and molecular genetic studies of OCD and obsessive-compulsive symptoms.ResultsOCD is a heritable, polygenic disorder with contributions from both common and rare variants, includingde novodeleterious variations. Multiple studies have provided reliable support for a large additive genetic contribution to liability to OCD, with discrete OCD symptom dimensions having both shared and unique genetic risks. Genome-wide association studies have not produced significant results yet, likely because of small sample sizes, but larger meta-analyses are forthcoming. Both twin and genome-wide studies show that OCD shares genetic risk with its comorbid conditions (e.g. Tourette syndrome and anorexia nervosa).ConclusionsDespite significant efforts to uncover the genetic basis of OCD, the mechanistic understanding of how genetic and environmental risk factors interact and converge at the molecular level to result in OCD's heterogeneous phenotype is still mostly unknown. Future investigations should increase ancestral genetic diversity, explore age and/or sex differences in genetic risk for OCD and expand the study of pharmacogenetics, gene expression, gene × environment interactions and epigenetic mechanisms for OCD.

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.

Objective Obsessive-compulsive symptoms in the population have been linked to obsessive-compulsive disorder (OCD) in previous genetic and epidemiological studies. Genetic studies also show a link to insulin signalling. Here we aim to assess the presence and extent of genetic and biological overlap between OCD, OCD symptoms in the population, and insulin signalling, making use of the largest data sets currently available. Methods We used phenotypic and genetic data from a population based cohort (n=650) of children and adolescents to conduct genome-wide association studies (GWAS) to six factors derived from exploratory factor analyses on OCD symptom scores. We performed polygenic risk score analyses to check whether these OCD symptom traits had a shared genetic etiology with clinically diagnosed OCD (using GWAS data of the PGC, n=2688 OCD cases and 7037 controls). Subsequently we investigated potential shared biology performing gene-set analyses with an earlier defined set of 51 OCD-associated genes centered around insulin-regulated synaptic function and polygenic risk score analyses of five peripheral insulin signaling-related traits (type 2 diabetes (T2D) and the blood levels of four T2D biomarkers (n between 42,854-159,208)). Results We found genetic sharing between diagnosed OCD and four out of six factors based on OCD symptoms in the population: ‘impairment’, ‘contamination/cleaning’, ‘guilty taboo thoughts’, and ‘symmetry/counting/ordering’. Gene-set analysis with insulin-related genes revealed an association with ‘symmetry/counting/ordering’. We also identified genetic sharing between OCD, the total score of OCD symptoms and six of the derived symptom factors with the peripheral insulin signaling-related traits. We were able to validate part of our results on symmetry/counting/ordering and contamination/cleaning in an independent population-based cohort (n=5047). Conclusions Our findings suggest that GWASs of OCD symptoms in population-based cohorts could be used to discover OCD-relevant genes. Our results also imply that altered insulin signaling, as relevant to T2D, is also involved in different aspects of compulsive and obsessive behaviours and clinical OCD. This may open up a new field of brain-based insulin-related disorders.

Background Hoarding, originally only considered a symptom of obsessive-compulsive disorder (OCD), is now categorized as a separate disorder in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). We studied candidate serotonergic genes and the distinctness of hoarding in children and adolescents and hypothesized that unique gene variants would be associated with hoarding alone. Methods We examined obsessive-compulsive (OC) traits, including hoarding, in a total of 5,213 pediatric participants in the community. We genotyped candidate serotonin genes (5-HTTLPR polymorphism in SLC6A4 for 2,018 individuals and single nucleotide polymorphisms [SNPs] across genes SLC6A4, HTR2A, and HTR1B for 4,711 individuals). In a previous study conducted by our group in the same sample, we identified a significant association between 5-HTTLPR and hoarding in males. In this study, we examined hoarding more closely by testing the association between serotonin gene variants and hoarding traits with and without other accompanying OC traits. Results The [LG +S] variant in 5-HTTLPR was significantly associated with hoarding alone in males (p-value of 0.009). There were no significant findings for 5-HTTLPR in females. There were no significant findings after correction for multiple comparisons using SNP array data, but top SNP findings suggested that variation downstream of HTR1B may be implicated in hoarding alone in females. Conclusions Our results suggest specific serotonin gene variants are associated with hoarding traits alone, differing between sexes. Top findings are in line with our former study, suggesting that individuals with hoarding alone were driving previous results. Our paper supports hoarding disorder's new designation.

