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1. The genetic architecture of youth anxiety: a study protocol

Author: Laina McAusland, Christie L. Burton, Alexa Bagnell, Khrista Boylan, Taylor Hatchard, Patricia Lingley-Pottie, Abdullah Al Maruf, Patrick McGrath, Amanda S. Newton, Karen Rowa, Russell J. Schachar, S-M Shaheen, Sam Stewart, Paul D. Arnold, Jennifer Crosbie, Manuel Mattheisen, Noam Soreni, S. Evelyn Stewart, and Sandra Meier
Subjects: Genetics, Anxiety disorders, Child & adolescent psychiatry, Psychiatry, RC435-571
Abstract: Abstract Background Anxiety disorders are the most common psychiatric problems among Canadian youth and typically have an onset in childhood or adolescence. They are characterized by high rates of relapse and chronicity, often resulting in substantial impairment across the lifespan. Genetic factors play an important role in the vulnerability toward anxiety disorders. However, genetic contribution to anxiety in youth is not well understood and can change across developmental stages. Large-scale genetic studies of youth are needed with detailed assessments of symptoms of anxiety disorders and their major comorbidities to inform early intervention or preventative strategies and suggest novel targets for therapeutics and personalization of care. Methods The Genetic Architecture of Youth Anxiety (GAYA) study is a Pan-Canadian effort of clinical and genetic experts with specific recruitment sites in Calgary, Halifax, Hamilton, Toronto, and Vancouver. Youth aged 10–19 (n = 13,000) will be recruited from both clinical and community settings and will provide saliva samples, complete online questionnaires on demographics, symptoms of mental health concerns, and behavioural inhibition, and complete neurocognitive tasks. A subset of youth will be offered access to a self-managed Internet-based cognitive behavioral therapy resource. Analyses will focus on the identification of novel genetic risk loci for anxiety disorders in youth and assess how much of the genetic risk for anxiety disorders is unique or shared across the life span. Discussion Results will substantially inform early intervention or preventative strategies and suggest novel targets for therapeutics and personalization of care. Given that the GAYA study will be the biggest genomic study of anxiety disorders in youth in Canada, this project will further foster collaborations nationally and across the world.
Published: 2024
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2. The role of parenting practices in parent and child mental health over time

Author: Katherine T. Cost, Piyumi Mudiyanselage, Eva Unternaehrer, Daphne J. Korczak, Jennifer Crosbie, Evdokia Anagnastou, Suneeta Monga, Elizabeth Kelley, Russell Schachar, Jonathon Maguire, Paul Arnold, Christie L. Burton, Stelios Georgiades, Rob Nicolson, Catherine S. Birken, and Alice Charach
Subjects: Carers, out-patient treatment, psychosocial interventions, childhood experience, shared parenting, Psychiatry, RC435-571
Abstract: Background Parent and child mental health has suffered during the pandemic and transition phase. Structured and shared parenting may be intervention targets beneficial to families who are struggling with parent or child mental health challenges. Aims First, we investigated associations between structured and shared parenting and parent depression symptoms. Second, we investigated associations between structured and shared parenting and depression, hyperactivity/inattention and irritability symptoms in children. Method A total of 1027 parents in two-parent households (4797 observations total; 85.1% mothers) completed online surveys about themselves and their children (aged 2–18 years) from April 2020 to July 2022. Structured parenting and shared parenting responsibilities were assessed from April 2020 to November 2021. Symptoms of parent depression, child depression, child hyperactivity and inattention, child irritability, and child emotional and conduct problems were assessed repeatedly (one to 14 times; median of four times) from April 2020 to July 2022. Results Parents who reported higher levels of shared parenting responsibilities had lower depression symptoms (β = −0.09 to −0.32, all P < 0.01) longitudinally. Parents who reported higher levels of shared parenting responsibilities had children with fewer emotional problems (ages 2–5 years; β = −0.07, P < 0.05), fewer conduct problems (ages 2–5 years; β = −0.09, P < 0.01) and less irritability (ages 13–18 years; β = −0.27, P < 0.001) longitudinally. Structured parenting was associated with fewer conduct problems (ages 2–5 years; β = −0.05, P < 0.05). Conclusions Shared parenting is beneficial for parent and child mental health, even under chaotic or inflexible life conditions. Structured parenting is beneficial for younger children.
Published: 2023
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3. Meta-analysis of genome-wide association studies of hoarding symptoms in 27,537 individuals

Author: Nora I. Strom, Dirk J. A. Smit, Talisa Silzer, Conrad Iyegbe, Christie L. Burton, René Pool, Mathieu Lemire, James J. Crowley, Jouke-Jan Hottenga, Volen Z. Ivanov, Henrik Larsson, Paul Lichtenstein, Patrik Magnusson, Christian Rück, Russell J. Schachar, Hei Man Wu, Sandra M. Meier, Jennifer Crosbie, Paul D. Arnold, Manuel Mattheisen, Dorret I. Boomsma, David Mataix-Cols, and Danielle Cath
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Abstract 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 = 27,537 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.
Published: 2022
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4. Hyperfocus or flow? Attentional strengths in autism spectrum disorder

Author: Annie Dupuis, Piyumi Mudiyanselage, Christie L. Burton, Paul D. Arnold, Jennifer Crosbie, and Russell J. Schachar
Subjects: autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), impairment, attention, strengths, hyperfocus, Psychiatry, RC435-571
Abstract: 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.
Published: 2022
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5. Participating in extracurricular activities and school sports during the COVID-19 pandemic: Associations with child and youth mental health

Author: Kaitlyn LaForge-MacKenzie, Katherine Tombeau Cost, Kimberley C. Tsujimoto, Jennifer Crosbie, Alice Charach, Evdokia Anagnostou, Catherine S. Birken, Suneeta Monga, Elizabeth Kelley, Christie L. Burton, Robert Nicolson, Stelios Georgiades, and Daphne J. Korczak
Subjects: extracurricular activities, school sports, children and youth, mental health, COVID-19 pandemic, Sports, GV557-1198.995
Abstract: In Ontario, Canada, school extracurricular activities and sports were modified or canceled for a prolonged period due to public health restrictions resulting from the COVID-19 pandemic. The present study aims to examine the association of changes to extracurricular and sport participation and child and youth mental health. Data were collected on child and youth mental health symptoms (n = 908) and participation in extracurricular activities and sports in the 2019–2020 and 2020–2021 academic years. Results indicated that pre-COVID (2019–2020) participation in either extracurricular activities or sports was associated with reduced anxiety, inattention, and hyperactivity during the pandemic (β range −0.08 to −0.11, p < 0.05). Participation in either extracurricular activities or sports during-COVID (2020–2021) was associated with lower depressive symptoms (β range −0.09 to −0.10, p < 0.05). Findings suggest that participation in extracurricular activities and/or school sports both before or during the COVID-19 pandemic were associated with better mental health outcomes in children and youth. Implications of this work consider future situations where restrictions on extracurricular and sport participation are reinstated and the impact of child and youth mental health.
Published: 2022
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6. Genome-wide association study of pediatric obsessive-compulsive traits: shared genetic risk between traits and disorder

Author: Christie L. Burton, Mathieu Lemire, Bowei Xiao, Elizabeth C. Corfield, Lauren Erdman, Janita Bralten, Geert Poelmans, Dongmei Yu, S.-M. Shaheen, Tara Goodale, Vanessa M. Sinopoli, OCD Working Group of the Psychiatric Genomics Consortium, Noam Soreni, Gregory L. Hanna, Kate D. Fitzgerald, David Rosenberg, Gerald Nestadt, Andrew D. Paterson, Lisa J. Strug, Russell J. Schachar, Jennifer Crosbie, and Paul D. Arnold
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Abstract Using a novel trait-based measure, we examined genetic variants associated with obsessive-compulsive (OC) traits and tested whether OC traits and obsessive-compulsive disorder (OCD) shared genetic risk. We conducted a genome-wide association analysis (GWAS) of OC traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community (Spit for Science sample). We tested the hypothesis that genetic variants associated with OC traits from the community would be associated with clinical OCD using a meta-analysis of all currently available OCD cases. Shared genetic risk was examined between OC traits and OCD in the respective samples using polygenic risk score and genetic correlation analyses. A locus tagged by rs7856850 in an intron of PTPRD (protein tyrosine phosphatase δ) was significantly associated with OC traits at the genome-wide significance level (p = 2.48 × 10−8). rs7856850 was also associated with OCD in a meta-analysis of OCD case/control genome-wide datasets (p = 0.0069). The direction of effect was the same as in the community sample. Polygenic risk scores from OC traits were significantly associated with OCD in case/control datasets and vice versa (p’s
Published: 2021
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7. Obsessive-compulsive disorder and attention-deficit/hyperactivity disorder: distinct associations with DNA methylation and genetic variation

Author: Sarah J. Goodman, Christie L. Burton, Darci T. Butcher, Michelle T. Siu, Mathieu Lemire, Eric Chater-Diehl, Andrei L. Turinsky, Michael Brudno, Noam Soreni, David Rosenberg, Kate D. Fitzgerald, Gregory L. Hanna, Evdokia Anagnostou, Paul D. Arnold, Jennifer Crosbie, Russell Schachar, and Rosanna Weksberg
Subjects: DNA methylation, Epigenetics, OCD, ADHD, Biomarker, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Abstract Background A growing body of research has demonstrated associations between specific neurodevelopmental disorders and variation in DNA methylation (DNAm), implicating this molecular mark as a possible contributor to the molecular etiology of these disorders and/or as a novel disease biomarker. Furthermore, genetic risk variants of neurodevelopmental disorders have been found to be enriched at loci associated with DNAm patterns, referred to as methylation quantitative trait loci (mQTLs). Methods We conducted two epigenome-wide association studies in individuals with attention-deficit/hyperactivity disorder (ADHD) or obsessive-compulsive disorder (OCD) (aged 4–18 years) using DNA extracted from saliva. DNAm data generated on the Illumina Human Methylation 450 K array were used to examine the interaction between genetic variation and DNAm patterns associated with these disorders. Results Using linear regression followed by principal component analysis, individuals with the most endorsed symptoms of ADHD or OCD were found to have significantly more distinct DNAm patterns from controls, as compared to all cases. This suggested that the phenotypic heterogeneity of these disorders is reflected in altered DNAm at specific sites. Further investigations of the DNAm sites associated with each disorder revealed that despite little overlap of these DNAm sites across the two disorders, both disorders were significantly enriched for mQTLs within our sample. Conclusions Our DNAm data provide insights into the regulatory changes associated with genetic variation, highlighting their potential utility both in directing GWAS and in elucidating the pathophysiology of neurodevelopmental disorders.
Published: 2020
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8. Clinical validation of the parent‐report Toronto Obsessive–Compulsive Scale (TOCS): A pediatric open‐source rating scale

Author: Laura J. Lambe, Christie L. Burton, Evdokia Anagnostou, Elizabeth Kelley, Robert Nicolson, Stelios Georgiades, Noam Soreni, Russell J. Schachar, Gregory L. Hanna, Paul D. Arnold, and Jennifer Crosbie
Subjects: cross‐disorder phenotyping, neurodevelopmental disorders, obsessive–compulsive disorder, obsessive–compulsive traits, ROC analysis, scale development, Pediatrics, RJ1-570, Psychiatry, RC435-571
Abstract: Abstract Background There is a need to develop a multipurpose obsessive–compulsive disorder (OCD) measure that is useful for cross disorder research and as a reliable clinical rating scale. The current study examined the psychometric properties and established clinical cutoffs for the parent‐report version of the Toronto Obsessive–Compulsive Scale (TOCS), a 21‐item rating scale of obsessive–compulsive traits. Method Participants ranged in age from 6 to 21 years old and had a primary diagnosis of OCD (n = 350, 50% female), attention‐deficit/hyperactivity disorder (ADHD) (n = 820, 25% female), autism spectrum disorder (ASD) (n = 794, 22% female), or were typically developing controls (n = 391, 51% female). Confirmatory factor analyses, internal consistency reliability, and convergent and divergent validity of the TOCS were examined in the OCD group. Using various scoring approaches, receiver operating characteristic (ROC) analyses were used to establish a clinical cut‐off by splitting the OCD group into a discovery sample (166 OCD cases, 164 controls) and a validation sample (184 OCD cases, 227 controls). Classification accuracy and TOCS scores were compared across OCD, ADHD, and ASD groups. Results The psychometric properties of the TOCS were confirmed. ROC analyses across TOCS scoring approaches in the discovery sample indicated excellent diagnostic discrimination (AUC ≥0.95, sensitivity 77%–92%, specificity 92%–98%). Established cutoffs, when applied in the independent validation sample of OCD cases and controls, showed an overall classification accuracy of 85%–90%. The TOCS total score and symptom count showed good discrimination of OCD from ADHD (AUC ≥0.86) and ASD (AUC ≥0.81). The OCD group scored significantly higher on all TOCS dimensions (except Hoarding) than the ADHD and ASD groups. Conclusion The TOCS is a reliable and valid rating scale with strong sensitivity and specificity in discriminating OCD cases from controls, as well as from ASD and ADHD. It is a quantitative OCD measure with important clinical and research applications, with particular relevance for cross disorder phenotyping and population‐based studies.
Published: 2021
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9. Correction: Meta-analysis of genome-wide association studies of hoarding symptoms in 27,537 individuals

