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1. Genome-wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome

Author

Fotis Tsetsos, Apostolia Topaloudi, Pritesh Jain, Zhiyu Yang, Dongmei Yu, Petros Kolovos, Zeynep Tumer, Renata Rizzo, Andreas Hartmann, Christel Depienne, Yulia Worbe, Kirsten R. Müller-Vahl, Danielle C. Cath, Dorret I. Boomsma, Tomasz Wolanczyk, Cezary Zekanowski, Csaba Barta, Zsofia Nemoda, Zsanett Tarnok, Shanmukha S. Padmanabhuni, Joseph D. Buxbaum, Dorothy Grice, Jeffrey Glennon, Hreinn Stefansson, Bastian Hengerer, Evangelia Yannaki, John A. Stamatoyannopoulos, Noa Benaroya-Milshtein, Francesco Cardona, Tammy Hedderly, Isobel Heyman, Chaim Huyser, Pablo Mir, Astrid Morer, Norbert Mueller, Alexander Munchau, Kerstin J. Plessen, Cesare Porcelli, Veit Roessner, Susanne Walitza, Anette Schrag, Davide Martino, Jay A. Tischfield, Gary A. Heiman, A. Jeremy Willsey, Andrea Dietrich, Lea K. Davis, James J. Crowley, Carol A. Mathews, Jeremiah M. Scharf, Marianthi Georgitsi, Pieter J. Hoekstra, Peristera Paschou, Cathy L. Barr, James R. Batterson, Cheston Berlin, Cathy L. Budman, Giovanni Coppola, Nancy J. Cox, Sabrina Darrow, Yves Dion, Nelson B. Freimer, Marco A. Grados, Erica Greenberg, Matthew E. Hirschtritt, Alden Y. Huang, Cornelia Illmann, Robert A. King, Roger Kurlan, James F. Leckman, Gholson J. Lyon, Irene A. Malaty, William M. McMahon, Benjamin M. Neale, Michael S. Okun, Lisa Osiecki, Mary M. Robertson, Guy A. Rouleau, Paul Sandor, Harvey S. Singer, Jan H. Smit, Jae Hoon Sul, Christos Androutsos, Entela Basha, Luca Farkas, Jakub Fichna, Piotr Janik, Mira Kapisyzi, Iordanis Karagiannidis, Anastasia Koumoula, Peter Nagy, Joanna Puchala, Natalia Szejko, Urszula Szymanska, Vaia Tsironi, Alan Apter, Juliane Ball, Benjamin Bodmer, Emese Bognar, Judith Buse, Marta Correa Vela, Carolin Fremer, Blanca Garcia-Delgar, Mariangela Gulisano, Annelieke Hagen, Julie Hagstrøm, Marcos Madruga-Garrido, Alessandra Pellico, Daphna Ruhrman, Jaana Schnell, Paola Rosaria Silvestri, Liselotte Skov, Tamar Steinberg, Friederike Tagwerker Gloor, Victoria L. Turner, Elif Weidinger, John Alexander, Tamas Aranyi, Wim R. Buisman, Jan K. Buitelaar, Nicole Driessen, Petros Drineas, Siyan Fan, Natalie J. Forde, Sarah Gerasch, Odile A. van den Heuvel, Cathrine Jespersgaard, Ahmad S. Kanaan, Harald E. Möller, Muhammad S. Nawaz, Ester Nespoli, Luca Pagliaroli, Geert Poelmans, Petra J.W. Pouwels, Francesca Rizzo, Dick J. Veltman, Ysbrand D. van der Werf, Joanna Widomska, Nuno R. Zilhäo, Lawrence W. Brown, Keun-Ah Cheon, Barbara J. Coffey, Thomas V. Fernandez, Donald L. Gilbert, Hyun Ju Hong, Laura Ibanez-Gomez, Eun-Joo Kim, Young Key Kim, Young-Shin Kim, Yun-Joo Koh, Sodahm Kook, Samuel Kuperman, Bennett L. Leventhal, Athanasios Maras, Tara L. Murphy, Eun-Young Shin, Dong-Ho Song, Jungeun Song, Matthew W. State, Frank Visscher, Sheng Wang, Samuel H. Zinner, Psychiatry, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Anatomy and neurosciences, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Neurodegeneration, Radiology and nuclear medicine, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Systems & Network Neuroscience, Biological Psychology, and Amsterdam Reproduction & Development

Subjects
meta-analysis, Medizin, GWAS, Biological Psychiatry, NR2F1, Tourette Syndrome
Abstract

Background: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. Methods: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. Results: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. Conclusions: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

Published
2023

2. Investigation of gene-environment interactions in relation to tic severity

Author

Frank Visscher, Kerstin J. Plessen, Tammy Hedderly, Jungeun Song, Bennett L. Leventhal, Eun-Young Shin, Lawrence W. Brown, Alexander Münchau, Robert A. King, Young Key Kim, Young Shin Kim, Veit Roessner, Andrea Dietrich, Samuel Kuperman, Thomas V. Fernandez, Keun-Ah Cheon, Carol A. Mathews, Athanasios Maras, Donald L. Gilbert, Yun-Joo Koh, Laura Ibanez-Gomez, Dongmei Yu, Astrid Morer, Sodahm Kook, Marcos Madruga-Garrido, Julie Hagstrøm, Dorothy E. Grice, Jay A. Tischfield, Lisa Osiecki, Mohamed Abdulkadir, Blanca Garcia-Delgar, Samuel H. Zinner, Chaim Huyser, Barbara J. Coffey, Dong-Ho Song, Gary A. Heiman, Pieter J. Hoekstra, Hyun Ju Hong, Pablo Mir, Isobel Heyman, Jeremiah M. Scharf, National Institute of Mental Health (US), Tourette Syndrome Association of New Jersey, Judah Foundation, Tourette Association of America, National Institutes of Health (US), Instituto de Salud Carlos III, Junta de Andalucía, Sociedad Andaluza de Neurología, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, Jacques and Gloria Gossweiler Foundation, Generalitat de Catalunya, German Research Foundation, National Institute of Environmental Health Sciences (US), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Child Psychiatry, Paediatric Psychosocial Care, and Amsterdam Neuroscience - Cellular & Molecular Mechanisms

Subjects
Candidate gene, Tic severity, Autism Spectrum Disorder, Autism, Intellectual and Developmental Disabilities (IDD), Single-nucleotide polymorphism, Genome-wide association study, Neurodegenerative, Tourette syndrome, Severity of Illness Index, Attention Deficit Disorder with Hyperactivity/genetics, Autism Spectrum Disorder/genetics, Female, Gene-Environment Interaction, Genome-Wide Association Study, Humans, Pregnancy, Tics, Tourette Syndrome, Gene–environment interaction, Pre- and perinatal complications, mental disorders, medicine, Genetics, SNP, 2.1 Biological and endogenous factors, Psychology, Aetiology, Biological Psychiatry, Genetic association, Pediatric, Neurology & Neurosurgery, business.industry, Psychiatry and Preclinical Psychiatric Studies - Original Article, Human Genome, Neurosciences, medicine.disease, Serious Mental Illness, Gene-environment interaction, Brain Disorders, Psychiatry and Mental health, Mental Health, Neurology, Autism spectrum disorder, Attention Deficit Disorder with Hyperactivity, Neurology (clinical), business
Abstract