Obsessive-compulsive disorder (OCD) is phenotypically heterogeneous and genetically complex. This study aimed to reduce heterogeneity using structural brain imaging to study putative intermediate phenotypes for OCD. We hypothesized that select serotonin gene variants would differ in their relationship with brain volume in specific regions of the cortico-striato-thalamo-cortical (CSTC) circuits between OCD patients and controls. In a total of 200 pediatric subjects, we genotyped candidate serotonin genes (SLC6A4, HTR2A, HTR1B, and HTR2C) and conducted structural magnetic resonance imaging (sMRI) to measure regional brain volumes within CSTC circuits. In males and females separately, we first tested the association between serotonin gene variants and OCD and the effect of serotonin gene variants on brain volume irrespective of diagnosis. We then carried out a series of analyses to assess the effect of genotype-diagnosis interaction on brain volume. In females, but not in males, we identified a statistically significant genotype-diagnosis interaction for two single nucleotide polymorphisms (SNPs) in HTR2C, rs12860460 (interaction term estimate of 5.45 cc and interaction P value of 9.70e-8) and rs12854485 (interaction term estimate of 4.28 cc and interaction P value of 2.07e-6). The tested allele in each SNP was associated with decreased anterior cingulate cortex (ACC) volume in controls and with increased ACC volume in OCD patients. Our findings suggest that, in females, sequence variation in HTR2C influences ACC volume in pediatric OCD. The variants may contribute to differences in ACC volume and to OCD in a sex-specific manner when acting together with other genetic, biological, and/or environmental factors.

Background Serotonin system genes are commonly studied in obsessive-compulsive disorder (OCD), but genetic studies to date have produced inconsistent results, possibly because phenotypic heterogeneity has not been adequately accounted for. In this paper, we studied candidate serotonergic genes and homogenous phenotypic subgroups as presented through obsessive-compulsive (OC) trait dimensions in a general population of children and adolescents. We hypothesized that different serotonergic gene variants are associated with different OC trait dimensions and, furthermore, that they vary by sex. Methods Obsessive-compulsive trait dimensions (Cleaning/Contamination, Counting/Checking, Symmetry/Ordering, Superstition, Rumination, and Hoarding) were examined in a total of 5,213 pediatric participants in the community using the Toronto Obsessive-Compulsive Scale (TOCS). We genotyped candidate serotonin genes (directly genotyping the 5-HTTLPR polymorphism in SLC6A4 for 2018 individuals and using single nucleotide polymorphism (SNP) array data for genes SLC6A4, HTR2A, and HTR1B for 4711 individuals). We assessed the association between variants across these genes and each of the OC trait dimensions, within males and females separately. We analyzed OC traits as both (a) dichotomized based on a threshold value and (b) quantitative scores. Results The [LG + S] variant in 5-HTTLPR was significantly associated with hoarding in males (p-value of 0.003 and 0.004 for categorical and continuous analyses, respectively). There were no significant findings for 5-HTTLPR in females. Using SNP array data, there were significant findings for rumination in males for HTR2A SNPs (p-value of 1.04e-6 to 5.20e-6). Conclusions This represents the first genetic association study of OC trait dimensions in a community-based pediatric sample. Our strongest results indicate that hoarding and rumination may be distinct in their association with serotonin gene variants and that serotonin gene variation may be specific to sex. Future genetic association studies in OCD should properly account for heterogeneity, using homogenous subgroups stratified by symptom dimension, sex, and age group.