Author: Nora I. Strom, Dirk J. A. Smit, Talisa Silzer, Conrad Iyegbe, Christie L. Burton, René Pool, Mathieu Lemire, James J. Crowley, Jouke-Jan Hottenga, Volen Z. Ivanov, Henrik Larsson, Paul Lichtenstein, Patrik Magnusson, Christian Rück, Russell J. Schachar, Hei Man Wu, Sandra M. Meier, Jennifer Crosbie, Paul D. Arnold, Manuel Mattheisen, Dorret I. Boomsma, David Mataix-Cols, and Danielle Cath
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Published: 2022
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10. Characterization of mice bearing humanized androgen receptor genes (h/mAr) varying in polymorphism length

Author: Zsuzsa Lindenmaier, Yohan Yee, Adrienne Kinman, Darren Fernandes, Jacob Ellegood, Christie L. Burton, Diane M. Robins, Armin Raznahan, Paul Arnold, and Jason P. Lerch
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: The androgen receptor (AR) is known for masculinization of behavior and brain. To better understand the role that AR plays, mice bearing humanized Ar genes with varying lengths of a polymorphic N-terminal glutamine (Q) tract were created (Albertelli et al., 2006). The length of the Q tract is inversely proporitional to AR activity. Biological studies of the Q tract length may also provide a window into potential AR contributions to sex-biases in disease risk. Here we take a multi-pronged approach to characterizing AR signaling effects on brain and behavior in mice using the humanized Ar Q tract model. We first map effects of Q tract length on regional brain anatomy, and consider if these are modified by gonadal sex. We then test the notion that spatial patterns of anatomical variation related to Q tract length could be organized by intrinsic spatiotemporal patterning of AR gene expression in the mouse brain. Finally, we test influences of Q tract length on four behavioral tests.Altering Q tract length led to neuroanatomical differences in a non-linear dosage-dependent fashion. Gene expression analyses indicated that adult neu- roanatomical changes due to Q tract length are only associated with neurode- velopment (as opposed to adulthood). No significant effect of Q tract length was found on the behavior of the three mouse models. These results indicate that AR activity differentially mediates neuroanatomy and behavior, that AR activity alone does not mediate sex differences, and that neurodevelopmen- tal processes are associated with spatial patterns of volume changes due to Q tract length in adulthood. They also indicate that androgen sensitivity in adulthood is not likely to lead to autism-related behaviors or neuroanatomy, although neurodevelopmental processes may play a role earlier. Further study into sex differences, development, other behaviors, and other sex-specific mech- anisms are needed to better understand AR sensitivity, neurodevelopmental disorders, and the sex difference in their prevalence.
Published: 2021
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11. Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder: Shared or Unique Neurocognitive Profiles?

Author: Russell J. Schachar, Annie Dupuis, Paul D. Arnold, Evdokia Anagnostou, Elizabeth Kelley, Stelios Georgiades, Robert Nicolson, Parker Townes, Christie L. Burton, and Jennifer Crosbie
Subjects: Psychiatry and Mental health, Attention Deficit Disorder with Hyperactivity, Autism Spectrum Disorder, Reaction Time, Developmental and Educational Psychology, Humans, Attention, Comorbidity
Abstract: 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.
Published: 2022
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12. Gene copy number variation and pediatric mental health/neurodevelopment in a general population

Author: Mehdi Zarrei, Christie L Burton, Worrawat Engchuan, Edward J Higginbotham, John Wei, Sabah Shaikh, Nicole M Roslin, Jeffrey R MacDonald, Giovanna Pellecchia, Thomas Nalpathamkalam, Sylvia Lamoureux, Roozbeh Manshaei, Jennifer Howe, Brett Trost, Bhooma Thiruvahindrapuram, Christian R Marshall, Ryan K C Yuen, Richard F Wintle, Lisa J Strug, Dimitri J Stavropoulos, Jacob A S Vorstman, Paul Arnold, Daniele Merico, Marc Woodbury-Smith, Jennifer Crosbie, Russell J Schachar, and Stephen W Scherer
Subjects: Genetics, General Medicine, Molecular Biology, Genetics (clinical)
Abstract: We assessed the relationship of gene copy number variation (CNV) in mental health/neurodevelopmental traits and diagnoses, physical health and cognition in a community sample of 7100 unrelated children and youth of European or East Asian ancestry (Spit for Science). Clinically significant or susceptibility CNVs were present in 3.9% of participants and were associated with elevated scores on a continuous measure of attention-deficit/hyperactivity disorder (ADHD) traits (P = 5.0 × 10−3), longer response inhibition (a cognitive deficit found in several mental health and neurodevelopmental disorders; P = 1.0 × 10−2) and increased prevalence of mental health diagnoses (P = 1.9 × 10−6, odds ratio: 3.09), specifically ADHD, autism spectrum disorder anxiety and learning problems/learning disorder (P’s
Published: 2023
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13. Investigating executive functions in youth with OCD and hoarding symptoms

Author: James MacKillop, Jennifer Crosbie, Geoffrey B. Hall, Duncan H. Cameron, Melissa Elgie, Randi E. McCabe, Noam Soreni, Christie L. Burton, and Karen Rowa
Subjects: Adult, Obsessive-Compulsive Disorder, Adolescent, Perseveration, Cognitive flexibility, Hoarding, Executive functions, Executive Function, Psychiatry and Mental health, Clinical Psychology, Inhibitory control, medicine, Humans, Pshychiatric Mental Health, medicine.symptom, Child, Psychology, Clinical psychology
Abstract: 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.
Published: 2021
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14. Obsessive‐compulsive disorder in children and youth: neurocognitive function in clinic and community samples

Author: Paul D. Arnold, Annie Dupuis, Christie L. Burton, Jennifer Crosbie, Russell Schachar, Stelios Georgiades, Evdokia Anagnostou, and Noam Soreni
Subjects: Obsessive-Compulsive Disorder, Adolescent, Comorbidity, behavioral disciplines and activities, 03 medical and health sciences, Typically developing, 0302 clinical medicine, Group differences, Obsessive compulsive, mental disorders, Reaction Time, Developmental and Educational Psychology, medicine, Humans, Attention, Child, Response inhibition, Error processing, medicine.disease, humanities, 030227 psychiatry, Psychiatry and Mental health, Phenotype, Pediatrics, Perinatology and Child Health, Performance monitoring, Psychology, Neurocognitive, 030217 neurology & neurosurgery, Clinical psychology
Abstract: 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.
Published: 2021
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15. Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33 943 individuals from the general population

Author: Nora I. Strom, Christie L. Burton, Conrad Iyegbe, Talisa Silzer, Lilit Antonyan, René Pool, Mathieu Lemire, James J. Crowley, Jouke-Jan Hottenga, Volen Z. Ivanov, Henrik Larsson, Paul Lichtenstein, Patrik Magnusson, Christian Rück, Russell Schachar, Hei Man Wu, Danielle Cath, Jennifer Crosbie, David Mataix-Cols, Dorret I. Boomsma, Manuel Mattheisen, Sandra M. Meier, Dirk J.A. Smit, and Paul D. Arnold
Abstract: While 1-2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (∼15-40%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (GWAS) meta-analysis of parent- or self-reported OCS to date (N = 33,943 with complete phenotypic and genome-wide data), combining the results from seven large-scale population-based cohorts from Sweden, the Netherlands, England, and Canada (including six twin cohorts and one cohort of unrelated individuals). We found no genome-wide significant associations on the SNP or gene-level, but a polygenic risk score (PRS) based on the OCD GWAS previously published by the Psychiatric Genetics Consortium (PGC-OCD) was significantly associated with OCS (Pfixed= 3.06 ×10−5). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (Ngenes= 28, Beta = 0.79, SE = 0.16, Pbon= 0.008). Expression of genes in this set is high at sites of insulin-mediated glucose disposal. Dysregulated insulin signaling in the etiology of OCS has been suggested by a previous study describing a genetic overlap of OCS with insulin signaling-related traits in children and adolescents. We report a SNP heritability of 4.1% (P = 0.0044) in the meta-analyzed GWAS, and heritability estimates based on the twin cohorts of 33% - 43%. Genetic correlation analysis showed that OCS were most strongly associated with OCD (rG= 0.72, p = 0.0007) among all tested psychiatric disorders (N = 11). Of all 97 tested phenotypes, 24 showed a significant genetic correlation with OCS, and 66 traits showed concordant directions of effect with OCS and OCD. OCS have a significant polygenic contribution and share genetic risk with diagnosed OCD, supporting the hypothesis that OCD represents the extreme end of widely distributed OCS in the population.
Published: 2022
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16. Gene copy number variation in pediatric mental illness in a general population

Author: Mehdi Zarrei, Christie L. Burton, Worrawat Engchuan, Edward J Higginbotham, John Wei, Sabah Shaikh, Nicole M. Roslin, Jeffrey R. MacDonald, Giovanna Pellecchia, Thomas Nalpathamkalam, Sylvia Lamoureux, Roozbeh Manshaei, Jennifer Howe, Brett Trost, Bhooma Thiruvahindrapuram, Christian R. Marshall, Ryan K.C. Yuen, Richard F. Wintle, Lisa J Strug, Dimitri J. Stavropoulos, Jacob A.S. Vorstman, Paul Arnold, Daniele Merico, Marc Woodbury-Smith, Jennifer Crosbie, Russell Schachar, and Stephen W. Scherer
Abstract: We assessed the relationship of gene copy number variation (CNV) in mental health/neurodevelopmental traits and diagnoses, physical health, and cognitive biomarkers in a community sample of 7,100 unrelated European, and East Asian children and youth (Spit for Science). Diagnoses of mental health disorders were found in 17.5% of participants and 27.6% scored in the highest 10% on either or both ADHD and OCD trait measures. Clinically relevant CNVs were present in 3.9% of participants and were associated with elevated scores on a continuous measure of ADHD (p=5.0×10−3), on a cognitive biomarker of mental health (response inhibition (p=1.0×10−2)), and on prevalence of mental disorders (p=1.9×10−6, odds ratio: 3.09). With a rise of mental illness, our data establishes a baseline for delineating genetic contributors in paediatric-onset conditions.One Sentence SummaryCopy number variation predicts neurodevelopmental and mental health phenotypes in the general population.
Published: 2022
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17. Genetics of obsessive-compulsive disorder

Author: Christie L. Burton, Julia Boberg, Katharina Bey, and Behrang Mahjani
Subjects: Multifactorial Inheritance, Obsessive-Compulsive Disorder, medicine.medical_specialty, Anorexia Nervosa, genetic epidemiology, Biology, behavioral disciplines and activities, Tourette syndrome, 03 medical and health sciences, 0302 clinical medicine, Molecular genetics, mental disorders, medicine, Humans, Applied Psychology, Genetic association, Genetics, Genetic diversity, Invited Review, medicine.disease, Twin study, humanities, 030227 psychiatry, Psychiatry and Mental health, Phenotype, Genetic epidemiology, Anorexia nervosa (differential diagnoses), obsessive-compulsive symptoms, molecular genetics, Twin Studies as Topic, 030217 neurology & neurosurgery, Pharmacogenetics, Tourette Syndrome
Abstract: 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.
Published: 2021
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18. Meta-Analysis of Genome-Wide Association Studies of Hoarding Symptoms in 27 537 Individuals