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive–compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene–environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene–environment studies., This research was funded by National Institute of Mental Health (NIMH) grant R01MH092293 (to GAH and JAT) and NJCTS (New Jersey Center for Tourette Syndrome and Associated Disorders; to GAH and JAT). This work was also supported by grants from the Judah Foundation, the Tourette Association of America, National Institute of Health (NIH) Grants NS40024, NS016648, MH079489, MH073250, the American Recovery and Re-investment Act (ARRA) Grants NS040024-07S1; NS16648-29S1; NS040024-09S1; MH092289; MH092290; MH092291; MH092292; R01MH092293; MH092513; MH092516; MH092520; MH071507; MH079489; MH079487; MH079488; and MH079494. Dr. Mir has received grants from the Instituto de Salud Carlos III (PI10/01674, PI13/01461), the Consejería de Economía, Innovación, Ciencia y Empresa de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0741/2010, PI-0437-2012, PI-0471-2013), the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña and the Jaques and Gloria Gossweiler Foundation. Dr. Morer has received grants from the Fundacion Alicia Koplowitz and belongs to the research group of the Comissionat per Universitats i Recerca del Departmanent d’Innovacio (DIUE) 2009SGR1119. Dr. Münchau has received grants from the Deutsche Forschungsgemeinschaft (DFG: MU 1692/3-1, MU 1692/4-1 and FOR 2698). This study was also supported by a Grant from the National Institute for Environmental Health Science (R01 ES021462).

Published
2021

3. Is Persistent Motor or Vocal Tic Disorder a Milder Form of Tourette Syndrome?

Author

Sang-Wahn Koo, Erica Greenberg, Daniel A. Geller, Matthew E. Hirschtritt, Mary M. Robertson, Benjamin D. Greenberg, Robert A. King, Karla Claudio-Campos, James A. Knowles, Jack Samuels, Mark A. Riddle, Cornelia Illmann, Oscar J. Bienvenu, Lisa Osiecki, Gholson J. Lyon, Gerald Nestadt, Cathy Budman, Sabrina M. Darrow, Jeremiah M. Scharf, Janice Krasnow, Daniel A. Stevens, Marco A. Grados, James T. McCracken, Carol A. Mathews, Danielle C. Cath, Guy A. Rouleau, Paul Sandor, Fernando S. Goes, Franjo Ivankovic, Paul C. Lee, and Alexa Valko

Subjects
0301 basic medicine, Tic disorder, Pediatrics, medicine.medical_specialty, Obsessive-Compulsive Disorder, Movement disorders, Population, severity, Regular Issue Articles, Comorbidity, Tourette syndrome, chronic tics, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, Attention deficit hyperactivity disorder, Humans, Spectrum disorder, education, Research Articles, education.field_of_study, business.industry, Tourette, medicine.disease, meta-analysis, 030104 developmental biology, Mood, Neurology, meta‐analysis, Attention Deficit Disorder with Hyperactivity, Tic Disorders, Tics, Anxiety, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Research Article, Tourette Syndrome
Abstract

Background Persistent motor or vocal tic disorder (PMVT) has been hypothesized to be a forme fruste of Tourette syndrome (TS). Although the primary diagnostic criterion for PMVT (presence of motor or vocal tics, but not both) is clear, less is known about its clinical presentation. Objective The goals of this study were to compare the prevalence and number of comorbid psychiatric disorders, tic severity, age at tic onset, and family history for TS and PMVT. Methods We analyzed data from two independent cohorts using generalized linear equations and confirmed our findings using meta-analyses, incorporating data from previously published literature. Results Rates of obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) were lower in PMVT than in TS in all analyses. Other psychiatric comorbidities occurred with similar frequencies in PMVT and TS in both cohorts, although meta-analyses suggested lower rates of most psychiatric disorders in PMVT compared with TS. ADHD and OCD increased the odds of comorbid mood, anxiety, substance use, and disruptive behaviors, and accounted for observed differences between PMVT and TS. Age of tic onset was approximately 2 years later, and tic severity was lower in PMVT than in TS. First-degree relatives had elevated rates of TS, PMVT, OCD, and ADHD compared with population prevalences, with rates of TS equal to or greater than PMVT rates. Conclusions Our findings support the hypothesis that PMVT and TS occur along a clinical spectrum in which TS is a more severe and PMVT a less severe manifestation of a continuous neurodevelopmental tic spectrum disorder. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Published
2021

4. Investigation of gene-environment interactions in relation to tic severity

Author

Hyun Ju Hong, Y.-J. Koh, Andrea Dietrich, J. Song, Pablo Mir, Dong-Ho Song, Samuel Kuperman, Keun-Ah Cheon, Pieter J. Hoekstra, Gary A. Heiman, Barbara J. Coffey, Jeremiah M. Scharf, Tammy Hedderly, Young Shin Kim, Jay A. Tischfield, Chaim Huyser, Lawrence W. Brown, Mohamed Abdulkadir, Blanca Garcia-Delgar, Marcos Madruga-Garrido, Laura Ibanez-Gomez, Bennett L. Leventhal, Frank Visscher, Astrid Morer, Robert A. King, Dorothy E. Grice, Carol A. Mathews, Donald L. Gilbert, Dongmei Yu, Veit Roessner, Alexander Münchau, Samuel H. Zinner, Eun-Young Shin, Thomas V. Fernandez, Isobel Heyman, Athanasios Maras, Lisa Osiecki, Kerstin J. Plessen, Sodahm Kook, Yongsun Kim, and J. Hagstroem

Subjects
Genetics, Candidate gene, Autism spectrum disorder, mental disorders, Multiple comparisons problem, medicine, SNP, Genome-wide association study, Single-nucleotide polymorphism, Biology, medicine.disease, Tourette syndrome, Genetic association
Abstract

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N=518) design. We assessed 98 single nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate gene-studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene-environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene-environment studies.

Published
2021

5. Synaptic processes and immune-related pathways implicated in Tourette syndrome

Author

Fotis Tsetsos, Dongmei Yu, Jae Hoon Sul, Alden Y. Huang, Cornelia Illmann, Lisa Osiecki, Sabrina M. Darrow, Matthew E. Hirschtritt, Erica Greenberg, Kirsten R. Muller-Vahl, Manfred Stuhrmann, Yves Dion, Guy A. Rouleau, Harald Aschauer, Mara Stamenkovic, Monika Schlögelhofer, Paul Sandor, Cathy L. Barr, Marco A. Grados, Harvey S. Singer, Markus M. Nöthen, Johannes Hebebrand, Anke Hinney, Robert A. King, Thomas V. Fernandez, Csaba Barta, Zsanett Tarnok, Peter Nagy, Christel Depienne, Yulia Worbe, Andreas Hartmann, Cathy L. Budman, Renata Rizzo, Gholson J. Lyon, William M. McMahon, James R. Batterson, Danielle C. Cath, Irene A. Malaty, Michael S. Okun, Cheston Berlin, Douglas W. Woods, Paul C. Lee, Joseph Jankovic, Mary M. Robertson, Donald L. Gilbert, Lawrence W. Brown, Barbara J. Coffey, Andrea Dietrich, Pieter J. Hoekstra, Samuel Kuperman, Samuel H. Zinner, Michael Wagner, James A. Knowles, A. Jeremy Willsey, Jay A. Tischfield, Gary A. Heiman, Nancy J. Cox, Nelson B. Freimer, Benjamin M. Neale, Lea K. Davis, Giovanni Coppola, Carol A. Mathews, Jeremiah M. Scharf, Peristera Paschou, on behalf of the Tourette Association of America International Consortium for Genetics, Sabrina Darrow, Roger Kurlan, James F. Leckman, Jan H. Smit, the Gilles de la Tourette GWAS Replication Initiative, Harald Aschauer Harald Aschauer, Anastasios Konstantinidis, Kirsten Müller-Vahl, Tomasz Wolanczyk, the Tourette International Collaborative Genetics Study, Lawrence Brown, Keun-Ah Cheon, Blanca Garcia-Delgar, Donald Gilbert, Dorothy E. Grice, Julie Hagstrøm, Tammy Hedderly, Isobel Heyman, Chaim Huyser, Young Key Kim, Young-Shin Kim, Yun-Joo Koh, Sodahm Kook, Bennett L. Leventhal, Marcos Madruga-Garrido, Pablo Mir, Astrid Morer, Alexander Münchau, Kerstin J. Plessen, Veit Roessner, Eun-Young Shin, Dong-Ho Song, Jungeun Song, Samuel Zinner, and the Psychiatric Genomics Consortium Tourette Syndrome Working Group, Thomas Fernandez, Gary Heiman, Pieter Hoekstra, Jay Tischfield, Douglas Woods, European Commission, State Scholarships Foundation, National Institutes of Health (US), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Child Psychiatry, ANS - Cellular & Molecular Mechanisms, Tourette Association of America International Consortium for Genetics, Gilles de la Tourette GWAS Replication Initiative, Tourette International Collaborative Genetics Study, Psychiatric Genomics Consortium Tourette Syndrome Working Group, Psychiatry, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep

Subjects
0301 basic medicine, Cell type, Genotype, Medizin, LOCI, Genome-wide association study, GENE-SET ANALYSIS, Biology, Molecular neuroscience, Tourette syndrome, Article, lcsh:RC321-571, TIC DISORDERS, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Humans, Copy-number variation, GENOME-WIDE ASSOCIATION, AUTISM, Cell adhesion, Gene, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Neurons, COPY NUMBER VARIANTS, Cell adhesion molecule, Comparative genomics, medicine.disease, Genetic architecture, 3. Good health, PREVALENCE, Psychiatry and Mental health, 030104 developmental biology, HISTIDINE-DECARBOXYLASE, HEALTH, Neuroscience, 030217 neurology & neurosurgery, SYSTEM, Genome-Wide Association Study, Tourette Syndrome
Abstract

Tsetsos, Fotis et al., Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS., This research is co-financed by Greece and the European Union (European Social Fund—ESF) through the Operational Programme «Human Resources Development, Education and Lifelong Learning» in the context of the project “Reinforcement of Postdoctoral Researchers - 2nd Cycle” (MIS-5033021), implemented by the State Scholarships Foundation (IKY). L.K.D. was supported by grants from the National Institutes of Health including U54MD010722-04, R01NS102371, R01MH113362, U01HG009086, R01MH118223, DP2HD98859, R01DC16977, R01NS105746, R56MH120736, R21HG010652, and RM1HG009034.

Published
2021

6. Relationship between adverse childhood experiences and symptom severity in adult men with Tourette Syndrome

Author

Kelly Yang, Angela Essa, Daisy Noriega, Dongmei Yu, Lisa Osiecki, Caitlin A. Gauvin, Cornelia Illmann, Marco Bortolato, Erin C. Dunn, Carol A. Mathews, and Jeremiah M. Scharf

Subjects
Adult, Male, Psychiatry and Mental health, Adverse Childhood Experiences, Tics, Humans, Severity of Illness Index, Biological Psychiatry, Genome-Wide Association Study, Retrospective Studies, Tourette Syndrome
Abstract

Childhood adversity is associated with the development or expression of many neuropsychiatric disorders, including those with strong genetic underpinnings. Despite reported associations between perceived stress and tic severity, the relationship between potentially traumatic events in childhood and Tourette Syndrome (TS), a highly heritable neuropsychiatric disorder, is unknown. This study aimed to assess whether exposure to eight categories of adverse childhood experiences (ACEs) is associated with TS severity and impairment, and whether TS genetic risk modifies this association. Online survey data were collected from 351 adult males with TS who previously participated in genetic studies. Participants completed the ACE questionnaire and a lifetime version of the Yale Global Tic Severity Scale (YGTSS). Demographic and relevant health data were assessed; polygenic risk scores (PRS) measuring aggregated TS genetic risk were derived using genome-wide association data. Univariable and multivariable linear regressions examined the relationships between childhood adversity and retrospectively recalled worst-ever tic severity and impairment, adjusting for covariates. Potential gene-by-environment (GxE) interactions between ACE and PRS were estimated. After covariate adjustment, there was a significant graded dose-response relationship between ACE Scores and increases in lifetime worst-ever tic severity and impairment. There was some evidence that TS genetic risk moderated the relationship between ACE Score and tic impairment, but not tic severity, particularly for individuals with higher TS polygenic risk. We provide evidence that childhood adversity is associated with higher lifetime TS severity and impairment, although future longitudinal studies with genetically-sensitive designs are needed to determine whether these relationships are causal and/or directional.