Altres ajuts: VR has served on the speakers for Eli Lilly, Rubio, and Shire in the last 5 years. She has received travel awards from Eli Lilly and Co. and Shire for participating in psychiatric meetings. The ADHD Program has received unrestricted educational and research support from Eli Lilly and Co., Janssen-Cilag, Shire, Rovi, Psious, and Laboratorios Rubió in the past 2 years. MC received travel awards for taking part in psychiatric meetings from Shire. CF received travel awards for taking part in psychiatric meetings from Shire and Lundbeck. GEM received travel awards for taking part in psychiatric meetings from Shire. EJSS-B received speaker fees, consultancy, research funding, and conference support from Shire Pharma. Consultancy from Neurotech Solutions, Copenhagen University and Berhanderling, Skolerne & KU Leuven. Book royalties from OUP and Jessica Kingsley. Financial support-Arhus University and Ghent University for visiting Professorship. Editor-in-Chief JCPP-supported by a buy-out of time to University of Southampton and personal Honorarium. King's College London received payments for work conducted by PA: consultancy for Shire, Eli Lilly, Novartis, and Lundbeck; educational and/or research awards from Shire, Eli Lilly, Novartis, Vifor Pharma, GW Pharma, and QbTech; speaker at events sponsored by Shire, Eli Lilly, Janssen-Cilag, and Novartis. JKB has been in the past 3 years a consultant to/member of advisory board of and/or speaker for Shire, Roche, Medice, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. In the past year, SVF received income, potential income, travel expenses continuing education support and/or research support from Tris, Otsuka, Arbor, Ironshore, Shire, Akili Interactive Labs, Enzymotec, Sunovion, Supernus, and Genomind. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child's Mental Health, Oxford University Press: Schizophrenia: The Facts and Elsevier: ADHD: Non-Pharmacologic Interventions. He is principal investigator of www.adhdinadults.com. JK has given talks at educational events sponsored by Medice; all funds are received by King's College London and used for studies of ADHD. HL has served as a speaker for Evolan Pharma and Shire and has received research grants from Shire; all outside the submitted work. K-PL served as a speaker for Eli Lilly and received research support from Medice, and travel support from Shire, all outside the submitted work. LAR reported receiving honoraria, serving on the speakers' bureau/advisory board, and/or acting as a consultant for Eli Lilly, Janssen-Cilag, Novartis, and Shire in the last 3 years; receiving authorship royalties from Oxford Press and ArtMed; and receiving travel awards from Shire for his participation in the 2015 WFADHD meetings and from Novartis to take part of the 2016 AACAP meeting. The ADHD and juvenile bipolar disorder outpatient programs chaired by him received unrestricted educational and research support from the following pharmaceutical companies in the last 3 years: Janssen-Cilag, Novartis, and Shire. MC has received travel grants and research support from Eli Lilly and Co., Janssen-Cilag, Shire, and Lundbeck and served as consultant for Eli Lilly and Co., Janssen-Cilag, Shire, and Lundbeck. BF has received educational speaking fees from Medice and Shire. JAR-Q was on the speakers' bureau and/or acted as consultant for Eli Lilly, Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, Braingaze, Sincrolab, Medice, and Rubió in the last 5 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire, Medice, and Eli- Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 5 years: Eli Lilly, Lundbeck, Janssen- Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Psious, and Rubió. The other authors have nothing to disclose. All members of the 23andMe Research Team are current or former employees of 23andMe, Inc. and hold stock or stock options in 23andMe. Authors of the ADHD Working group of the PGC that participated in this study: Catharina A. Hartman, Ziarih Hawi, Jennifer Crosbie, Sandra Loo, Josephine Elia, Russell Schachar, Christie Burton, Ted Reichborn-Kjennerud, Aribert Rothenberger, Søren Dalsgaard, Irwin Waldman, Mark Bellgrove, Hakon Hakonarson, Johannes Hebebrand, Anke Hinney, and Robert Oades have nothing to disclose. Joseph Biederman 2019-2020: he received research support from Genentech, Headspace Inc., Lundbeck AS, Neurocentria Inc, Pfizer Pharmaceuticals, Roche TCRC Inc., Shire Pharmaceuticals Inc., Sunovion Pharmaceuticals Inc., and Tris. He was a consultant for Akili, Avekshan, Jazz Pharma, and Shire/Takeda. Through MGH CTNI, he participated in a scientific advisory board for Supernus. Dr Biederman's program has received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Bracket Global, Ingenix, Prophase, Shire, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH. Tobias Banaschewski served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire, and Infectopharm. He received conference support or speaker's fee by Lilly, Medice, and Shire. He received royalties from Hogrefe, Kohlhammer, CIP Medien, and Oxford University Press. James McGough is an expert testimony for Eli Lilly; DSMB for Sunovion. Benjamin Neale is a member of the scientific advisory board at Deep Genomics and consultant for Camp4 Therapeutics, Takeda Pharmaceutical, and Biogen. Ole Andreas Andreassen received speaker's honorarium from Lundbeck, and is a consultant for HealthLytix. The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 602805 (Aggressotype) as well as from the European Union H2020 Programme (H2020/2014-2020). The work was also supported by the ECNP Network "ADHD across the Lifespan" (https://www.ecnp.eu/research-innovation/ECNP-networks/List-ECNP-Networks/ADHD.aspx). Over the course of this investigation, PR is a recipient of a pre-doctoral fellowship from the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR), Generalitat de Catalunya, Spain. The iPSYCH project is funded by the Lundbeck Foundation (grant nos. R102-A9118 and R155-2014-1724) and the universities, and university hospitals of Aarhus and Copenhagen. ADB and NRM's work is also supported by the EU's Horizon 2020 programme. Data handling and analysis was supported by NIMH (1U01MH109514-01 to Michael O'Donovan and ADB). CSM is a recipient of a Sara Borrell contract from the Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad, Spain. K-PL and his team are supported by the Deutsche Forschungsgemeinschaft (DFG: CRU 125, CRC TRR 58 A1/A5, no. 44541416), ERA-Net NEURON/RESPOND, no. 01EW1602B, ERA-Net NEURON/DECODE, no. 01EW1902, and 5-100 Russian Academic Excellence Project. JH thanks Stiftelsen K.G. Jebsen, University of Bergen, the Western Norwegian Health Authorities (Helse Vest). HL thanks the Swedish research council. BC received financial support from the Spanish "Ministerio de Economía y Competitividad" and AGAUR. MSA is a recipient of a contract from the Biomedical Network Research Center on Mental Health (CIBERSAM), Madrid, Spain. MR is a recipient of a Miguel de Servet contract from the Instituto de Salud Carlos III, Spain. The research leading to these results has received funding from the Instituto de Salud Carlos III , and cofinanced by the European Regional Development Fund (ERDF), from the Pla estratègic de recerca i innovació en salut (PERIS); Generalitat de Catalunya, from "la Marató de TV3" (092330/31) and from the Agència de Gestió d'Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya. ES's work is supported by a personal Hypatia grant from the Radboud University Medical Center. MH received a Veni grant from of the Netherlands Organization for Scientific Research (NWO, grant number 91619115). The NeuroIMAGE study was supported by NIH Grant R01MH62873 (to SVF), NWO Large Investment Grant 1750102007010 (to JKB), ZonMW grant 60-60600-97-193, NWO grants 056-13-015 and 433-09-242, and matching grants from Radboud University Nijmegen Medical Center, University Medical Center Groningen and Accare, and Vrije Universiteit Amsterdam. Organization for Scientific Research (NWO; grant 016-130-669). BF and MK's work is supported by the Dutch National Science Agenda (NWA) for the NeurolabNL project (grant 400-17-602). This paper represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. BF received additional funding from a personal Vici grant of the Dutch. Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