Author: Nora I. Strom, Dirk J.A. Smit, Talisa Silzer, Conrad Iyegbe, Christie L. Burton, René Pool, Mathieu Lemire, James J. Crowley, Jouke-Jan Hottenga, Volen Z. Ivanov, Henrik Larsson, Paul Lichtenstein, Patrik Magnusson, Christian Rück, Russell Schachar, Hei Man Wu, Sandra M. Meier, Jennifer Crosbie, Paul D. Arnold, Manuel Mattheisen, Dorret I. Boomsma, David Mataix-Cols, and Danielle Cath
Abstract: 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 = 27 537 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 found a significant contribution of common genetic factors to HS, as indicated by substantial SNP-based twin-heritability estimates ranging between 26% and 48% and a SNP-heritability of 11% for one 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.
Published: 2022
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19. 1.30 The Distinction Between Social Connectedness and Support When Examining Depression Among Children and Youth During the COVID-19 Pandemic

Author: Caroline Park, Kimberley C. Tsujimoto, Katherine T. Cost, Evdokia Anagnostou, Catherine S. Birken, Alice Charach, Suneeta Monga, Elizabeth Kelley, Rob Nicolson, Stelios Georgiadis, Christie L. Burton, Jennifer Crosbie, and Daphne J. Korczak
Subjects: Psychiatry and Mental health, Developmental and Educational Psychology
Published: 2022
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20. 3.52 Hyperfocus or Flow? Attentional Strengths in ASD

Author: Annie Dupuis, Piyumi K. Mudiyanselage, Christie L. Burton, Paul Arnold, Jennifer Crosbie, and Russell J. Schachar
Subjects: Psychiatry and Mental health, Developmental and Educational Psychology
Published: 2022
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21. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author: Gabriëlla A.M. Blokland, Jakob Grove, Chia-Yen Chen, Chris Cotsapas, Stuart Tobet, Robert Handa, David St Clair, Todd Lencz, Bryan J. Mowry, Sathish Periyasamy, Murray J. Cairns, Paul A. Tooney, Jing Qin Wu, Brian Kelly, George Kirov, Patrick F. Sullivan, Aiden Corvin, Brien P. Riley, Tõnu Esko, Lili Milani, Erik G. Jönsson, Aarno Palotie, Hannelore Ehrenreich, Martin Begemann, Agnes Steixner-Kumar, Pak C. Sham, Nakao Iwata, Daniel R. Weinberger, Pablo V. Gejman, Alan R. Sanders, Joseph D. Buxbaum, Dan Rujescu, Ina Giegling, Bettina Konte, Annette M. Hartmann, Elvira Bramon, Robin M. Murray, Michele T. Pato, Jimmy Lee, Ingrid Melle, Espen Molden, Roel A. Ophoff, Andrew McQuillin, Nicholas J. Bass, Rolf Adolfsson, Anil K. Malhotra, Nicholas G. Martin, Janice M. Fullerton, Philip B. Mitchell, Peter R. Schofield, Andreas J. Forstner, Franziska Degenhardt, Sabrina Schaupp, Ashley L. Comes, Manolis Kogevinas, José Guzman-Parra, Andreas Reif, Fabian Streit, Lea Sirignano, Sven Cichon, Maria Grigoroiu-Serbanescu, Joanna Hauser, Jolanta Lissowska, Fermin Mayoral, Bertram Müller-Myhsok, Beata Świątkowska, Thomas G. Schulze, Markus M. Nöthen, Marcella Rietschel, John Kelsoe, Marion Leboyer, Stéphane Jamain, Bruno Etain, Frank Bellivier, John B. Vincent, Martin Alda, Claire O’Donovan, Pablo Cervantes, Joanna M. Biernacka, Mark Frye, Susan L. McElroy, Laura J. Scott, Eli A. Stahl, Mikael Landén, Marian L. Hamshere, Olav B. Smeland, Srdjan Djurovic, Arne E. Vaaler, Ole A. Andreassen, Bernhard T. Baune, Tracy Air, Martin Preisig, Rudolf Uher, Douglas F. Levinson, Myrna M. Weissman, James B. Potash, Jianxin Shi, James A. Knowles, Roy H. Perlis, Susanne Lucae, Dorret I. Boomsma, Brenda W.J.H. Penninx, Jouke-Jan Hottenga, Eco J.C. de Geus, Gonneke Willemsen, Yuri Milaneschi, Henning Tiemeier, Hans J. Grabe, Alexander Teumer, Sandra Van der Auwera, Uwe Völker, Steven P. Hamilton, Patrik K.E. Magnusson, Alexander Viktorin, Divya Mehta, Niamh Mullins, Mark J. Adams, Gerome Breen, Andrew M. McIntosh, Cathryn M. Lewis, David M. Hougaard, Merete Nordentoft, Ole Mors, Preben B. Mortensen, Thomas Werge, Thomas D. Als, Anders D. Børglum, Tracey L. Petryshen, Jordan W. Smoller, Jill M. Goldstein, Stephan Ripke, Benjamin M. Neale, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Sandra Meier, Carin J. Meijer, Bela Melegh, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Vihra Milanova, Younes Mokrab, Derek W. Morris, Kieran C. Murphy, Inez Myin-Germeys, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Ulrich Schall, Christian R. Schubert, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Hon-Cheong So, Chris C.A. Spencer, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Douglas H.R. Blackwood, Ariel Darvasi, Enrico Domenici, Michael Gill, Hugh Gurling, Christina M. Hultman, Assen V. Jablensky, Kenneth S. Kendler, Jo Knight, Qingqin S. Li, Jianjun Liu, Steven A. McCarroll, Jennifer L. Moran, Michael J. Owen, Carlos N. Pato, Danielle Posthuma, Pamela Sklar, Jens R. Wendland, Mark J. Daly, Michael C. O’Donovan, Peter Donnelly, Ines Barroso, Jenefer M. Blackwell, Matthew A. Brown, Juan P. Casas, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Gavin Band, Céline Bellenguez, Colin Freeman, Eleni Giannoulatou, Garrett Hellenthal, Richard Pearson, Matti Pirinen, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Sarah Edkins, Matthew Gillman, Emma Gray, Rhian Gwilliam, Naomi Hammond, Sarah E. Hunt, Alagurevathi Jayakumar, Jennifer Liddle, Owen T. McCann, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew Waller, Paul Weston, Pamela Whittaker, Sara Widaa, Mark I. McCarthy, Maria J. Arranz, Steven Bakker, Stephan Bender, Benedicto Crespo-Facorro, Jeremy Hall, Conrad Iyegbe, Stephen Lawrie, Kuang Lin, Don H. Linszen, Ignacio Mata, Muriel Walshe, Matthias Weisbrod, Durk Wiersma, Vassily Trubetskoy, Yunpeng Wang, Jonathan R.I. Coleman, Héléna A. Gaspar, Christiaan A. de Leeuw, Jennifer M. Whitehead Pavlides, Maciej Trzaskowski, Enda M. Byrne, Liam Abbott, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, Miquel Casas, Felecia Cerrato, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W. Craig, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Jurgen Del-Favero, J. Raymond DePaulo, Amanda L. Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Christine Fraser, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Weihua Guan, Martin Hautzinger, Urs Heilbronner, Maria Hipolito, Dominic Holland, Laura Huckins, Jessica S. Johnson, Radhika Kandaswamy, Robert Karlsson, Sarah Kittel-Schneider, Anna C. Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Chunyu Liu, Anna Maaser, Donald J. MacIntyre, Pamela B. Mahon, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Fan Meng, Grant W. Montgomery, Thomas W. Mühleisen, Hoang Nguyen, Caroline M. Nievergelt, Annelie Nordin Adolfsson, Evaristus A. Nwulia, Claire O'Donovan, Loes M. Olde Loohuis, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Amy Perry, Andrea Pfennig, Eline J. Regeer, Céline S. Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Nicholas J. Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Christine Søholm Hansen, Anne T. Spijker, Michael Steffens, John S. Strauss, Szabolcs Szelinger, Robert C. Thompson, Thorgeir E. Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J. Watson, Thomas W. Weickert, Simon Xi, Wei Xu, Allan H. Young, Peter Zandi, Peng Zhang, Sebastian Zöllner, Abdel Abdellaoui, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Fernando S. Goes, Lynsey S. Hall, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Christel M. Middeldorp, Evelin Mihailov, Francis M. Mondimore, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O'Reilly, Hogni Oskarsson, Jodie N. Painter, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Katherine E. Tansey, Henning Teismann, Wesley Thompson, Pippa A. Thomson, Matthew Traylor, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Shantel Marie Weinsheimer, Jürgen Wellmann, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Klaus Berger, Udo Dannlowski, Katharina Domschke, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Pamela AF. Madden, Patrik K. Magnusson, Preben Bo Mortensen, Michael C. O'Donovan, Sara A. Paciga, Nancy L. Pedersen, David J. Porteous, Catherine Schaefer, Henry Völzke, Marco Bortolato, Janita Bralten, Cynthia M. Bulik, Christie L. Burton, Caitlin E. Carey, Lea K. Davis, Laramie E. Duncan, Howard J. Edenberg, Lauren Erdman, Stephen V. Faraone, Slavina B. Goleva, Wei Guo, Christopher Hübel, Laura M. Huckins, Ekaterina A. Khramtsova, Joanna Martin, Carol A. Mathews, Elise Robinson, Eli Stahl, Barbara E. Stranger, Michela Traglia, Raymond K. Walters, Lauren A. Weiss, Stacey J. Winham, Yin Yao, Kristjar Skajaa, Markus Nöthen, Michael Owen, Robert H. Yolken, Niels Plath, Jonathan Mill, Daniel Geschwind, Psychiatry 1, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Functional Genomics, Biological Psychology, APH - Mental Health, APH - Methodology, Sociology and Social Gerontology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Blokland, Gabriella AM, Grove, Jakob, Chen, Chia Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, Lee, Sang Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, ANS - Complex Trait Genetics, and ANS - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: 0301 basic medicine, Male, Bipolar Disorder, Schizophrenia/genetics, LD SCORE REGRESSION, Genome-wide association study, 0302 clinical medicine, Receptors, SCHIZOPHRENIA, Psychotic Disorders/genetics, KYNURENINE PATHWAY METABOLISM, Genetics, RISK, Sex Characteristics, Vascular Endothelial Growth Factor, Bipolar Disorder/genetics, Major/genetics, Single Nucleotide, AFFECTIVE STIMULI IMPACT, Schizophrenia, Sulfurtransferases, Major depressive disorder, Female, Depressive Disorder, Major/genetics, Bipolar disorder, Locus (genetics), Genomics, Biology, Polymorphism, Single Nucleotide, Article, DYSPHORIC MOOD, 03 medical and health sciences, Sex differences, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Genotype-by-sex interaction, Biological Psychiatry, Depressive Disorder, Major, Depressive Disorder, GENDER-DIFFERENCES, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], PARAVENTRICULAR NUCLEUS, 3112 Neurosciences, Endothelial Cells, MAJOR DEPRESSION, medicine.disease, Genetic architecture, 030104 developmental biology, Mood, Receptors, Vascular Endothelial Growth Factor, Psychotic Disorders, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
Published: 2022
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22. Vulnerability pathways to mental health outcomes in children and parents during COVID-19