Published
2020

7. De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis

Author

Sheng Wang, Jeffrey D. Mandell, Yogesh Kumar, Nawei Sun, Montana T. Morris, Juan Arbelaez, Cara Nasello, Shan Dong, Clif Duhn, Xin Zhao, Zhiyu Yang, Shanmukha S. Padmanabhuni, Dongmei Yu, Robert A. King, Andrea Dietrich, Najah Khalifa, Niklas Dahl, Alden Y. Huang, Benjamin M. Neale, Giovanni Coppola, Carol A. Mathews, Jeremiah M. Scharf, Thomas V. Fernandez, Joseph D. Buxbaum, Silvia De Rubeis, Dorothy E. Grice, Jinchuan Xing, Gary A. Heiman, Jay A. Tischfield, Peristera Paschou, A. Jeremy Willsey, Matthew W. State, Mohamed Abdulkadir, Benjamin Bodmer, Yana Bromberg, Lawrence W. Brown, Keun-Ah Cheon, Barbara J. Coffey, Li Deng, Lonneke Elzerman, Carolin Fremer, Blanca Garcia-Delgar, Donald L. Gilbert, Julie Hagstrøm, Tammy Hedderly, Isobel Heyman, Pieter J. Hoekstra, Hyun Ju Hong, Chaim Huyser, Eun-Joo Kim, Young Key Kim, Young-Shin Kim, Yun-Joo Koh, Sodahm Kook, Samuel Kuperman, Bennett L Leventhal, Andrea G. Ludolph, Marcos Madruga-Garrido, Athanasios Maras, Pablo Mir, Astrid Morer, Montana T Morris, Kirsten Müller-Vahl, Alexander Münchau, Tara L. Murphy, Kerstin J. Plessen, Hannah Poisner, Veit Roessner, Stephan J. Sanders, Eun-Young Shin, Dong-Ho Song, Jungeun Song, Joshua K. Thackray, Jennifer Tübing, Frank Visscher, Sina Wanderer, A Jeremy Willsey, Martin Woods, Yeting Zhang, Samuel H. Zinner, Christos Androutsos, Csaba Barta, Luca Farkas, Jakub Fichna, Marianthi Georgitsi, Piotr Janik, Iordanis Karagiannidis, Anastasia Koumoula, Peter Nagy, Joanna Puchala, Renata Rizzo, Natalia Szejko, Urszula Szymanska, Zsanett Tarnok, Vaia Tsironi, Tomasz Wolanczyk, Cezary Zekanowski, Cathy L. Barr, James R. Batterson, Cheston Berlin, Ruth D. Bruun, Cathy L. Budman, Danielle C. Cath, Sylvain Chouinard, Nancy J. Cox, Sabrina Darrow, Lea K. Davis, Yves Dion, Nelson B. Freimer, Marco A. Grados, Matthew E. Hirschtritt, Cornelia Illmann, Roger Kurlan, James F. Leckman, Gholson J. Lyon, Irene A. Malaty, William M. MacMahon, Michael S. Okun, Lisa Osiecki, David L. Pauls, Danielle Posthuma, Vasily Ramensky, Mary M. Robertson, Guy A. Rouleau, Paul Sandor, Harvey S. Singer, Jan Smit, Jae-Hoon Sul, Tourette International Collaborative Genetics Study (TIC Genetics), Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE), Tourette Association of America International Consortium for Genetics (TAAICG), Abdulkadir, M., Arbelaez, J., Bodmer, B., Bromberg, Y., Brown, L.W., Cheon, K.A., Coffey, B.J., Deng, L., Dietrich, A., Dong, S., Duhn, C., Elzerman, L., Fernandez, T.V., Fremer, C., Garcia-Delgar, B., Gilbert, D.L., Grice, D.E., Hagstrøm, J., Hedderly, T., Heiman, G.A., Heyman, I., Hoekstra, P.J., Hong, H.J., Huyser, C., Kim, E.J., Kim, Y.K., Kim, Y.S., King, R.A., Koh, Y.J., Kook, S., Kuperman, S., Leventhal, B.L., Ludolph, A.G., Madruga-Garrido, M., Mandell, J.D., Maras, A., Mir, P., Morer, A., Morris, M.T., Müller-Vahl, K., Münchau, A., Murphy, T.L., Nasello, C., Plessen, K.J., Poisner, H., Roessner, V., Sanders, S.J., Shin, E.Y., Song, D.H., Song, J., State, M.W., Sun, N., Thackray, J.K., Tischfield, J.A., Tübing, J., Visscher, F., Wanderer, S., Wang, S., Willsey, A.J., Woods, M., Xing, J., Zhang, Y., Zhao, X., Zinner, S.H., Androutsos, C., Barta, C., Farkas, L., Fichna, J., Georgitsi, M., Janik, P., Karagiannidis, I., Koumoula, A., Nagy, P., Paschou, P., Puchala, J., Rizzo, R., Szejko, N., Szymanska, U., Tarnok, Z., Tsironi, V., Wolanczyk, T., Zekanowski, C., Barr, C.L., Batterson, J.R., Berlin, C., Bruun, R.D., Budman, C.L., Cath, D.C., Chouinard, S., Coppola, G., Cox, N.J., Darrow, S., Davis, L.K., Dion, Y., Freimer, N.B., Grados, M.A., Hirschtritt, M.E., Huang, A.Y., Illmann, C., Kurlan, R., Leckman, J.F., Lyon, G.J., Malaty, I.A., Mathews, C.A., MacMahon, W.M., Neale, B.M., Okun, M.S., Osiecki, L., Pauls, D.L., Posthuma, D., Ramensky, V., Robertson, M.M., Rouleau, G.A., Sandor, P., Scharf, J.M., Singer, H.S., Smit, J., Sul, J.H., and Yu, D.

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, DNA Copy Number Variations, Receptors, Cell Surface, Biology, Genome, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, RARE, SCHIZOPHRENIA, medicine, Humans, Copy-number variation, Child, NEURODEVELOPMENTAL DISORDERS, Gene, lcsh:QH301-705.5, Exome sequencing, 030304 developmental biology, Medicinsk genetik, Sequence (medicine), Genetics, 0303 health sciences, SEVERE INTELLECTUAL DISABILITY, Cadherin, MUTATIONS, AUTISM SPECTRUM DISORDER, Cell Polarity, OBSESSIVE-COMPULSIVE DISORDER, Cadherins, medicine.disease, Pedigree, PREVALENCE, CONGENITAL HEART-DISEASE, GENOME, 030104 developmental biology, lcsh:Biology (General), Schizophrenia, Medical genetics, Female, Cadherins/genetics, Receptors, Cell Surface/genetics, Tourette Syndrome/genetics, Tourette Syndrome/pathology, TIC Genetics, Tourette disorder, cell polarity, copy number variants, de novo variants, gene discovery, microarray genotyping, multiplex, simplex, whole exome sequencing, Medical Genetics, 030217 neurology & neurosurgery, Tourette Syndrome
Abstract

SUMMARY We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk., In Brief Wang et al. expand their earlier exome-sequencing work in TD, adding 291 trios and conducting combined analyses suggesting de novo variants carry more risk in individuals with unaffected parents, establishing de novo structural variants as risk factors, identifying CELSR3 as a risk gene, and implicating cell polarity in pathogenesis., Graphical Abstract

Published
2018

8. Prevalence and predictors of hair pulling disorder and excoriation disorder in Tourette syndrome

Author

Carol A. Mathews, Paul Sandor, Nancy J. Keuthen, Erin E. Curley, Gholson J. Lyon, Marco A. Grados, Erica Greenberg, David L. Pauls, Cathy L. Budman, Robert A. King, Yves Dion, Esther S. Tung, Angela Essa, Jeremiah M. Scharf, Matthew E. Hirschtritt, Kelly G. Yang, Lisa Osiecki, Sabrina M. Darrow, Caitlin Gauvin, and Cornelia Illmann

Subjects
Male, Obsessive-Compulsive Disorder, Excoriation, Prevalence, Comorbidity, Neurodegenerative, Obsessive–compulsive disorder, Tourette syndrome, Excoriation disorder/skin picking disorder, Body-focused repetitive behaviors, Trichotillomania, 0302 clinical medicine, Hair-pulling, Surveys and Questionnaires, Developmental and Educational Psychology, Child and adolescent psychiatry, Psychology, Child, Trichotillomania (hair-pulling disorder), Female sex, General Medicine, Serious Mental Illness, Anxiety Disorders, Psychiatry and Mental health, Mental Health, Female, Tourette Association of America International Consortium for Genetics, medicine.medical_specialty, Clinical Sciences, Developmental & Child Psychology, Article, 03 medical and health sciences, Clinical Research, Internal medicine, mental disorders, medicine, Genetic predisposition, Humans, Trichotillomania/hair pulling disorder, Psychiatry, business.industry, medicine.disease, Brain Disorders, 030227 psychiatry, Pediatrics, Perinatology and Child Health, business, Self-Injurious Behavior, 030217 neurology & neurosurgery, Tourette Syndrome
Abstract

OBJECTIVE: Trichotillomania/hair pulling disorder (HPD) and excoriation/skin picking disorder (SPD) are childhood-onset, body-focused repetitive behaviors that are thought to share genetic susceptibility and underlying pathophysiology with obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). We sought to determine the prevalence of DSM-5 HPD and SPD in TS patients, and to identify clinical factors most associated with their co-morbidity with TS. METHOD: Participants included 811 TS patients recruited from TS specialty clinics for a multi-center genetic study. Patients were assessed using standardized, validated semi-structured interviews. HPD and SPD diagnoses were determined using a validated self-report questionnaire. HPD/SPD prevalence rates were calculated, and clinical predictors were evaluated using regression modeling. RESULTS: 3.8% and 13.0% of TS patients met DSM-5 criteria for HPD and SPD, respectively. In univariable analyses, female sex, OCD, and both tic and obsessive-compulsive severity were among those associated with HPD and/or SPD. In multivariable analyses, only lifetime worst-ever motor tic severity remained significantly associated with HPD. Female sex, co-occurring OCD, ADHD and motor tic severity remained independently associated with SPD. CONCLUSION: This is the first study to examine HPD and SPD prevalence in a TS sample using semi-structured diagnostic instruments. The prevalence of HPD and SPD in TS patients, and their association with increased tic severity and co-occurring OCD, suggests that clinicians should screen children with TS and related disorders for HPD/SPD, particularly in females and in those with co-occurring OCD. This study also helps set a foundation for subsequent research regarding HPD/SPD risk factors, pathophysiology, and treatment models.