Anorexia nervosa (AN) and obsessive-compulsive disorder (OCD) are often comorbid and likely to share genetic risk factors. Hence, we examine their shared genetic background using a crossdisorder GWAS meta-analysis of 3,495 AN cases, 2,688 OCD cases and 18,013 controls. We confirmed a high genetic correlation between AN and OCD (rg= 0.49 ± 0.13,p= 9.07×10−7) and a sizable SNP heritability (SNPh2= 0.21 ± 0.02) for the cross-disorder phenotype. Although no individual loci reached genome-wide significance, the cross-disorder phenotype showed strong positive genetic correlations with other psychiatric phenotypes (e.g., bipolar disorder, schizophrenia, neuroticism) and negative correlations with metabolic phenotypes (e.g., BMI, triglycerides). Follow-up analyses revealed that although AN and OCD overlap heavily in their shared risk with other psychiatric phenotypes, the relationship with metabolic and anthropometric traits is markedly stronger for AN than for OCD. We further tested whether shared genetic risk for AN/OCD was associated with particular tissue or cell-type gene expression patterns and found that the basal ganglia and medium spiny neurons were most enriched for AN/OCD risk, consistent with neurobiological findings for both disorders. Our results confirm and extend genetic epidemiological findings of shared risk between AN and OCD and suggest that larger GWASs are warranted.