Author: Alice Charach, Suneeta Monga, Elizabeth Kelley, Daphne J. Korczak, Rob Nicolson, Jala Rizeq, Jennifer Crosbie, Katherine Tombeau Cost, Christie L. Burton, Evdokia Anagnostou, and Catherine S Birken
Subjects: Deprivation, Coronavirus disease 2019 (COVID-19), Family functioning, Vulnerability, Risk factor (computing), Stress, Mental health, Article, Structural equation modeling, Psychology, Psychosocial, Socioeconomic status, General Psychology, Clinical psychology
Abstract: We examined pathways from pre-existing psychosocial and economic vulnerability to mental health difficulties and stress in families during the COVID-19 pandemic. Data from two time points from a multi-cohort study initiated during the COVID-19 pandemic were used. Parents of children 6–18 years completed questionnaires on pre-COVID-19 socioeconomic and demographic factors in addition to material deprivation and stress due to COVID-19 restrictions, mental health, and family functioning. Youth 10 years and older also completed their own measures of mental health and stress. Using structural equation modelling, pathways from pre-existing vulnerability to material deprivation and stress due to COVID-19 restrictions, mental health, and family functioning, including reciprocal pathways, were estimated. Pre-existing psychosocial and economic vulnerability predicted higher material deprivation due to COVID-19 restrictions which in turn was associated with parent and child stress due to restrictions and mental health difficulties. The reciprocal effects between increased child and parent stress and greater mental health difficulties at Time 1 and 2 were significant. Reciprocal effects between parent and child mental health were also significant. Finally, family functioning at Time 2 was negatively impacted by child and parent mental health and stress due to COVID-19 restrictions at Time 1. Psychosocial and economic vulnerability is a risk factor for material deprivation during COVID-19, increasing the risk of mental health difficulties and stress, and their reciprocal effects over time within families. Implications for prevention policy and parent and child mental health services are discussed. Supplementary Information The online version contains supplementary material available at 10.1007/s12144-021-02459-z.
Published: 2021
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23. Insights into attention-deficit/hyperactivity disorder from recent genetic studies

Author: Isabell Brikell, Nina Roth Mota, Joanna Martin, and Christie L. Burton
Subjects: Multifactorial Inheritance, Population, Genome-wide association study, Biology, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Risk Factors, mental disorders, medicine, Attention deficit hyperactivity disorder, Humans, ADHD, GWAS, genetics, Allele, education, Molecular Biology, Applied Psychology, education.field_of_study, medicine.disease, Precision medicine, Twin study, Genetic architecture, 030227 psychiatry, 3. Good health, Psychiatry and Mental health, Phenotype, twin studies, Evolutionary biology, Attention Deficit Disorder with Hyperactivity, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: 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.
Published: 2021
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24. Genome-wide association study identifies new locus associated with OCD

Author: Danielle Posthuma, Bernie Devlin, Edna Grünblatt, Ying Wang, Daniele Cusi, Stephan Ruhrmann, Steven A. Rasmussen, Michael S. Breen, Julia Klawohn, Ana Gabriela Hounie, Aline S. Sampaio, Cristina Barlassina, Marta Ribasés, Jackson G. Thorp, Cynthia M. Bulik, Marco A. Grados, Dan J. Stein, Abby Fyer, Vladimir Coric, Martha J. Falkenstein, Stephanie Le Hellard, Behrang Mahjani, Nathaniel McGregor, Homero Vallada, Miguel Casas, Laurent F. Thomas, Janice Krasnow, Abraham Reichenberg, Donald W. Black, Gwyneth Zai, Norbert Kathmann, Manuel Mattheisen, Nicholas G. Martin, Jason W. Krompinger, Josep Antoni Ramos-Quiroga, Judith Becker Nissen, Helga Ask, Damiaan Denys, Carolina Cappi, Euripedes Constantino Miguel, O. Joseph Bienvenu, Bengt T. Fundin, Lisa Osiecki, Karin J. H. Verweij, Paul Sandor, Jeremy Veenstra-VanderWeele, Maureen Mulhern, Sarah E. Medland, David M. Hougaard, Lauren Erdman, Jan Haavik, James L. Kennedy, Christopher P. Walker, Jurjen J. Luykx, Tim B. Bigdeli, Ian M. Hickie, Nienke Vulink, Maurizio Turiel, Peter Falkai, Enda M. Byrne, Valentina Ciullo, Daniel A. Geller, Liang Kung-Yee, Miriam A. Schiele, Lambertus Klei, Götz Berberich, Thomas Werge, Brion S. Maher, Christie L. Burton, Julia M. Sealock, Sandra Meier, Bernadette Cullen, Stephan Ripke, Dorothy E. Grice, Richard Delorme, Ted Reichborn-Kjennerud, Dongmei Yu, Danielle C. Cath, Lili Milani, Abdel Abdellaoui, Andres Metspalu, María Soler Artigas, Maria Conceição do Rosário, Ole Mors, Brian P. Brennan, Barbara E. Stranger, Ann E. Pulver, Nora I. Strom, Joseph D. Buxbaum, Hans J. Grabe, Jens R. Wendland, Michael H. Bloch, Srdjan Djurovic, Raquel Rabionet, Angel Carracedo, Carlos N. Pato, Erika L. Nurmi, Janet L. Sobell, Kevin S. O’Connell, Michael Wagner, David R. Rosenberg, Jonathan R. I. Coleman, Jeremiah M. Scharf, Kerry J. Ressler, Jaakko Kaprio, Edwin H. Cook, Scott L. Rauch, Federica Piras, Merete Nordentoft, Christian Rück, Fabrizio Piras, John-Anker Zwart, Jason A. Elias, Christopher Pittenger, Lea K. Davis, Margaret A. Richter, Evonne McArthur, Bendik S. Winsvold, Yin Yao, James J. Crowley, David L. Pauls, Rosa Bosch, Xavier Estivil, Matthew Halvorsen, Adrian Camarena, Nancy L. Pedersen, Pino Alonso, Eric A. Storch, Bjarne Hansen, Helena Brentani, James T. McCracken, Jan Maerten Smit, Donald Hucks, Alexandra Havdahl, Gerome Breen, Christina M. Hultman, Benjamin M. Neale, Gregory L. Hanna, Mikael Landén, Christine Lochner, Dirk J.A. Smit, Fabio Macciardi, Carol A. Mathews, Nuria Lanzagorta, Laura G. Sloofman, Cristina Rodriguez-Fontenla, Michael A. Jenike, Michele T. Pato, Marion Leboyer, Humberto Nicolini, Anders D. Børglum, Maria Cristina Cavallini, Wei Guo, Benjamin D. Greenberg, Maiken Elvestad Gabrielsen, Magdalena Janecka, Mark A. Riddle, Paul S. Nestadt, Beatriz Camarena, Valsamma Eapen, Susanne Walitza, Jack Samuels, Fernando S. Goes, Nicole C.R. McLaughlin, S. Evelyn Stewart, Jennifer Reichert, Sven Sandin, Gerd Kvale, Katharina Domschke, Ole A. Andreassen, Elles de Schipper, Paul D. Arnold, Kristi Krebs, Zachary Gerring, Teemu Palviainen, Kathleen D. Askland, Alfredo Ramirez, James A. Knowles, Laura Bellodi, Kristen Hagen, Julia Boberg, Thomas V. Fernandez, Gerald Nestadt, John Piacentini, Jakob Grove, Eske M. Derks, Preben Bo Mortensen, Elinor K. Karlsson, Gianfranco Spalletta, David Mataix-Cols, Katharina Bey, and Jonas Bybjerg-Grauholm
Subjects: Genetics, business.industry, Locus (genetics), Genome-wide association study, Single-nucleotide polymorphism, Heritability, behavioral disciplines and activities, humanities, Genetic architecture, Anorexia nervosa (differential diagnoses), mental disorders, medicine, Anxiety, SNP, medicine.symptom, business
Abstract: Obsessive-compulsive disorder (OCD) is a heritable disorder, but no definitive, replicated OCD susceptibility loci have yet been identified by any genome-wide association study (GWAS). Here, we report results from a GWAS in the largest OCD case-control sample (N = 14,140 OCD cases and N = 562,117 controls) to date. We explored the genetic architecture of OCD, including its genetic relationships to other psychiatric and non-psychiatric phenotypes. In the GWAS analysis, we identified one SNP associated with OCD at a genome-wide significant level. Subsequent gene-based analyses identified additional two genes as potentially implicated in OCD pathogenesis. All SNPs combined explained 16% of the heritability of OCD. We show sub-stantial positive genetic correlations between OCD and a range of psychiatric disorders, including anxiety disorders, anorexia nervosa, and major depression. We thus for the first time provide evidence of a genome-wide locus implicated in OCD and strengthen previous literature suggesting a polygenic nature of this disorder.
Published: 2021
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25. Polygenic Risk and Neural Substrates of Attention-Deficit/Hyperactivity Disorder Symptoms in Youths With a History of Mild Traumatic Brain Injury

Author: Stephanie H. Ameis, M. Mallar Chakravarty, Russell Schachar, Christie L. Burton, Rutwik Bangali, Gabriel A. Devenyi, Peter Szatmari, Sonja Stojanovski, Lauren J. O'Donnell, Anne L. Wheeler, Saba Shahab, Daniel Felsky, Joseph D. Viviano, and Aristotle N. Voineskos
Subjects: Male, 0301 basic medicine, Multifactorial Inheritance, Genu of the corpus callosum, Adolescent, Traumatic brain injury, Neuroimaging, Corpus callosum, Severity of Illness Index, behavioral disciplines and activities, Article, Basal Ganglia, Corpus Callosum, Young Adult, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Genetic predisposition, Humans, Medicine, Attention deficit hyperactivity disorder, Medical history, Child, Brain Concussion, Biological Psychiatry, business.industry, Sequela, medicine.disease, White Matter, nervous system diseases, Diffusion Tensor Imaging, 030104 developmental biology, nervous system, Attention Deficit Disorder with Hyperactivity, Case-Control Studies, Anisotropy, Female, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract: Background Attention-deficit/hyperactivity disorder (ADHD) is a major sequela of traumatic brain injury (TBI) in youths. The objective of this study was to examine whether ADHD symptoms are differentially associated with genetic risk and brain structure in youths with and without a history of TBI. Methods Medical history, ADHD symptoms, genetic data, and neuroimaging data were obtained from a community sample of youths. ADHD symptom severity was compared between those with and without TBI (TBI n = 418, no TBI n = 3193). The relationship of TBI history, genetic vulnerability, brain structure, and ADHD symptoms was examined by assessing 1) ADHD polygenic score (discovery sample ADHD n = 19,099, control sample n = 34,194), 2) basal ganglia volumes, and 3) fractional anisotropy in the corpus callosum and corona radiata. Results Youths with TBI reported greater ADHD symptom severity compared with those without TBI. Polygenic score was positively associated with ADHD symptoms in youths without TBI but not in youths with TBI. The negative association between the caudate volume and ADHD symptoms was not moderated by a history of TBI. However, the relationship between ADHD symptoms and structure of the genu of the corpus callosum was negative in youths with TBI and positive in youths without TBI. Conclusions The identification of distinct ADHD etiology in youths with TBI provides neurobiological insight into the clinical heterogeneity in the disorder. Results indicate that genetic predisposition to ADHD does not increase the risk for ADHD symptoms associated with TBI. ADHD symptoms associated with TBI may be a result of a mechanical insult rather than neurodevelopmental factors.
Published: 2019
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26. 3.53 Validation of a Youth Self-Report and Parent-Report Version of the Autism Spectrum Quotient Questionnaire (AQ-28)

Author: Theodore C.K. Cheung, Annie Dupuis, Christie L. Burton, Russell J. Schachar, and Jennifer Crosbie
Subjects: Psychiatry and Mental health, Developmental and Educational Psychology
Published: 2022
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27. 1.56 Investigating Ethnic Disparities in Youth Mental Health Diagnoses Within a Large Canadian Community-Based Sample

Author: Andrew S. Dissanayake, Noam Soreni, Annie Dupuis, Amy Gajaria, Christie L. Burton, Jennifer Crosbie, and Russell J. Schachar
Subjects: Psychiatry and Mental health, Developmental and Educational Psychology
Published: 2022
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28. 22.1 Gene Copy Number Variation in Pediatric Mental Health

Author: Mehdi Zarrei and Christie L. Burton
Subjects: Psychiatry and Mental health, Developmental and Educational Psychology
Published: 2022
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29. 1.81 The Role of Structured Parenting and Shared Parenting Responsibilities in Parental Mental Health During the COVID-19 Pandemic

Author: Katherine T. Cost, Piyumi K. Mudiyanselage, Eva Unternaehrer, Evdokia Anagnostou, Paul Arnold, Christie L. Burton, Jennifer Crosbie, Stelios Georgiadis, Elizabeth Kelley, Daphne J. Korczak, Jonathon L. Maguire, Suneeta Monga, Rob Nicolson, Russell J. Schachar, Catherine S. Birken, and Alice Charach
Subjects: Psychiatry and Mental health, Developmental and Educational Psychology
Published: 2022
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30. Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits

Author: Joanna Martin, Ekaterina A. Khramtsova, Slavina B. Goleva, Gabriëlla A.M. Blokland, Michela Traglia, Raymond K. Walters, Christopher Hübel, Jonathan R.I. Coleman, Gerome Breen, Anders D. Børglum, Ditte Demontis, Jakob Grove, Thomas Werge, Janita Bralten, Cynthia M. Bulik, Phil H. Lee, Carol A. Mathews, Roseann E. Peterson, Stacey J. Winham, Naomi Wray, Howard J. Edenberg, Wei Guo, Yin Yao, Benjamin M. Neale, Stephen V. Faraone, Tracey L. Petryshen, Lauren A. Weiss, Laramie E. Duncan, Jill M. Goldstein, Jordan W. Smoller, Barbara E. Stranger, Lea K. Davis, Martin Alda, Marco Bortolato, Christie L. Burton, Enda Byrne, Caitlin E. Carey, Lauren Erdman, Laura M. Huckins, Manuel Mattheisen, Elise Robinson, Eli Stahl, Psychiatrie & Neuropsychologie, and RS: MHeNs - R2 - Mental Health
Subjects: DISORDER, 0301 basic medicine, Male, Multifactorial Inheritance, Sex Differentiation, Evolution of sexual reproduction, Genome-wide association study, Medical and Health Sciences, Correlation, 0302 clinical medicine, GWAS, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, RISK, Psychiatry, Sex Characteristics, 0303 health sciences, Single Nucleotide, Biological Sciences, OVERLAP, Archival Report, Phenotype, Mental Health, DISEASES, Trait, Female, Biotechnology, Genetic correlation, Biology, BIOBANK, Polymorphism, Single Nucleotide, MECHANISMS, Heritability, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Sex differences, Genetics, Humans, SNP, GENOME-WIDE ASSOCIATION, Polymorphism, Gene, Biological Psychiatry, Behavioral, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Prevention, Human Genome, Psychology and Cognitive Sciences, Genetic architecture, 030104 developmental biology, Neurodevelopmental Disorders, Evolutionary biology, JACKKNIFE, Psychiatric, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: BackgroundThe origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations across these traits, we tested for a sex-differentiated genetic architecture within and between traits.MethodsUsing genome-wide association study (GWAS) summary statistics for 20 neuropsychiatric and behavioral traits, we tested for differences in SNP-based heritability (h2) and genetic correlation (rgResultsWith current sample sizes (and power), we found no significant, consistent sex differences in SNP-based h2. Between-sex, within-trait genetic correlations were consistently high, although significantly less than 1 for educational attainment and risk-taking behavior. We identified genome-wide significant genes with sex-differentiated effects for eight traits. Several trait pairs shared sex-differentiated effects. The top 0.1% of genes with sex-differentiated effects across traits overlapped with neuron- and synapse-related gene sets. Most between-trait genetic correlation estimates were similar across sex, with several exceptions (e.g. educational attainment & risk-taking behavior).ConclusionsSex differences in the common autosomal genetic architecture of neuropsychiatric and behavioral phenotypes are small and polygenic, requiring large sample sizes. Genes with sex-differentiated effects are enriched for neuron-related gene sets. This work motivates further investigation of genetic, as well as environmental, influences on sex differences.
Published: 2021
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31. 61. GENOME-WIDE ASSOCIATION STUDY OF OBSESSIVE-COMPULSIVE SYMPTOMS AND HOARDING SYMPTOMS IN THE GENERAL POPULATION

Author: Danielle C. Cath, Talisa Silzer, Jouke-Jan Hottenga, Dorret I. Boomsma, Mathieu Lemire, Sandra Meier, David Mataix-Cols, René Pool, Manuel Mattheisen, Conrad Iyegbe, Nora I. Strom, Christie L. Burton, Jennifer Crosbie, Paul D. Arnold, and Dirk J.A. Smit
Subjects: Pharmacology, medicine.medical_specialty, education.field_of_study, business.industry, Population, Hoarding, Genome-wide association study, Obsessive compulsive symptoms, Psychiatry and Mental health, Neurology, medicine, Pharmacology (medical), Neurology (clinical), Psychiatry, business, education, Biological Psychiatry
Published: 2021
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32. Characterization of mice bearing humanized androgen receptor genes (h/mAr) varying in polymorphism length

Author: Diane M. Robins, Yohan Yeea, Armin Raznahan, Adrienne Kinman, Darren J. Fernandes, Jacob Ellegood, Paul D. Arnold, Zsuzsa Lindenmaier, Christie L. Burton, and Jason P. Lerch
Subjects: Male, medicine.medical_specialty, Cognitive Neuroscience, Biology, 050105 experimental psychology, lcsh:RC321-571, 03 medical and health sciences, Mice, 0302 clinical medicine, Then test, Polymorphism (computer science), Internal medicine, Gene expression, medicine, Animals, Humans, 0501 psychology and cognitive sciences, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Gene, 030304 developmental biology, 0303 health sciences, Sex Characteristics, Polymorphism, Genetic, Behavior, Animal, 05 social sciences, Brain, Androgen sensitivity, Glutamine, Androgen receptor, Endocrinology, medicine.anatomical_structure, Neurology, Receptors, Androgen, Female, 030217 neurology & neurosurgery, Neuroanatomy
Abstract: The androgen receptor (AR) is known for masculinization of behavior and brain. To better understand the role that AR plays, mice bearing humanizedArgenes with varying lengths of a polymorphic N-terminal glutamine (Q) tract were created (Albertelli et al 2006). The length of the Q tract is inversely proporitional to AR activity. Biological studies of the Q tract length may also provide a window into potential AR contributions to sex-biases in disease risk.Here we take a multi-pronged approach to characterizing AR signaling effects on brain and behavior in mice using the humanizedArQ tract model. We first map effects of Q tract length on regional brain anatomy, and consider if these are modified by gonadal sex. We then test the notion that spatial patterns of anatomical variation related to Q tract length could be organized by intrinsic spatiotemporal patterning of AR gene expression in the mouse brain. Finally, we test influences of Q tract length on four behavioral tests.Altering Q tract length led to neuroanatomical differences in a non-linear dosage-dependent fashion. Gene expression analyses indicated that adult neuroanatomical changes due to Q tract length are only associated with neurodevelopment (as opposed to adulthood). No significant effect of Q tract length was found on the behavior of the three mouse models. These results indicate that AR activity differentially mediates neuroanatomy and behavior, that AR activity alone does not mediate sex differences, and that neurodevelopmental processes are associated with spatial patterns of volume changes due to Q tract length in adulthood. They also indicate that androgen sensitivity in adulthood does not directly lead to autism-related behaviors or neuroanatomy, although neurodevelopmental processes may play a role earlier. Further study into sex differences, development, other behaviors, and other sex-specific mechanisms are needed to better understand AR sensitivity, neurodevelopmental disorders, and the sex difference in their prevalence.
Published: 2020

33. Shared genetic etiology between obsessive-compulsive disorder, obsessive-compulsive symptoms in the population, and insulin signaling

Author: Ward De Witte, Jeremiah M. Scharf, Jan K. Buitelaar, Carol A. Mathews, Mathieu Lemire, Jennifer Crosbie, Janita Bralten, Russell Schachar, Dongmei Yu, Geert Poelmans, Paul D. Arnold, Barbara Franke, Christie L. Burton, and Joanna Widomska
Subjects: medicine.medical_specialty, Obsessive-Compulsive Disorder, Adolescent, medicine.medical_treatment, Population, Genome-wide association study, Type 2 diabetes, Comorbidity, behavioral disciplines and activities, Article, lcsh:RC321-571, Cohort Studies, Cellular and Molecular Neuroscience, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Epidemiology, mental disorders, medicine, Genetics, Humans, Insulin, education, Child, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, 030304 developmental biology, Genetic association, Psychiatric Status Rating Scales, 0303 health sciences, education.field_of_study, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Mechanism (biology), business.industry, medicine.disease, humanities, 3. Good health, Psychiatry and Mental health, Diabetes Mellitus, Type 2, Cohort, Etiology, business, Psychiatric disorders, 030217 neurology & neurosurgery, Clinical psychology, Genome-Wide Association Study
Abstract: 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.
Published: 2020

34. TH51. ASSOCIATIONS BETWEEN POLYGENIC SCORES FOR CORTICAL AND SUB-CORTICAL BRAIN STRUCTURES AND EXECUTIVE FUNCTION

Author: Jennifer Crosbie, Paul Arnold, Christie L. Burton, Talisa Silzer, Mathieu Lemire, and Russell Schachar
Subjects: Pharmacology, Psychiatry and Mental health, Neurology, Pharmacology (medical), Neurology (clinical), Function (mathematics), Biology, Neuroscience, Biological Psychiatry
Published: 2021
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35. TH38. TRANS-ANCESTRY GENOME WIDE ASSOCIATION STUDY OF EXECUTIVE FUNCTIONS IN UP TO 14,877 SUBJECTS

Author: Naomi P. Friedman, Jennifer Crosbie, Michael Mooney, Mark A. Bellgrove, Aurina Arnatkeviciute, Claire L Morrison, Russell Schachar, Christie L. Burton, Mathieu Lemire, and Joel T. Nigg
Subjects: Pharmacology, Genetics, Psychiatry and Mental health, Neurology, Pharmacology (medical), Genome-wide association study, Neurology (clinical), Biology, Executive functions, Biological Psychiatry
Published: 2021
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36. A review of the role of serotonin system genes in obsessive-compulsive disorder

Author: Christie L. Burton, Vanessa M. Sinopoli, Paul D. Arnold, and Sefi Kronenberg
Subjects: Obsessive-Compulsive Disorder, Serotonin, Candidate gene, rs6311, Rs6313, Cognitive Neuroscience, Bioinformatics, Neuropsychiatry, behavioral disciplines and activities, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, mental disorders, Animals, Humans, Genetic Predisposition to Disease, Serotonin transporter, Genetic association, biology, Genetic heterogeneity, humanities, 3. Good health, 030227 psychiatry, Neuropsychology and Physiological Psychology, 5-HTTLPR, biology.protein, Psychology, 030217 neurology & neurosurgery, Clinical psychology
Abstract: Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder that causes the patient to experience intrusive thoughts and/or to carry out repetitive, ritualized behaviors that are time consuming and impairing. OCD is familial and heritable. The genetic factors responsible for pathogenesis, however, remain largely unknown despite the numerous candidate gene studies conducted. Based on efficacy of serotonin reuptake inhibitors (SRIs) in treating OCD, serotonin system genes have been a dominant focus in OCD candidate gene studies. We review the most commonly studied candidate serotonin system gene variants (specifically in SLC6A4, HTR2A, HTR1B, and HTR2C) and their association with OCD. Although findings to date are mixed, serotonin transporter polymorphism 5-HTTLPR and HTR2A polymorphism rs6311 (or rs6313) are most consistently associated with OCD. Mixed findings may be the result of genetic complexity and phenotypic heterogeneity that future studies should account for. Homogenous patient subgroups reflecting OCD symptom dimensions, OCD subtypes, and sex should be used for gene discovery.
Published: 2017
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37. A large data resource of genomic copy number variation across neurodevelopmental disorders

Author: Tara Goodale, Wendy Roberts, Jason P. Lerch, Bridget A. Fernandez, Melissa T. Carter, Vorstman Jas, Flanagan J, Bhooma Thiruvahindrapuram, Lonnie Zwaigenbaum, Jennifer Crosbie, Paul D. Arnold, Christian R. Marshall, Drmic I, Muhammad Faheem, Rohan V. Patel, Russell Schachar, Jennifer L. Howe, Kozue Samler, Stephen W. Scherer, Lu C, Rob Nicolson, Janet A. Buchanan, Edward J Higginbotham, Tara Paton, Mayada Elsabbagh, Chan Ajs, Stelios Georgiades, Peter Szatmari, Cheryl Cytrynbaum, Bahareh A. Mojarad, Daniele Merico, Sylvia Lamoureux, Evdokia Anagnostou, Barbara Kellam, Xudong Liu, Dimitri J. Stavropoulos, Christie L. Burton, Brett Trost, Ny Hoang, MacDonald, Young Ej, Anne S. Bassett, Heung T, Worrawat Engchuan, Wang X, Richard F. Wintle, Gregory A. Costain, Yuen Rkc, Marc Woodbury-Smith, Maian Roifman, Giovanna Pellecchia, Susan Walker, David R. Rosenberg, John Wei, Rosanna Weksberg, Mehdi Zarrei, Miron K, Wang T, Gregory L. Hanna, and Marsha Speevak
Subjects: 0301 basic medicine, medicine.medical_specialty, lcsh:QH426-470, Microarray, lcsh:Medicine, Neurogenetics, Pathogenesis, Article, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Genetics, medicine, Attention deficit hyperactivity disorder, Copy-number variation, Molecular Biology, Genetics (clinical), Molecular medicine, business.industry, lcsh:R, Neurodevelopmental disorders, medicine.disease, 3. Good health, lcsh:Genetics, 030104 developmental biology, Autism spectrum disorder, Schizophrenia, Etiology, Medical genetics, business, 030217 neurology & neurosurgery
Abstract: Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in NRXN1, SEH1L, LDLRAD4, GNAL, GNG13, MKRN1, DCTN2, KNDC1, PCMTD2, KIF5A, SYNM, and long non-coding RNAs: AK127244 and PTCHD1-AS. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.
Published: 2019