Published
2017

9. De Novo Coding Variants Are Strongly Associated with Tourette Disorder

Author

A. Jeremy Willsey, Thomas V. Fernandez, Dongmei Yu, Robert A. King, Andrea Dietrich, Jinchuan Xing, Stephan J. Sanders, Jeffrey D. Mandell, Alden Y. Huang, Petra Richer, Louw Smith, Shan Dong, Kaitlin E. Samocha, Benjamin M. Neale, Giovanni Coppola, Carol A. Mathews, Jay A. Tischfield, Jeremiah M. Scharf, Matthew W. State, Gary A. Heiman, Mohamed Abdulkadir, Julia Bohnenpoll, Yana Bromberg, Lawrence W. Brown, Keun-Ah Cheon, Barbara J. Coffey, Li Deng, Lonneke Elzerman, Odette Fründt, Blanca Garcia-Delgar, Erika Gedvilaite, Donald L. Gilbert, Dorothy E. Grice, Julie Hagstrøm, Tammy Hedderly, Isobel Heyman, Pieter J. Hoekstra, Hyun Ju Hong, Chaim Huyser, Laura Ibanez-Gomez, Young Key Kim, Young-Shin Kim, Yun-Joo Koh, Sodahm Kook, Samuel Kuperman, Andreas Lamerz, Bennett Leventhal, Andrea G. Ludolph, Claudia Lühr da Silva, Marcos Madruga-Garrido, Athanasios Maras, Pablo Mir, Astrid Morer, Alexander Münchau, Tara L. Murphy, Cara Nasello, Thaïra J.C. Openneer, Kerstin J. Plessen, Veit Roessner, Stephan Sanders, Eun-Young Shin, Deborah A. Sival, Dong-Ho Song, Jungeun Song, Anne Marie Stolte, Nawei Sun, Jennifer Tübing, Frank Visscher, Michael F. Walker, Sina Wanderer, Shuoguo Wang, Martin Woods, Yeting Zhang, Anbo Zhou, Samuel H. Zinner, Cathy L. Barr, James R. Batterson, Cheston Berlin, Ruth D. Bruun, Cathy L. Budman, Danielle C. Cath, Sylvain Chouinard, Nancy J. Cox, Sabrina Darrow, Lea K. Davis, Yves Dion, Nelson B. Freimer, Marco A. Grados, Matthew E. Hirschtritt, Cornelia Illmann, Roger Kurlan, James F. Leckman, Gholson J. Lyon, Irene A. Malaty, William M. MaMahon, Michael S. Okun, Lisa Osiecki, David L. Pauls, Danielle Posthuma, Vasily Ramensky, Mary M. Robertson, Guy A. Rouleau, Paul Sandor, Harvey S. Singer, Jan Smit, Jae-Hoon Sul, Psychiatry, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Reproduction & Development (AR&D), Human genetics, Other departments, and Child Psychiatry

Subjects
0301 basic medicine, Proband, Adult, Male, Parents, INTELLECTUAL DISABILITY, FUNCTIONAL GENOMICS EXPERIMENTS, DNA-SEQUENCING DATA, AUTISM SPECTRUM DISORDERS, Cell Cycle Proteins, Receptors, Cell Surface, Biology, medicine.disease_cause, Bioinformatics, Tourette syndrome, Article, TIC DISORDERS, Cohort Studies, 03 medical and health sciences, medicine, Odds Ratio, Missense mutation, Humans, Genetic Predisposition to Disease, Copy-number variation, Child, Gene, Exome sequencing, Genetics, COPY NUMBER VARIANTS, Mutation, MUTATIONS, General Neuroscience, PSYCHIATRIC-DISORDERS, Intracellular Signaling Peptides and Proteins, Genetic Variation, Proteins, NIPBL, OBSESSIVE-COMPULSIVE DISORDER, LANGE-SYNDROME, Sequence Analysis, DNA, medicine.disease, Cadherins, Phosphoproteins, Fibronectins, 030104 developmental biology, Female, Tourette Syndrome
Abstract

Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186 trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably damaging missense) are overrepresented in probands (RR 1.37, p = 0.003). We identify four likely risk genes with multiple de novo damaging variants in unrelated probands: WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1). Overall, we estimate that de novo damaging variants in approximately 400 genes contribute risk in 12% of clinical cases. Video Abstract [Figure presented]

Published
2017

10. Genome-wide association study of Tourette's syndrome

Author

Lea K. Davis, Harvey S. Singer, Thomas L. Lowe, Jacquelyn Crane, James F. Leckman, P. C. Lee, Simon Girard, Yves Dion, Danielle Posthuma, Rainald Moessner, Gary A. Heiman, Jubel Morgan, Gholson J. Lyon, K. Anderson, Andres Ruiz-Linares, William Cornejo Ochoa, Robert A. King, Daniel B. Mirel, Jesen Fagerness, Gerald Erenberg, John T. Walkup, Patrick Evans, Pieter J. Hoekstra, Buhm Han, James A. Knowles, Desmond Campbell, Paul Sandor, Gabriel Bedoya Berrío, Martha Rangel-Lugo, Eric R. Gamazon, Lisa Osiecki, William M. McMahon, Eric Strengman, S. E. Stewart, Mark Leppert, David L. Pauls, Anna Pluzhnikov, Luis Diego Herrera, AB Singleton, Priya Moorjani, Nelson B. Freimer, Ben A. Oostra, Peter Heutink, Shaun Purcell, Guy A. Rouleau, Cathy L. Budman, David V. Conti, Anna Tikhomirov, John Hardy, S. C. Mesa Restrepo, Barbara Kremeyer, S. Davarya, Cornelia Illmann, Kenneth K. Kidd, Andrew Crenshaw, J.R. Kidd, J. C. Cardona Silgado, R. Kurlan, Chunyu Liu, Robert B. Weiss, Mary M. Robertson, A.J. Pakstis, A. V. Valencia Duarte, Thomas V. Fernandez, Roel A. Ophoff, Matthew W. State, Sylvain Chouinard, Cathy L. Barr, N. Phan, Eduardo Fournier, H. Müller, Nancy J. Cox, Nicholas T. Weiss, Varda Gross-Tsur, Eskin E, Roxana Romero, Jay A. Tischfield, J. R. Gibbs, Allan L. Naarden, J.H. Smit, Marco A. Grados, Anuar Konkashbaev, Chiara Sabatti, Melissa Parkin, Christopher K. Edlund, Carol A. Mathews, Ruth D. Bruun, Joseph Jankovic, Donald L. Gilbert, Fortu Benarroch, Victor I. Reus, Michael Wagner, Jeremiah M. Scharf, Dongmei Yu, Danielle C. Cath, Benjamin M. Neale, Yehuda Pollak, Psychiatry, Human genetics, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, Functional Genomics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Child and Adolescent Psychiatry / Psychology, and Clinical Genetics