Background Population-based samples with valid, quantitative and genetically informative trait measures of psychopathology could be a powerful complement to case/control genetic designs. We report the convergent and predictive validity of the parent- and self-report versions of the Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Rating Scale (SWAN). We tested if SWAN scores were associated with ADHD diagnosis, ADHD polygenic risk, as well as traits and polygenic risk for disorders that co-occur with ADHD: anxiety and obsessive-compulsive disorder (OCD). Methods We collected parent- and self-report SWAN scores in a sample of 15,560 children and adolescents (6-17 years) recruited at a science museum (Spit for Science sample). We established age and sex norms for the SWAN. Sensitivity-specificity analyses determined SWAN cut-points that discriminated those with and without a reported ADHD diagnosis. These cut-points were validated in a clinic sample (266 ADHD cases; 36 controls). Convergent validity was established using the Conners' parent- and self-report scales. Using Spit for Science participants with genome-wide data (n = 5,154), we tested if low, medium and high SWAN scores were associated with polygenic risk for ADHD, OCD and anxiety disorders. Results Parent- and self-report SWAN scores showed high convergent validity with Conners' scales and distinguished ADHD participants with high sensitivity and specificity in the Spit for Science sample. In a clinic sample, the Spit for Science cut-points discriminated ADHD cases from controls with a sensitivity of 84% and specificity of 92%. High SWAN scores and scores above the Spit for Science cut-points were significantly associated with polygenic risk for ADHD. SWAN scores were not associated with polygenic risk for OCD or anxiety disorders. Conclusions Our study supports the validity of the parent- and self-report SWAN scales and their potential in ADHD population-based genetic research.

Obsessive–compulsive disorder (OCD) is a heritable childhood-onset psychiatric disorder that may represent the extreme of obsessive–compulsive (OC) traits that are widespread in the general population. We report the heritability of the Toronto Obsessive–Compulsive Scale (TOCS), a new measure designed to assess the complete range of OC traits in youth. We also examined the dimensional nature of the TOCS and the degree to which genetic effects are unique or shared between dimensions. OC traits were measured using the TOCS in 16,718 youth (6–18 years) at a science museum. We conducted a factor analysis to identify OC trait dimensions. We used univariate and multivariate twin models to estimate the heritability of OC trait dimensions in a subset of twins (220 pairs). Six OC dimensions were identified: Cleaning/Contamination, Symmetry/Ordering, Rumination, Superstition, Counting/Checking, and Hoarding. The TOCS total score (74%) and each OC dimension was heritable (30–77%). Hoarding was not highly correlated with other OC dimensions, but did share genetic effects. Shared genetics accounted for most of the shared variance among dimensions, whereas unique environment accounted for the majority of dimension-specific variance. One exception was Hoarding, which had considerable unique genetic factors. A latent trait did not account for the shared variance between dimensions. In conclusion, OC traits and individual OC dimensions were heritable, although the degree of shared and dimension-specific etiological factors varied by dimension. The TOCS may be informative for genetic research of OC traits in youth. Genetic research of OC traits should consider both OC dimension and total trait scores.