38. Genome-wide Association Study of Pediatric Obsessive-Compulsive Traits: Shared Genetic Risk between Traits and Disorder

Author: Elizabeth Corfield, Dongmei Yu, S-M Shaheen, Russell Schachar, Jennifer Crosbie, Paul D. Arnold, Bowei Xiao, Noam Soreni, Andrew D. Paterson, Lauren Erdman, Christie L. Burton, Mathieu Lemire, Gregory L. Hanna, Tara Goodale, Kate D. Fitzgerald, Gerald Nestadt, David R. Rosenberg, Lisa J. Strug, Janita Bralten, and Geert Poelmans
Subjects: Genetics, 0303 health sciences, Obsessive-compulsive trait, Single-nucleotide polymorphism, Genome-wide association study, Locus (genetics), Biology, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Trait, SNP, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, GRID2
Abstract: ObjectiveTo identify genetic variants associated with obsessive-compulsive (OC) traits and test for sharing of genetic risks between OC traits and obsessive-compulsive disorder (OCD).MethodsWe conducted a genome-wide association analysis of OC traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community (Spit for Science sample). We tested the hypothesis that genetic variants associated with OC traits from the community would be associated with clinical OCD using a meta-analysis of three OCD case-controls samples (cases=3384, controls=8363). Shared genetic risk was examined between OC traits and OCD in the respective samples using polygenic risk score and genetic correlation analyses.ResultsA locus tagged by rs7856850 in an intron ofPTPRD(protein tyrosine phosphatase δ) was significantly associated with OC traits at the genome-wide significance level (p=2.48×10−8). The rs7856850 locus was also associated with OCD in a meta-analysis of three independent OCD case/control genome-wide datasets (p=0.0069). Polygenic risk scores derived from OC traits were significantly associated with OCD in a sample of childhood-onset OCD and vice versa (p’srg=0.83,p=0.07).ConclusionsWe report the first validated genome-wide significant variant for OC traits. OC traits measured in the community sample shared genetic risk with OCD case/control status. Our results demonstrate the importance of the type of measure used to measure traits as well as the feasibility and power of using trait-based approaches in community samples for genetic discovery.
Published: 2019
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39. Serotonin system genes and hoarding with and without other obsessive-compulsive traits in a population-based, pediatric sample: A genetic association study

Author: S-M Shaheen, Annie Dupuis, Janet Shan, Laura S. Park, Vanessa M. Sinopoli, Russell Schachar, Lauren Erdman, Christie L. Burton, Jennifer Crosbie, Paul D. Arnold, and Tara Goodale
Subjects: Male, Obsessive-Compulsive Disorder, Serotonin, Adolescent, Hoarding, Single-nucleotide polymorphism, Biology, Serotonergic, 03 medical and health sciences, 0302 clinical medicine, Hoarding Disorder, Polymorphism (computer science), medicine, Hoarding disorder, SNP, Humans, Child, Genetic Association Studies, Genetic association, Genetics, Serotonin Plasma Membrane Transport Proteins, 030227 psychiatry, 3. Good health, Diagnostic and Statistical Manual of Mental Disorders, Psychiatry and Mental health, Clinical Psychology, Receptor, Serotonin, 5-HT1B, Female, medicine.symptom, 030217 neurology & neurosurgery, SNP array
Abstract: 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.
Published: 2019

40. Serotonin system gene variants and regional brain volume differences in pediatric OCD

Author: Julie Coste, S-M Shaheen, David R. Rosenberg, Vanessa M. Sinopoli, Gregory L. Hanna, Kelli Peterman, Lauren Erdman, Christie L. Burton, Gregory Baldwin, Paul D. Arnold, Phillip C. Easter, and Rageen Rajendram
Subjects: Male, medicine.medical_specialty, Obsessive-Compulsive Disorder, Serotonin, Cognitive Neuroscience, Single-nucleotide polymorphism, Biology, behavioral disciplines and activities, Polymorphism, Single Nucleotide, 050105 experimental psychology, 03 medical and health sciences, Behavioral Neuroscience, Cellular and Molecular Neuroscience, 0302 clinical medicine, Neuroimaging, Internal medicine, medicine, Receptor, Serotonin, 5-HT2C, SNP, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, Allele, Child, Anterior cingulate cortex, Serotonin Plasma Membrane Transport Proteins, 05 social sciences, Neuropsychology, Brain, Magnetic Resonance Imaging, Psychiatry and Mental health, Endocrinology, medicine.anatomical_structure, Neurology, Brain size, Female, Neurology (clinical), 030217 neurology & neurosurgery
Abstract: 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.
Published: 2019

41. Serotonin system genes and obsessive-compulsive trait dimensions in a population-based, pediatric sample: a genetic association study

Author: Tara Goodale, Janet Shan, Laura S. Park, S-M Shaheen, Jennifer Crosbie, Paul D. Arnold, Lauren Erdman, Christie L. Burton, Annie Dupuis, Russell Schachar, and Vanessa M. Sinopoli
Subjects: Male, Obsessive-Compulsive Disorder, Serotonin, Adolescent, Population, Single-nucleotide polymorphism, Hoarding, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Developmental and Educational Psychology, medicine, Humans, 0501 psychology and cognitive sciences, Receptor, Serotonin, 5-HT2A, education, Child, Genetic Association Studies, Genetic association, Genetics, Serotonin Plasma Membrane Transport Proteins, education.field_of_study, Sex Characteristics, Genetic heterogeneity, 05 social sciences, Psychiatry and Mental health, Rumination, Cognitive, 5-HTTLPR, Pediatrics, Perinatology and Child Health, Rumination, Trait, Compulsive Behavior, Receptor, Serotonin, 5-HT1B, Female, medicine.symptom, Obsessive Behavior, Psychology, 030217 neurology & neurosurgery, 050104 developmental & child psychology, SNP array, Personality
Abstract: 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.
Published: 2019

42. Shared genetic background between children and adults with attention deficit/hyperactivity disorder

Author: Elizabeth S. Noblin, Joanna L. Mountain, Michelle Agee, Sarah L. Elson, Angélica Salatino-Oliveira, Barbara Franke, Diego L. Rovaris, Josep Antoni Ramos-Quiroga, Vladimir Vacic, Tatyana Strekalova, Claiton H.D. Bau, Christian Fadeuilhe, Peter Almos, Mara H. Hutz, David A. Hinds, Henrik Larsson, Jonna Kuntsi, Olga Rivero, Anders D. Børglum, Laura Vilar, Lorena Arribas, Catherine H. Wilson, Marieke Klein, Adam Auton, Anke Hinney, Katarzyna Bryc, Mark A. Bellgrove, Christie L. Burton, J. Fah Sathirapongsasuti, Olga V. Sazonova, Luis Augusto Rohde, Edmund J.S. Sonuga-Barke, Andreas Reif, Ted Reichborn-Kjennerud, Sarah Kittel-Schneider, Anne Halmøy, Bru Cormand, Miquel Casas, Joyce Y. Tung, Robert D. Oades, Matthew H. McIntyre, Nicholas A. Furlotte, Janie F. Shelton, Alysa E. Doyle, Iris Garcia-Martínez, Marta Ribasés, Johannes Hebebrand, Søren Dalsgaard, Tetyana Zayats, María Soler Artigas, Carrie A.M. Northover, Steven J. Pitts, Ole A. Andreassen, Chao Tian, Karen E. Huber, Josephine Elia, Montserrat Corrales, Jennifer C. McCreight, Benjamin M. Neale, Aribert Rothenberger, Sandra K. Loo, Cristina Sánchez-Mora, Stefan Johansson, Hakon Hakonarson, Christian Jacob, Mireia Pagerols, Jan Haavik, Joseph Biederman, Paula Rovira, Rosa Bosch, Alejandro Arias-Vasquez, Stephen V. Faraone, Catharina A. Hartman, Vanesa Richarte, Oliver Grimm, Irwin D. Waldman, Heike Weber, Martine Hoogman, Per M. Knappskog, Aaron Kleinman, Suyash Shringarpure, Jan K. Buitelaar, Philip Asherson, James J. McGough, Emma Sprooten, Russell Schachar, Ditte Demontis, Klaus-Peter Lesch, Nadia K. Litterman, Gemma Martín, Xin Wang, Evgeniy Svirin, Babak Alipanahi, Ziarih Hawi, Tobias Banaschewski, Bruna Santos da Silva, Robert K. Bell, Eugenio H. Grevet, Pierre Fontanillas, Nina Roth Mota, Jennifer Crosbie, Astri J. Lundervold, Psychiatrie & Neuropsychologie, and RS: MHeNs - R3 - Neuroscience
Subjects: Persistence (psychology), Trastorns per dèficit d'atenció amb hiperactivitat en els infants, SYMPTOMS, LD SCORE REGRESSION, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], CHILDHOOD, Genome-wide association study, Attention deficit disorder with hyperactivity in children, CA2+-DEPENDENT ACTIVATOR PROTEIN, 0302 clinical medicine, Neurodevelopmental disorder, Child, SECRETION 2, 0303 health sciences, HERITABILITY, 220 Statistical Imaging Neuroscience, Psychiatry and Mental health, Phenotype, Trastorns per dèficit d'atenció amb hiperactivitat en els adults, medicine.symptom, Genetic Background, Clinical psychology, Adult, DEFICIT HYPERACTIVITY DISORDER, Impulsivity, behavioral disciplines and activities, Genetic correlation, Article, 03 medical and health sciences, mental disorders, medicine, Humans, ADHD, Attention deficit hyperactivity disorder, GENOME-WIDE ASSOCIATION, METAANALYSIS, 030304 developmental biology, Genetic association, Pharmacology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, medicine.disease, Genetic architecture, Attention Deficit Disorder with Hyperactivity, Impulsive Behavior, Attention deficit, Genetic markers, Attention deficit disorder with hyperactivity in adults, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: 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.
Published: 2019
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43. Examination of the shared genetic basis of anorexia nervosa and obsessive-compulsive disorder

Author: Matthew Halvorsen, Manuel Mattheisen, Gwyneth Zai, James A. Knowles, Carol A. Mathews, James J. Crowley, Nadia Micali, Cynthia M. Bulik, Paul D. Arnold, Lauren Erdman, Julien Bryois, Gerome Breen, Lea K. Davis, Christie L. Burton, Zeynep Yilmaz, Stephanie Zerwas, Jeremiah M. Scharf, Rainald Moessner, Dongmei Yu, Gerald Nestadt, Laura M. Thornton, Martien J H Kas, and Kas lab
Subjects: 0301 basic medicine, Obsessive-Compulsive Disorder, Anorexia Nervosa, SNP, Genome-wide association study, Comorbidity, heritability, Biology, Genetic correlation, behavioral disciplines and activities, Article, Body Mass Index, 03 medical and health sciences, Cellular and Molecular Neuroscience, ddc:616.89, 0302 clinical medicine, Anorexia Nervosa/genetics, mental disorders, medicine, Humans, GWAS, Bipolar disorder, Molecular Biology, Obsessive-Compulsive Disorder/genetics, 030304 developmental biology, Genetics, 0303 health sciences, business.industry, Heritability, medicine.disease, Neuroticism, 3. Good health, meta-analysis, Psychiatry and Mental health, Phenotype, 030104 developmental biology, Schizophrenia, Anorexia nervosa (differential diagnoses), genetic, business, Body mass index, 030217 neurology & neurosurgery, Clinical psychology, Genome-Wide Association Study
Abstract: 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.
Published: 2020
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44. Contributors