Subjects
Male, DISORDER, Obsessive-Compulsive Disorder, Fibrillar Collagens, International Cooperation, Genome-wide association study, Tourette syndrome, 0302 clinical medicine, DEPENDENCE, SCHIZOPHRENIA, GWAS, genetics, Copy-number variation, Genetics, COPY NUMBER VARIANTS, 0303 health sciences, education.field_of_study, SLITRK1 VAR321, tics, COMMON VARIANTS, Ashkenazi jews, 3. Good health, FAMILY, Psychiatry and Mental health, Female, Psychology, Chromosomes, Human, Pair 9, Adult, Tics, Adolescent, Genotype, Population, Tourette's syndrome, Polymorphism, Single Nucleotide, White People, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, Meta-Analysis as Topic, medicine, Humans, Genetic Predisposition to Disease, 1000 Genomes Project, education, Molecular Biology, 030304 developmental biology, MUTATIONS, POLR3B, medicine.disease, neurodevelopmental disorder, INDIVIDUALS, Attention Deficit Disorder with Hyperactivity, Case-Control Studies, 030217 neurology & neurosurgery, Imputation (genetics), Genome-Wide Association Study, Tourette Syndrome
Abstract

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P

Published
2013

11. Identification of two heritable cross-disorder endophenotypes for Tourette Syndrome

Author

Cornelia Illmann, Dongmei Yu, Danielle C. Cath, Jeremiah M. Scharf, Robert A. King, Yves Dion, Carol A. Mathews, Marco Grados, William M. McMahon, Gholson J. Lyon, Cathy L. Budman, Paul C. Lee, Sabrina M. Darrow, Matthew E. Hirschtritt, Erica Greenberg, Kevin L. Delucchi, David L. Pauls, Lisa Osiecki, Paul Sandor, Lauren M. McGrath, and Lea K. Davis

Subjects
Adult, Male, medicine.medical_specialty, Multifactorial Inheritance, Obsessive-Compulsive Disorder, Adolescent, Endophenotypes, Mothers, Comorbidity, Tourette syndrome, Risk Assessment, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Child of Impaired Parents, mental disorders, medicine, Attention deficit hyperactivity disorder, Humans, Genetic Predisposition to Disease, Adhd symptoms, Psychiatry, Child, Genetic heterogeneity, Heritability, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Phenotype, Attention Deficit Disorder with Hyperactivity, Endophenotype, Child, Preschool, Female, Psychology, 030217 neurology & neurosurgery, Genome-Wide Association Study, Tourette Syndrome
Abstract

Phenotypic heterogeneity in Tourette syndrome is partly due to complex genetic relationships among Tourette syndrome, obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD). Identifying symptom-based endophenotypes across diagnoses may aid gene-finding efforts.Assessments for Tourette syndrome, OCD, and ADHD symptoms were conducted in a discovery sample of 3,494 individuals recruited for genetic studies. Symptom-level factor and latent class analyses were conducted in Tourette syndrome families and replicated in an independent sample of 882 individuals. Classes were characterized by comorbidity rates and proportion of parents included. Heritability and polygenic load associated with Tourette syndrome, OCD, and ADHD were estimated.The authors identified two cross-disorder symptom-based phenotypes across analyses: symmetry (symmetry, evening up, checking obsessions; ordering, arranging, counting, writing-rewriting compulsions, repetitive writing tics) and disinhibition (uttering syllables/words, echolalia/palilalia, coprolalia/copropraxia, and obsessive urges to offend/mutilate/be destructive). Heritability estimates for both endophenotypes were high and statistically significant (disinhibition factor=0.35, SE=0.03; symmetry factor=0.39, SE=0.03; symmetry class=0.38, SE=0.10). Mothers of Tourette syndrome probands had high rates of symmetry (49%) but not disinhibition (5%). Polygenic risk scores derived from a Tourette syndrome genome-wide association study (GWAS) were significantly associated with symmetry, while risk scores derived from an OCD GWAS were not. OCD polygenic risk scores were significantly associated with disinhibition, while Tourette syndrome and ADHD risk scores were not.The analyses identified two heritable endophenotypes related to Tourette syndrome that cross traditional diagnostic boundaries. The symmetry phenotype correlated with Tourette syndrome polygenic load and was present in otherwise Tourette-unaffected mothers, suggesting that this phenotype may reflect additional Tourette syndrome (rather than OCD) genetic liability that is not captured by traditional DSM-based diagnoses.

Published
2016

12. Effectiveness of a web-based protocol for the screening and phenotyping of individuals with tourette syndrome for genetic studies

Author

Elizabeth McLaughlin, Martha Rangel-Lugo, Lisa Osiecki, Crystelle A. Egan, David L. Pauls, Jeremiah M. Scharf, Julia A. O'Rourke, Justin D. Royal, Heather Cowley, Susan E. Marakovitz, Rachel Proujansky, Lauren Barton, Cornelia Illmann, and Carol A. Mathews

Subjects
Adult, Male, Obsessive-Compulsive Disorder, Adolescent, Genome-wide association study, Tourette syndrome, Article, Young Adult, Cellular and Molecular Neuroscience, Surveys and Questionnaires, medicine, Humans, Web application, Genetic Predisposition to Disease, Genetic Testing, Young adult, Child, Genetics (clinical), Genetic testing, Genetic association, Protocol (science), Internet, medicine.diagnostic_test, business.industry, Mental Disorders, Age Factors, medicine.disease, Psychiatry and Mental health, Phenotype, Attention Deficit Disorder with Hyperactivity, Sample size determination, Female, business, Genome-Wide Association Study, Tourette Syndrome, Clinical psychology
Abstract

Genome-wide association studies (GWAS) and other emerging technologies offer great promise for the identification of genetic risk factors for complex psychiatric disorders, yet such studies are constrained by the need for large sample sizes. Web-based collection offers a relatively untapped resource for increasing participant recruitment. Therefore, we developed and implemented a novel web-based screening and phenotyping protocol for genetic studies of Tourette syndrome (TS), a childhood-onset neuropsychiatric disorder characterized by motor and vocal tics. Participants were recruited over a 13-month period through the membership of the Tourette Syndrome Association (TSA; n = 28,878). Of the TSA members contacted, 4.3% (1,242) initiated the questionnaire, and 79.5% (987) of these were enrollment eligible. 63.9% (631) of enrolled participants completed the study by submitting phenotypic data and blood specimens. Age was the only variable that predicted study completion; children and young adults were significantly less likely to be study completers than adults 26 and older. Compared to a clinic-based study conducted over the same time period, the web-based method yielded a 60% larger sample. Web-based participants were older and more often female; otherwise, the sample characteristics did not differ significantly. TS diagnoses based on the web-screen demonstrated 100% accuracy compared to those derived from in-depth clinical interviews. Our results suggest that a web-based approach is effective for increasing the sample size for genetic studies of a relatively rare disorder and that our web-based screen is valid for diagnosing TS. Findings from this study should aid in the development of web-based protocols for other disorders. © 2012 Wiley Periodicals, Inc.