Background Rare Copy Number Variants (CNVs) likely play an important role in common childhood neuropsychiatric disorders such as ADHD and OCD. These disorders represent the extremes of broadly distributed behavioural traits that are influenced by underlying variation in fundamental cognitive processes such as response inhibition. Using behavioural and cognitive trait-based approaches in population samples can help reduce heterogeneity and improve power to detect rare CNVs associated with these disorders. Currently we do not know the prevalence of CNVs related to neuropsychiatric disorders in youth in the general population. Using the Spit for Science sample (Toronto, Canada), we examined the association of rare CNVs with ADHD, OCD and response inhibition traits. Methods We collected DNA and quantitative trait measures from 16,718 youth (ages 6–17 years) at a local science museum. We measured ADHD traits using the Strengths and Weaknesses of ADHD and Normal Behavior (SWAN) scale, obsessive-compulsive traits using the Toronto Obsessive-Compulsive scale (TOCS) and response inhibition, a putative endophenotype for ADHD, using the Stop-Task. We genotyped unrelated Caucasians (n=5,320) using Illumina HumanCoreExome beadchips. CNVs were called using three algorithms: iPattern (ipn), PennCNV (pcnv), and QuantiSNP (qsnp) and a high confidence dataset was generated by retaining variants detected by two or more algorithms and at least 10 kb in size. We defined rare variants as those with less than 0.1% frequency against our population controls. Using linear regression, we examined whether CNV burden, overall and within psychiatrically relevant gene sets (e.g., brain expression, synaptic function), is associated with response inhibition, ADHD and OCD traits. Results After stringent quality control, 4815 (90.5%) of participants remained with a total of 9,490 rare CNVs (1.97/individual on average). We observed CNVs affecting 23 genomic loci previously implicated in neurodevelopmental conditions (e.g. 22q11.2) in 59 (1.2%) of participants. Other large CNVs affecting known psychiatric genes (e.g., ASTN2, NRXN1) were also identified. Significantly more deletions (>500 kb; p=0.04) and enrichment of deletions in genes involved in synapse structure, neuron projection and neurophenotypes in mice (p Discussion In a large pediatric general population sample, brain-related CNVs were associated with neuropsychiatric traits in children although the pattern of enrichment differed between ADHD, OCD and response inhibition. Our results replicate several previous CNV burden findings for ADHD and OCD suggesting a similar genetic architecture between traits and disorders. Our approach shows the feasibility of CNV analysis and quality of CNV data from the HumanCoreExome array in a large population based sample.

Background Most common disorders, including Attention-Deficit Hyperactivity Disorder (ADHD) and Obsessive-Compulsive Disorder (OCD), are likely extremes of traits that are widely distributed in the general population. People are more or less restless, inattentive, impulsive, obsessional and compulsive; only the extreme of these traits demarcate a clinical diagnosis. Thus, quantitative psychiatric traits, which often share polygenic risk with their relevant diagnosis, will help us discover genes for disorders. Quantitative cognitive traits that might mediate part of the genetic risk of psychiatric disorders (i.e., cognitive endophenotypes) are often less heterogeneous than a diagnosis which could help reduce noise to improve power for gene discovery. Based on these alternative approaches, we designed the Spit for Science study to examine the genomics of childhood psychiatric disorders using behavioural traits and a cognitive endophenotype relevant to ADHD and OCD in a large population-based sample of youth. Methods Spit for Science is a sample of 17,263 children (6-17 years of age) seen at a local science museum with measures of psychiatric traits and DNA from saliva. Quantitative data on ADHD traits using the Strengths and Weaknesses of ADHD and Normal Behavior (SWAN) scale, obsessive-compulsive (OC) traits using the Toronto Obsessive-Compulsive scale (TOCS) and response inhibition using the Stop-Signal task was collected. We genotyped unrelated Caucasians (n=5,636) using Illumina HumanCoreExome beadchips. For common variant analyses, we conducted standard quality control and used hypothesis-driven genome-wide association analyses (GWAS-HD) to test biological hypotheses for each trait. For the GWAS-HD, permutation tests were used to test the whole gene set for association with each trait respectively. Copy number variants (CNVs) were called using three algorithms and only CNV calls detected by two algorithms and at least 10kb in size were retained. We examined CNV burden for each trait individually. Results We have identified the first genome-wide finding for OC traits (rs7856850; p = 2.9 x 10-8, β = 0.13) replicated in an independent sample of youth screened for OCD. Genes involved in central nervous system development were significantly associated with both OC traits and response inhibition. Polygenic risk score analyses are forthcoming. ADHD traits were associated with increased CNV deletions while response inhibition was associated with more CNV duplications and longer CNV deletions. Discussion Several promising findings have emerged from the Spit for Science study. We identified the first genome-wide finding for OC traits, identified a biological pathway involved in both OC traits and response inhibition, and demonstrated the relationship between rare CNVs with ADHD traits and response inhibition. Results to date demonstrate the feasibility, power and utility of using quantitative-trait based and cognitive endophenotype approaches in community samples to help uncover the underlying genetic architecture of psychiatric disorders.