Author: Ryan Abbott, Ahmed T. Ahmed, Martin Alda, Ananda B. Amstadter, Ole A. Andreassen, Victoria K. Arnet, Cedric Bardy, Csaba Barta, Bernhard T. Baune, Elisabeth R.B. Becker, Bettina H. Bewernick, Joanna M. Biernacka, Stefan Bleich, Marissa S. Blumenthal, Cristian Bonvicini, Chad A. Bousman, Lisa C. Brown, Christie L. Burton, Han Cao, Joanne S. Carpenter, Danielle Cath, Micah Cearns, Donald D. Chang, Alexander Charney, Christopher R.K. Ching, Kate M. Chitty, Liliana G. Ciobanu, Scott R. Clark, A.M. Cole, Jane L. Collinson, Lucía Colodro-Conde, A. Corvin, David R. Cotter, Shane P.M. Cross, Jacob J. Crouse, John F Cryan, Darina Czamara, Shareefa Dalvie, Franziska Degenhardt, Douglas L. Delahanty, Timothy G Dinan, Valsamma Eapen, Harris A. Eyre, Andreas J. Forstner, Helge Frieling, Mark A. Frye, Lillian J. Gehue, Daniel Geller, Nicholas Glozier, Beata R. Godlewska, Andrea N. Goldstein-Piekarski, Ilona Gorbovskaya, Hans Jörgen Grabe, Iria Grande, Paul Grant, Zarina Greenberg, Edna Grünblatt, Adam J. Guastella, Anand Gururajan, Tim Hahn, Alisha S.M. Hall, Blake A. Hamilton, Alfons O. Hamm, Catherine J. Harmer, Jessica Hartmann, Michael A. Hauser, Daniel F. Hermens, Ian B. Hickie, Frank Iorfino, Neda Jahanshad, Iris E. Jansen, Angela G. Junglen, Helmet T. Karim, Manreena Kaur, Nastassja Koen, Dagmar Koethe, Jim Lagopoulos, Rico S.Z. Lee, Sophie E. Legge, Douglas F. Levinson, F. Markus Leweke, Julio Licinio, David E.J. Linden, Jonathan C.W. Liu, Anita Lo, Falk W. Lohoff, Adriana Lori, Ulrike Lueken, Carlo Maj, Patrick D. McGorry, Roger S. McIntyre, Agnes B. McMahon, Divya Mehta, Cristina Mei, Rajendra A. Morey, Daniel J. Müller, Sharon L. Naismith, Barnaby Nelson, Alexandra Neyazi, Alissa Nichles, Caroline M. Nievergelt, Nicole R. Nugent, C. Ormond, Antonio F. Pardiñas, Seth W. Perry, Claudia Pisanu, Danielle Posthuma, Renee-Marie Ragguett, Cyrus Raji, Margarita Raygada, Owen M. Rennert, Charles F. Reynolds, Sophie Sabherwal, Estela Salagre, Pamela H. Saunders, Catia Scassellati, Thomas E. Schlaepfer, Lianne Schmaal, Klaus Oliver Schubert, Emanuel Schwarz, Elizabeth M. Scott, Jan Scott, Jonathan Sebat, Giovanni Severino, Christina Sheerin, Ajeet B. Singh, Balwinder Singh, Stephen F. Smagula, Olav B. Smeland, Alicia K. Smith, Jill L. Sorcher, Rachael Spooner, Alessio Squassina, Eli A. Stahl, Dan J. Stein, Fabian Streit, Patrick F. Sullivan, Jennifer A. Sumner, Paul M. Thompson, Ashleigh M. Tickell, Catherine Toben, Monica Uddin, Arshya Vahabzadeh, Linh K. Van, Margot P. van de Weijer, Odile A. van den Heuvel, Sandra Van der Auwera, Anouk H.A. Verboven, Eduard Vieta, Zoe Wainer, James T.R. Walters, Hunna J. Watson, Django White, Leanne M. Williams, Stephanie H. Witt, Yin Yao, Zeynep Yilmaz, Gwyneth Zai, and Natalia Zmicerevska
Published: 2019
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45. Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Author: Laura M. Thornton, Paul Lichtenstein, Verneri Anttila, Diego Albani, Josep Antoni Ramos-Quiroga, Roger A.H. Adan, Monika Schlögelhofer, Stephen Sanders, Enrique Castelao, Klaus Berger, Nina Dalkner, Urs Heilbronner, Engilbert Sigurdsson, Pablo Mir, Fuquan Zhang, James T.R. Walters, Patrick F. Sullivan, Fragiskos Gonidakis, F. Kyle Satterstrom, Sara Marsal, Per Hoffmann, Amy Perry, Valentina Ciullo, Beate Herpertz-Dahlmann, Catharina Lavebratt, Kieran C. Murphy, Tammy Hedderly, Hyun Ju Hong, Evald Saemundsen, Sascha B. Fischer, Hailiang Huang, Andrew D. Grotzinger, Nienke Vulink, Murray B. Stein, Mark A. Frye, Laura J. Scott, David Curtis, Todd Lencz, Janiece E. DeSocio, Richard A. Belliveau, Eduard Vieta, Andrea Dietrich, Wade H. Berrettini, Kenneth S. Kendler, Marquis P. Vawter, Paul S. Nestadt, Michael E. Talkowski, Manuel Mattheisen, Ingrid Agartz, Elisa Docampo, Bernhard T. Baune, Stefan Ehrlich, Jolanta Lissowska, Felecia Cerrato, Terje Nærland, Robin M. Murray, Jennifer Reichert, Annette M. Hartmann, Hannelore Ehrenreich, Howard J. Edenberg, Katherine A. Halmi, Qingqin S. Li, Peristera Paschou, Marie Bækvad-Hansen, Esther Walton, Alessio Maria Monteleone, Ted Reichborn-Kjennerud, Frank Bellivier, Jungeun Song, D. Blake Woodside, Young Shin Kim, Jochen Seitz, Jacques Pantel, Palmiero Monteleone, Erika L. Nurmi, Rodney J. Scott, Kang Sim, Ekaterina A. Khramtsova, Udo Dannlowski, Rolf Adolfsson, Danielle Posthuma, Melissa J. Green, Laura Ibanez-Gomez, Jakob Grove, Elvira Bramon, Gregory L. Hanna, Cynthia M. Bulik, Yiran Guo, Stephan Ripke, Mary M. Robertson, Harald N. Aschauer, Adebayo Anjorin, Joanna Martin, Bertram Müller-Myhsok, Deborah Kaminská, Jose Guzman-Parra, Benedetta Nacmias, Erik G. Jönsson, Jonathan R. I. Coleman, Douglas F. Levinson, Hamdi Mbarek, Gun Peggy Knudsen, Karin Egberts, Mette Nyegaard, Patrik K. E. Magnusson, Mark Adams, Douglas Blackwood, Elisabeth B. Binder, Marcus Ising, Anna R. Docherty, Jim van Os, Nese Direk, Lina Martinsson, Maria Arranz, Christel M. Middeldorp, Stefan Kloiber, Sintia Iole Belangero, Eske M. Derks, Ingrid Melle, Erlend Bøen, Jan Haavik, Federica Piras, Unna N. Danner, Anil K. Malhotra, Gerome Breen, Stephen V. Faraone, Amanda B Zheutlin, Timothy Poterba, Stephan Ruhrmann, Inge Joa, Ulrik Fredrik Malt, Sarah E. Bergen, Federica Tozzi, Lauren A. Weiss, Hana Papezova, Dominic Holland, Elliot S. Gershon, Jaakko Kaprio, Merete Nordentoft, Scott D. Gordon, Christopher Pittenger, Keun-Ah Cheon, Jennifer Jordan, Philip Gorwood, Myrna M. Weissman, Preben Bo Mortensen, Melissa A. Munn-Chernoff, Isobel Heyman, Eun-Young Shin, Christie L. Burton, Katherine Gordon-Smith, Sietske G. Helder, Peter Nagy, Till F. M. Andlauer, Yunpeng Wang, Young Key Kim, Kate Langley, Søren Dalsgaard, Richard Delorme, Torbjørn Elvsåshagen, Bennett L. Leventhal, Giovanni Gambaro, Christos Androutsos, Jennifer Tübing, Marion Roberts, Annelie Nordin Adolfsson, Hakon Hakonarson, Dorothy E. Grice, Vaughan J. Carr, Konstantinos Tziouvas, Stephanie Zerwas, Cathy L. Barr, Michael Conlon O'Donovan, Per Qvist, Beate St Pourcain, Samuel Kuperman, Leila Karhunen, Jack Samuels, Markus M. Nöthen, Martien J H Kas, Alfonso Tortorella, Mikael Landén, Jennifer Crosbie, Marco A. Grados, Joanna M. Biernacka, Paul D. Arnold, Irene A. Malaty, Jurjen J. Luykx, Nicholas Bass, Naomi R. Wray, Catharina A. Hartman, Christina M. Hultman, Michael S. Okun, Brandon Wormley, Michael Bauer, Daniel J. Smith, Ian Jones, Kathryn Roeder, Brien P. Riley, Caroline M. Nievergelt, Katrin Gade, Sarah Kittel-Schneider, Roy H. Perlis, James R. Mitchell, Ziarih Hawi, James Lee, Liz Forty, William E. Bunney, Thomas Damm Als, Catherine Schaefer, Digby Quested, Matteo Cassina, Anna C. Koller, Patrick Turley, Agnes A. Steixner, Anu Raevuori, Assen Jablensky, Peter Holmans, Dong-Ho Song, S. Evelyn Stewart, Jan K. Buitelaar, Fernando S. Goes, Alexander Münchau, Ayman H. Fanous, Nicolas Ramoz, James B. Potash, Monica Gratacos Mayora, Tobias Banaschewski, Céline S. Reinbold, Renata Rizzo, Arianna Di Florio, Lenka Foretova, Gianfranco Spalletta, Aarno Palotie, Eleftheria Zeggini, Lawrence W. Brown, Julie K. O'Toole, Lynn E. DeLisi, Ulrich Schall, Mary Roberson, Barbara J. Coffey, Bryan J. Mowry, Murray J. Cairns, Dan J. Stein, Glyn Lewis, Marta Ribasés, C. Robert Cloninger, Bettina Konte, John B. Vincent, Duncan S. Palmer, Radhika Kandaswamy, Christine Ladd-Acosta, Lars Alfredsson, Frank Visscher, Ulrike Schmidt, Aiden Corvin, Susan L. Santangelo, Brenda W.J.H. Penninx, David J. Porteous, Tetsuya Ando, Arne E. Vaaler, Bru Cormand, Laura Carlberg, Claire Churchhouse, Manfred Stuhrmann, Niamh Mullins, Christine Søholm Hansen, Cathy L. Budman, Hartmut Imgart, Dan E. Arking, James J. McGough, Michael Gill, Christel Depienne, Roland Burghardt, Antonio Julià, Anders M. Dale, Sven Sandin, Katharina Domschke, Maria Grigoroiu-Serbanescu, Susana Jiménez-Murcia, Marianne Giørtz Pedersen, Zsanett Tarnok, Gisli Baldursson, Michele T. Pato, David M. Hougaard, Thorgeir E. Thorgeirsson, Katharina Bey, Kerstin J. Plessen, Margaret A. Richter, Ole A. Andreassen, Claudine Laurent-Levinson, Leonid Padyukov, Jacques Mallet, Daniela Degortes, John R. Kelsoe, Robert D. Levitan, Andreas Reif, Chaim Huyser, Derek W. Morris, Sina Wanderer, William Byerley, Edna Grünblatt, E.J.C. de Geus, Hyejung Won, Josephine Elia, Rudolf Uher, Jay A. Tischfield, Andreas Karwautz, Gustavo Turecki, Pieter J. Hoekstra, Dorret I. Boomsma, Jacob Rosenthal, Daniele Cusi, Michael C. Neale, Sara Mostafavi, Gwyneth Zai, F. Anthony O'Neill, Gary Donohoe, Karola Rehnström, Harry Brandt, Helena Gaspar, Francis J. McMahon, H-Erich Wichmann, Andrew W. Bergen, Giovanni Coppola, Lea K. 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O., Lucae, S., Maaser, A., Malt, U. F., Martin, N. G., Martinsson, L., Mcelroy, S. L., Mcmahon, F. J., Mcquillin, A., Melle, I., Metspalu, A., Millischer, V., Mitchell, P. B., Montgomery, G. W., Morken, G., Morris, D. W., Muller-Myhsok, B., Mullins, N., Myers, R. M., Nievergelt, C. M., Nordentoft, M., Adolfsson, A. N., Nothen, M. M., Ophoff, R. A., Owen, M. J., Paciga, S. A., Pato, C. N., Pato, M. T., Perlis, R. H., Perry, A., Potash, J. B., Reinbold, C. S., Rietschel, M., Rivera, M., Roberson, M., Schalling, M., Schofield, P. R., Schulze, T. G., Scott, L. J., Serretti, A., Sigurdsson, E., Smeland, O. B., Stordal, E., Streit, F., Strohmaier, J., Thorgeirsson, T. E., Treutlein, J., Turecki, G., Vaaler, A. E., Vieta, E., Vincent, J. B., Wang, Y., Witt, S. H., Zandi, P., Adan, R. A. H., Alfredsson, L., Ando, T., Aschauer, H., Baker, J. H., Bencko, V., Bergen, A. W., Birgegard, A., Perica, V. 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K., Padyukov, L., Pantel, J., Papezova, H., Rabionet, R., Raevuori, A., Ramoz, N., Reichborn-Kjennerud, T., Ricca, V., Roberts, M., Rujescu, D., Rybakowski, F., Scherag, A., Schmidt, U., Seitz, J., Slachtova, L., Slof-Op't Landt, M. C. T., Slopien, A., Sorbi, S., Southam, L., Strober, M., Tortorella, A., Tozzi, F., Treasure, J., Tziouvas, K., van Elburg, A. A., Wade, T. D., Wagner, G., Walton, E., Watson, H. J., Wichmann, H. -E., Woodside, D. B., Zeggini, E., Zerwas, S., Zipfel, S., Adams, M. J., Andlauer, T. F. M., Berger, K., Binder, E. B., Boomsma, D. I., Castelao, E., Colodro-Conde, L., Direk, N., Docherty, A. R., Domenici, E., Domschke, K., Dunn, E. C., Foo, J. C., D, e. Geus E. J. C., Grabe, H. J., Hamilton, S. P., Horn, C., Hottenga, J. -J., Howard, D., Ising, M., Kloiber, S., Levinson, D. F., Lewis, G., Magnusson, P. K. E., Mbarek, H., Middeldorp, C. M., Mostafavi, S., Nyholt, D. R., Penninx, B. W., Peterson, R. E., Pistis, G., Porteous, D. J., Preisig, M., Quiroz, J. A., Schaefer, C., Schulte, E. C., Shi, J., Smith, D. J., Thomson, P. A., Tiemeier, H., Uher, R., van der Auwera, S., Weissman, M. M., Alexander, M., Begemann, M., Bramon, E., Buccola, N. G., Cairns, M. J., Campion, D., Carr, V. J., Cloninger, C. R., Cohen, D., Collier, D. A., Corvin, A., Delisi, L. E., Donohoe, G., Dudbridge, F., Duan, J., Freedman, R., Gejman, P. V., Golimbet, V., Godard, S., Ehrenreich, H., Hartmann, A. M., Henskens, F. A., Ikeda, M., Iwata, N., Jablensky, A. V., Joa, I., Jonsson, E. G., Kelly, B. J., Knight, J., Konte, B., Laurent-Levinson, C., Lee, J., Lencz, T., Lerer, B., Loughland, C. M., Malhotra, A. K., Mallet, J., Mcdonald, C., Mitjans, M., Mowry, B. J., Murphy, K. C., Murray, R. M., O'Neill, F. A., Oh, S. -Y., Palotie, A., Pantelis, C., Pulver, A. E., Petryshen, T. L., Quested, D. J., Riley, B., Sanders, A. R., Schall, U., Schwab, S. G., Scott, R. J., Sham, P. C., Silverman, J. M., Sim, K., Steixner, A. A., Tooney, P. A., van Os, J., Vawter, M. 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S., Paschou, P., Piras, F., Pittenger, C., Plessen, K. J., Richter, M. A., Rizzo, R., Robertson, M., Roessner, V., Ruhrmann, S., Samuels, J. F., Sandor, P., Schlogelhofer, M., Shin, E. -Y., Singer, H., Song, D. -H., Song, J., Spalletta, G., Stein, D. J., Stewart, S. E., Storch, E. A., Stranger, B., Stuhrmann, M., Tarnok, Z., Tischfield, J. A., Tubing, J., Visscher, F., Vulink, N., Wagner, M., Walitza, S., Wanderer, S., Woods, M., Worbe, Y., Zai, G., Zinner, S. H., Sullivan, P. F., Franke, B., Daly, M. J., Bulik, C. M., Mcintosh, A. M., O'Donovan, M. C., Zheutlin, A., Andreassen, O. A., Borglum, A. D., Breen, G., Edenberg, H. J., Fanous, A. H., Faraone, S. V., Gelernter, J., Mathews, C. A., Mattheisen, M., Mitchell, K. S., Neale, M. C., Nurnberger, J. I., Ripke, S., Santangelo, S. L., Scharf, J. M., Stein, M. B., Thornton, L. M., Walters, J. T. R., Wray, N. R., Geschwind, D. H., Neale, B. M., Kendler, K. S., and Smoller, J. W.
Subjects: Netherlands Twin Register (NTR), cross-disorder genetics, Medizin, Genome-wide association study, Tourette syndrome, functional genomics, gene expression, genetic architecture, genetic correlation, GWAS, neurodevelopment, pleiotropy, psychiatric disorders, Psychiatric genetics, 0302 clinical medicine, Pleiotropy, functional genomic, WIDE ASSOCIATION, cross-disorder genetic, 0303 health sciences, Mental Disorders, Genetic Pleiotropy, HUMAN BRAIN, INSIGHTS, Autism spectrum disorder, Schizophrenia, DISEASES, GENETIC CORRELATIONS, medicine.medical_specialty, Neurogenesis, Quantitative Trait Loci, BF, Biology, GENOTYPE IMPUTATION, Psychiatric geneticscross-disorder geneticspsychiatric disorderspleiotropyneurodevelopmentGWASgenetic correlationgene expressiongenetic architecturefunctional genomics, Article, General Biochemistry, Genetics and Molecular Biology, psychiatric disorder, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, TRANSCRIPTOME, Psychiatry, 030304 developmental biology, Gwas, Psychiatric Genetics, Cross-disorder Genetics, Functional Genomics, Gene Expression, Genetic Architecture, Genetic Correlation, Neurodevelopment, Psychiatric Disorders, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], IDENTIFICATION, MUTATIONS, medicine.disease, Genetic architecture, DEMETHYLASE, RC0321, 1182 Biochemistry, cell and molecular biology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.
Published: 2019
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46. Genetics of obsessive-compulsive disorder and tourette disorder