Published
2012

13. 896. Genetic and Phenotypic Overlap of Specific Obsessive-Compulsive Subtypes with Tourette Syndrome

Author

Lauren M. McGrath, Robert A. King, Cornelia Illmann, Erica Greenberg, David L. Pauls, Paul C. Lee, Dongmei Yu, Danielle C. Cath, Kevin L. Delucchi, Matthew E. Hirschtritt, Marco A. Grados, Yves Dion, Paul Sandor, Gholson J. Lyon, Carol A. Mathews, Jeremiah M. Scharf, Cathy L. Budman, Sabrina M. Darrow, William M. McMahon, and Lisa Osiecki

Subjects
Proband, medicine.medical_specialty, Hoarding, Cognition, medicine.disease, behavioral disciplines and activities, Tourette syndrome, humanities, Mood, Obsessive compulsive, mental disorders, medicine, Anxiety, Adhd symptoms, medicine.symptom, Psychology, Psychiatry, Biological Psychiatry, Clinical psychology
Abstract

Background The unique phenotypic and genetic aspects of obsessive-compulsive (OCD) and attention-deficit/hyperactivity disorder (ADHD) among individuals with Tourette syndrome (TS) have not been well characterized. Methods OCD and ADHD symptom patterns were identified among patients with TS and their family members (N=3494) using exploratory factor and latent class analyses; clinical associations and heritability of these factors were examined. Results Factor analyses yielded 2- and 8-factor models for ADHD and OCD, respectively. Both ADHD factors (inattention and hyperactivity/impulsiveness) were genetically related to TS, ADHD, and OCD; all OCD factors (related to symmetry/contamination, unusual thoughts, aggressive urges, and hoarding) were genetically related to OCD. The OCD aggressive urges factor was genetically associated with TS and ADHD, the symmetry/exactness and fear of harm factors were associated with TS, and the hoarding factor was associated with ADHD. Latent classes based on OCD and ADHD factor sum scores to examine the relationships between OCD and ADHD symptoms in probands and family members revealed a three-class solution: ADHD; OCD+ADHD; and asymmetry/exactness, hoarding, and ADHD. The majority of participants with TS, ADHD, mood, and anxiety disorders, as well as mothers, fathers, and probands, were classified in the ADHD class. In contrast, the largest percentage of participants with OCD and disruptive behavior disorders were classified in the asymmetry/exactness, hoarding, and ADHD class. Conclusions Symmetry/exactness, aggressive urges, fear of harm, and hoarding show complex genetic relationships with TS, OCD, and ADHD, and transcend diagnostic boundaries, perhaps representing a failure of top-down cognitive control common to all three disorders.

Published
2017

14. Cross-Disorder Genome-Wide Analyses Suggest a Complex Genetic Relationship Between Tourette's Syndrome and OCD

Author

Mary M. Robertson, Peter Heutink, Leonhard Lennertz, Victor I. Reus, John Hardy, Mark A. Riddle, Beatriz Camarena, Helena Garrido, Robert A. King, Simon Girard, Christine Lochner, Michael H. Bloch, Patrick Evans, Anuar Konkashbaev, Jack Samuels, Priya Moorjani, Chiara Sabatti, Andrew J. Pakstis, Ying Wang, O. Joseph Bienvenu, Richard Delorme, David L. Pauls, Rainald Moessner, Gary A. Heiman, Daniel A. Geller, Marco A. Grados, Eric R. Gamazon, John Piacentini, Dan J. Stein, William Cornejo Ochoa, Maria Conceição do Rosário, Karin Egberts, Thomas L. Lowe, Christopher K. Edlund, Jan Smit, Christopher Pittenger, Denise A. Chavira, Marion Leboyer, Homero Vallada, Sandra Catalina Mesa Restrepo, Jacquelyn Crane, Donald W. Black, David V. Conti, Paul Sandor, Humberto Nicolini, Lisa Osiecki, Jeremy Veenstra-VanderWeele, Catherine Mayerfeld, Danielle Posthuma, Edna Grünblatt, Carolina Cappi, Robert B. Weiss, Cristina Barlassina, Sara Lupoli, Chunyu Liu, Sian M. J. Hemmings, Ben A. Oostra, D. Denys, Susanne Walitza, Lea K. Davis, Stephen A. Haddad, Luis Diego Herrera, Jubel Morgan, Hans Joergen Grabe, Benjamin M. Neale, Thomas V. Fernandez, Yehuda Pollak, Roel A. Ophoff, Gerald Nestadt, Harvey S. Singer, Stephan Ruhrmann, Bernadette Cullen, Michael Wagner, Nuria Lanzagorta, Jeremiah M. Scharf, Cathy L. Budman, Ruth D. Bruun, R. Kurlan, Valsama Eapen, Jesen Fagerness, Desmond Campbell, James L. Kennedy, Carlos N. Pato, Nancy J. Cox, Pieter J. Hoekstra, Joseph Jankovic, Cathy L. Barr, Peter Falkai, Donald L. Gilbert, Fortu Benarroch, Dianne M. Hezel, Maria Cristina Cavallini, Brooke Sheppard, Fabio Macciardi, William M. McMahon, Laura Bellodi, Maurizio Turiel, Wolfgang Maier, Varda Gross-Tsur, Helena Brentani, Dongmei Yu, Danielle C. Cath, Ana V. Valencia Duarte, Eduardo Fournier, James A. Knowles, Tobias J. Renner, Erika L. Nurmi, Guy A. Rouleau, Benjamin D. Greenberg, Nelson B. Freimer, Shaun Purcell, Patience J. Gallagher, Roxana Romero, Gregory L. Hanna, Paolo Manunta, Edwin H. Cook, Michele T. Pato, Sylvain Chouinard, Scott L. Rauch, James T. McCracken, Gloria Gerber, Carol A. Mathews, Jens R. Wendland, Sampath Arepalli, Dennis L. Murphy, Daniele Cusi, Barbara Kremeyer, Vladimir Coric, Aline S. Sampaio, Erika Salvi, Julio C. Cardona Silgado, Cornelia Illmann, James F. Leckman, Euripedes Constantino Miguel, H. Müller, Yin Yao Shugart, Eric Strengman, Ana Gabriela Hounie, Michael E. Weale, Gabriel Bedoya Berrió, Margaret A. Richter, Maurizio Marconi, Allan L. Naarden, Michael A. Jenike, M.R. Cookson, David R. Rosenberg, Andres Ruiz-Linares, S. Evelyn Stewart, Paul D. Arnold, H.G.M. Westenberg, Yves Dion, Jay A. Tischfield, Eske M. Derks, Lauren M. McGrath, Child and Adolescent Psychiatry / Psychology, Clinical Genetics, Yu, D., Mathews, C. A., Scharf, J. M., Neale, B. M., Davis, L. K., Gamazon, E. R., Derks, E. M., Evans, P., Edlund, C. K., Crane, J., Fagerness, J. A., Osiecki, L., Gallagher, P., Gerber, G., Haddad, S., Illmann, C., Mcgrath, L. M., Mayerfeld, C., Arepalli, S., Barlassina, C., Barr, C. L., Bellodi, L., Benarroch, F., Berrio, G. B., Bienvenu, O. J., Black, D., Bloch, M. H., Brentani, H., Bruun, R. D., Budman, C. L., Camarena, B., Campbell, D. D., Cappi, C., Cardona Silgado, J. C., Cavallini, M. C., Chavira, D. A., Chouinard, S., Cook, E. H., Cookson, M. R., Coric, V., Cullen, B., Cusi, D., Delorme, R., Denys, D., Dion, Y., Eapen, V., Egberts, K., Falkai, P., Fernandez, T., Fournier, E., Garrido, H., Geller, D., Gilbert, D., Girard, S. L., Grabe, H. J., Grados, M. A., Greenberg, B. D., Gross-Tsur, V., Grunblatt, E., Hardy, J., Heiman, G. A., Hemmings, S. M. J., Herrera, L. D., Hezel, D. M., Hoekstra, P. J., Jankovic, J., Kennedy, J. L., King, R. A., Konkashbaev, A. I., Kremeyer, B., Kurlan, R., Lanzagorta, N., Leboyer, M., Leckman, J. F., Lennertz, L., Liu, C., Lochner, C., Lowe, T. L., Lupoli, S., Macciardi, F., Maier, W., Manunta, P., Marconi, M., Mccracken, J. T., Mesa Restrepo, S. C., Moessner, R., Moorjani, P., Morgan, J., Muller, H., Murphy, D. L., Naarden, A. L., Ochoa, W. C., Ophoff, R. A., Pakstis, A. J., Pato, M. T., Pato, C. N., Piacentini, J., Pittenger, C., Pollak, Y., Rauch, S. L., Renner, T., Reus, V. I., Richter, M. A., Riddle, M. A., Robertson, M. M., Romero, R., Rosario, M. C., Rosenberg, D., Ruhrmann, S., Sabatti, C., Salvi, E., Sampaio, A. S., Samuels, J., Sandor, P., Service, S. K., Sheppard, B., Singer, H. S., Smit, J. H., Stein, D. J., Strengman, E., Tischfield, J. A., Turiel, M., Valencia Duarte, A. V., Vallada, H., Veenstra-VanderWeele, J., Walitza, S., Walkup, J., Wang, Y., Weale, M., Weiss, R., Wendland, J. R., Westenberg, H. G. M., Yao, Y., Hounie, A. G., Miguel, E. C., Nicolini, H., Wagner, M., Ruiz-Linares, A., Cath, D. C., Mcmahon, W., Posthuma, D., Oostra, B. A., Nestadt, G., Rouleau, G. A., Purcell, S., Jenike, M. A., Heutink, P., Hanna, G. L., Conti, D. V., Arnold, P. D., Freimer, N., Stewart, S. E., Knowles, J. A., Cox, N. J., Pauls, D. L., Netherlands Institute for Neuroscience (NIN), Sub String Theory Cosmology and ElemPart, Leerstoel Hout, Experimental psychopathology, Psychiatry, Human genetics, NCA - Neurobiology of mental health, EMGO - Mental health, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Other departments, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Adult Psychiatry, Complex Trait Genetics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, and EMGO+ - Mental Health