Vulnerability to the effects of drugs of abuse during adolescence may be related to altered incentive motivation, a process believed to be important in addiction. Incentive motivation can be seen when a neutral stimulus acquires motivational properties through repeated association with a primary reinforcer. We compared adolescent (postnatal day (PND) 24-50) and adult (PND 70) rats on a measure of incentive motivation: responding for a conditioned reinforcer (CR). Rats learned to associate the delivery of 0.1 ml of 10% sucrose with a conditioned stimulus (CS; light and tone); 30 pairings per day were given over 14 days. Then, we measured responding on a lever delivering the CS (now a CR) after injections of amphetamine (0, 0.25 or 0.5 mg/kg). We also examined responding for CR when the CS and sucrose were paired or unpaired during conditioning, and responding for the primary reinforcer (10% sucrose) in control experiments. Finally, we examined the effects of D(1) and D(2) dopamine receptor antagonists (SCH 39166 and eticlopride, respectively) and an opioid receptor antagonist (naltrexone) on responding for a CR in adolescent rats. Adolescents but not adults acquired responding for a CR, but adolescents responded less than adults for the primary reinforcer. Responding for a CR depended upon the pairing of the CS and sucrose during conditioning. Both dopamine and opioid receptor antagonists reduced responding for the CR. Therefore, incentive motivation may be enhanced in adolescents compared with adults, and incentive motivation may be mediated in part by both dopamine and opioid systems.

Objective We assessed the prevalence and clinical correlates of hoarding, with and without obsessive-compulsive (OC) symptoms, in a community-based pediatric sample. Method We measured hoarding and OC symptoms using the Toronto Obsessive-Compulsive Scale (TOCS) in 16,718 youth aged 6 to 17 years in the community. We classified participants with high and low symptom counts for hoarding and OC into 4 groups: hoarding+OC; hoarding-only; OC-only; and control (no OC or hoarding symptoms). We compared these 4 groups on parent- or self-reported medical and psychiatric conditions, anxiety symptoms measured with the Child Behavior Checklist (CBCL), and attention-deficit/hyperactivity disorder (ADHD) symptoms measured with the Strengths and Weaknesses of Attention-Deficit/Hyperactivity Disorder Symptoms and Normal Behavior Scale (SWAN). Results Almost 10% of participants were in the high hoarding group. Of these participants, 40% did not fall into the high OC group. The prevalence of reported psychiatric disorders (e.g., ADHD, autism spectrum disorder, obsessive-compulsive disorder) was greater in the hoarding (hoarding+OC and hoarding-only) and OC groups (hoarding+OC and OC-only) than in the nonhoarding (OC-only and control) and non-OC groups (hoarding-only and control), respectively. ADHD, specifically inattentive, symptoms were more common in the hoarding-only than in the OC-only group while anxiety symptoms were more common in the OC-only than in the hoarding-only group. Conclusion In a community pediatric sample, hoarding symptoms occurred in both the presence and absence of obsessive-compulsive symptoms. Hoarding symptoms alone had some unique clinical correlates, in particular, more inattentive ADHD symptoms and fewer anxiety symptoms. These findings suggest that hoarding is distinct from OC traits in youth.