Author: Gwyneth Zai, Odile A. van den Heuvel, Daniel A. Geller, Csaba Barta, Danielle C. Cath, Obsessive Compulsive Disorder, Yin Yao, Christie L. Burton, Edna Grünblatt, Valsamma Eapen, Psychiatry, Amsterdam Neuroscience - Neurodegeneration, and Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention
Subjects: Genetics, Candidate gene, Genetic epidemiology, Imaging genetics, business.industry, mental disorders, Medicine, Genome-wide association study, Copy-number variation, Epigenetics, business, Pharmacogenetics, Genetic association
Abstract: Obsessive-compulsive disorder (OCD) and Tourette disorder (TD) are neuropsychiatric disorders in which genetic factors play a substantial, and very often shared, role in both disorders. This chapter reviews the current literature on the genetics of OCD and TD, including genetic epidemiology within and across disorders, familiality, candidate gene studies, genome-wide association studies (GWAS), copy number variants (CNVs), imaging genetics, pharmacogenetics, epigenetics, and gene-environment interaction.
Published: 2019
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47. SWAN scale for ADHD trait-based genetic research: a validity and polygenic risk study

Author: Jennifer Crosbie, Leah Wright, S-M Shaheen, Russell Schachar, Elizabeth Corfield, Bowei Xiao, Annie Dupuis, Tara Goodale, Christie L. Burton, Janet Shan, and Paul D. Arnold
Subjects: Predictive validity, Male, Parents, Multifactorial Inheritance, Adolescent, Population, behavioral disciplines and activities, Sensitivity and Specificity, 03 medical and health sciences, 0302 clinical medicine, Rating scale, mental disorders, Developmental and Educational Psychology, medicine, Humans, 0501 psychology and cognitive sciences, Genetic Predisposition to Disease, education, Child, education.field_of_study, 05 social sciences, Reproducibility of Results, Psychiatry and Mental health, Convergent validity, Attention Deficit Disorder with Hyperactivity, Scale (social sciences), Pediatrics, Perinatology and Child Health, Behavior Rating Scale, Trait, Anxiety, Female, Self Report, medicine.symptom, Psychology, 030217 neurology & neurosurgery, 050104 developmental & child psychology, Clinical psychology, Psychopathology
Abstract: 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.
Published: 2018

48. Response Time Adjustment in the Stop Signal Task: Development in Children and Adolescents

Author: Russell Schachar, Maheshan Indralingam, Paul D. Arnold, Jennifer Crosbie, Christie L. Burton, Annie Dupuis, and Andre Chevrier
Subjects: Male, medicine.medical_specialty, Adolescent, 05 social sciences, Response time, Audiology, Stop signal, 050105 experimental psychology, Education, Task (project management), Executive Function, Inhibition, Psychological, Pediatrics, Perinatology and Child Health, Developmental and Educational Psychology, medicine, Reaction Time, Humans, 0501 psychology and cognitive sciences, Female, Psychology, Child, Response inhibition, Psychomotor Performance, 050104 developmental & child psychology
Abstract: Adjusting speed to maintain fast and accurate performance is critical to goal-directed behavior. This study examined development of response time adjustments in the stop signal task in 13,709 individuals aged 6-17 years (49.0% Caucasian) across four trial types: correct and incorrect go, successful (stop-inhibit), and failed (stop-respond) trials. People sped more after correct than incorrect go responses and slowed more after failed than successful stop trials. Greater slowing after stop-respond but less slowing after stop-inhibit trials was associated with better response inhibition. Response time adjustments were evident in children as young as age 6, developed throughout childhood, and plateaued by age 10. Results were consistent with the predictions of the error detection and shifting goal priority hypotheses for adjustments. [ABSTRACT FROM AUTHOR]
Published: 2018

49. T62SHARED GENETIC RISK BETWEEN QUANTITATIVE OCD TRAITS AND CLINICAL OCD

Author: Christie L. Burton, Mathieu Lemire, Paul Arnold, Russell Schachar, and Jennifer Crosbie
Subjects: Pharmacology, Psychiatry and Mental health, Neurology, business.industry, Medicine, Pharmacology (medical), Neurology (clinical), Genetic risk, business, Biological Psychiatry, Clinical psychology
Published: 2019
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50. T64SHARED GENETIC ETIOLOGY BETWEEN OBSESSIVE-COMPULSIVE DISORDER, OBSESSIVE-COMPULSIVE SYMPTOMS IN THE POPULATION, AND INSULIN SIGNALING

Author: Barbara Franke, Jeremiah M. Scharf, Russell Schachar, Janita Bralten, Geert Poelmans, Jan K. Buitelaar, Ward De Witte, Christie L. Burton, Joanna Widomska, Paul Arnold, Mathieu Lemire, Jennifer Crosbie, Carol A. Mathews, and Dongmei Yu
Subjects: Pharmacology, education.field_of_study, medicine.medical_specialty, biology, business.industry, Population, Obsessive compulsive symptoms, Psychiatry and Mental health, Insulin receptor, Neurology, Obsessive compulsive, Genetic etiology, biology.protein, Medicine, Pharmacology (medical), Neurology (clinical), education, business, Psychiatry, Biological Psychiatry
Published: 2019
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