Background Genetics play an important role in ADHD and OCD but only a handful of mostly common risk variants have been identified in studies that compare ADHD/OCD patients with healthy controls. Copy number variants of high penetrance may play an important role in childhood neuropsychiatric disorders. Our current knowledge of CNVs in ADHD and OCD is based on relatively small samples of patients, and to interpret the significance of these CNVs we need to assess risk CNVs in the general population. To this end we determine the frequency of clinically relevant CNVs in a large population based sample of children and adolescents and examined the association of rare CNVs with ADHD and OCD traits. Methods Quantitative data on ADHD traits using the Strengths and Weaknesses of ADHD and Normal Behavior (SWAN) scale and OC traits using the Toronto Obsessive-Compulsive scale (TOCS) was collected from 17,263 youth (ages 6-17 years) from the community. We genotyped unrelated Caucasians (n=5,366) and East Asians (n=989) using Illumina HumanCoreExome beadchips. CNV were called using three algorithms: iPattern (ipn), PennCNV (pcnv), and QuantiSNP (qsnp) and a high confidence dataset was generated by retaining variants detected by two or more algorithms and at least 10kb in size. We defined rare variants as those with less than 0.1% frequency against our population controls. We plan to examine whether CNV burden, overall and within psychiatrically relevant gene sets (e.g., brain expression, brain development), is associated with ADHD and OCD traits. We will also test if individual CNVs are associated with ADHD and OCD traits. Results After stringent quality control, 4857 (90.5%) Caucasian and 933 (94.3%) East Asian samples remained. Total number of CNVs was 31,798 with a mean size of 117,316 base pairs and a maximum size of 7.1 MB. The average number of CNVs per participants was 6. We uncovered 9,836 rare variants, of which 4,151 are deletions and 5,687 are duplications. This comprises of 7,613 rare CNVs from European subjects (mean size = 139,856 kb) and 2,225 from Asian individuals (mean size =123,141 kb). This represented a mean of 1.57 and 2.38 rare CNVs per individuals, respectively. We identified a total of 15 different known genomic disorders from 41 subjects (0.7%) in this cohort. Quantitative trait results forthcoming. Discussion Our novel approach will help elucidate the rate of psychiatrically relevant CNVs in the general population and the association of these CNVs with ADHD and OCD. Our preliminary data shows the feasibility of CNV analysis and quality of CNV data from the HumanCoreExome array in a large population based sample. Financial Relationships I (or my spouse/partner) do have potential conflicts of interest to disclose.

Objective To describe the Toronto Obsessive-Compulsive Scale (TOCS), a novel 21-item parent- or self-report questionnaire that covers wide variation in obsessive-compulsive (OC) traits, and to evaluate its psychometric properties in a community-based pediatric sample. Method The TOCS was completed for 16,718 children and adolescents between the ages of 6 and 17 years in a community setting. Internal consistency, convergent validity with the Obsessive-Compulsive Scale of the Child Behaviour Checklist (CBCL-OCS), divergent validity with the Strengths and Weaknesses of ADHD (Attention-Deficit/Hyperactivity Disorder) Symptoms and Normal Behaviour Rating Scale (SWAN), interrater reliability, as well as sensitivity and specificity of the TOCS were assessed. Results The internal consistency of the 21 TOCS items was excellent (Cronbach’s α = 0.94). TOCS was moderately correlated with the CBCL-OCS (Spearman correlation = 0.51) and poorly correlated with the SWAN (Pearson correlation = 0.02). Sensitivity and specificity analyses indicated that a TOCS total score of greater than 0 successfully discriminated community-reported obsessive-compulsive disorder (OCD) cases from noncases. OC traits were continuously distributed both at the total score and dimensional level in our pediatric community sample. Conclusion TOCS is a multidimensional measure of OC traits in children and adolescents with sound psychometric properties. TOCS reveals that OC traits are common and continuously distributed in a community sample. TOCS may be a useful measure for studies of the characteristics and etiology of OC traits.