Subjects
Adult, Male, Obsessive-Compulsive Disorder, diagnosis [Tourette Syndrome], Tics, Single-nucleotide polymorphism, Genome-wide association study, Comorbidity, VARIANTS, Tourette syndrome, Polymorphism, Single Nucleotide, Severity of Illness Index, ASSOCIATION SCANS, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Polymorphism (computer science), Severity of illness, mental disorders, medicine, TICS, Humans, ddc:610, Polymorphism, 030304 developmental biology, Genetics, Psychiatric Status Rating Scales, genetics [Obsessive-Compulsive Disorder], 0303 health sciences, GENERALIST GENES, Single Nucleotide, OBSESSIVE-COMPULSIVE DISORDER, epidemiology [Tourette Syndrome], medicine.disease, Genetic architecture, Psychiatry and Mental health, genetics [Tourette Syndrome], Female, epidemiology [Obsessive-Compulsive Disorder], Psychology, 030217 neurology & neurosurgery, diagnosis [Obsessive-Compulsive Disorder], Genome-Wide Association Study, Tourette Syndrome
Abstract

Objective: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD.Method: The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders.Results: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders Polygenic score analyses identified a significant polygenic component for OCD (p=2x10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01).Conclusions: Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring burette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

Published
2015

15. Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture

Author

Patrick Evans, Jay A. Tischfield, Anuar Konkashbaev, Richard Delorme, Sandra Catalina Mesa Restrepo, Margaret A. Richter, Gregory L. Hanna, Allan L. Naarden, Michele T. Pato, Jian Yang, Denise A. Chavira, Damiaan Denys, Paul Sandor, Michael A. Jenike, Sian M. J. Hemmings, Paul D. Arnold, Stephan Ruhrmann, H.G.M. Westenberg, Yves Dion, Cathy L. Barr, Andres Ruiz-Linares, Brooke Sheppard, Leonhard Lennertz, Eske M. Derks, Lauren M. McGrath, Barbara Kremeyer, Marion Leboyer, Victor I. Reus, Cornelia Illmann, S. Evelyn Stewart, Dan J. Stein, Ana Gabriela Hounie, James T. McCracken, R. Kurlan, Chunyu Liu, Aline S. Sampaio, Thomas L. Lowe, Benjamin M. Neale, Yehuda Pollak, Desmond Campbell, Fabio Macciardi, Mary M. Robertson, Benjamin D. Greenberg, Ben A. Oostra, Rainald Moessner, Gary A. Heiman, Nuria Lanzagorta, Sylvain Chouinard, Rianne M. Blom, Karin Egberts, Carlos N. Pato, David V. Conti, Carol A. Mathews, Ying Wang, Marco A. Grados, Julio C. Cardona Silgado, S. Hong Lee, H. Müller, Eric R. Gamazon, Humberto Nicolini, Jan Smit, Euripedes Constantino Miguel, Jens R. Wendland, Cathy L. Budman, Laura Bellodi, Danielle Posthuma, Jubel Morgan, David R. Rosenberg, John Piacentini, Hans J. Grabe, Mark A. Riddle, Beatriz Camarena, Naomi R. Wray, Eric Strengman, Dennis L. Murphy, Simon Girard, Christine Lochner, Ruth D. Bruun, Joseph Jankovic, Edwin H. Cook, William M. McMahon, Scott L. Rauch, James F. Leckman, Peter Falkai, Fortu Benarroch, Christopher K. Edlund, Gabriel Bedoya Berrío, Homero Vallada, Susanne Walitza, Nelson B. Freimer, Stephen A. Haddad, Yin Yao Shugart, Danielle C. Cath, Nancy J. Cox, Varda Gross-Tsur, Guy A. Rouleau, Bernadette Cullen, Michael H. Bloch, Dieter Deforce, David L. Pauls, Thomas V. Fernandez, Roel A. Ophoff, Filip Van Nieuwerburgh, Gerald Nestadt, Dongmei Yu, Helena Garrido, Robert A. King, James L. Kennedy, Clare L. Keenan, Lisa Osiecki, Jack Samuels, Jeremy Veenstra-VanderWeele, Ana V. Valencia Duarte, James A. Knowles, Patience J. Gallagher, Carolina Cappi, Maria Conceição do Rosário, Andrew J. Pakstis, Christopher Pittenger, Michael Wagner, Jeremiah M. Scharf, Daniel A. Geller, Vladimir Coric, Tobias J. Renner, Oscar J. Bienvenu, Roxana Romero, William Cornejo Ochoa, Peter Heutink, Lea K. Davis, Harvey S. Singer, Maria Cristina Cavallini, Psychiatry, Human genetics, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, Department of Psychiatry and Mental Health, Faculty of Health Sciences, Univ Chicago, Harvard Univ, Broad Inst Harvard & MIT, Univ Amsterdam, Massachusetts Gen Hosp, Univ Queensland, Univ Hlth Network, Hosp Sick Children, Univ Vita Salute San Raffaele, Hadassah Hebrew Univ Med Ctr, Univ Pontificia Bolivariana, Johns Hopkins Univ, Yale Univ, North Shore Long Isl Jewish Med Ctr, NYU Med Ctr, North Shore Long Isl Jewish Hlth Syst, Hofstra Univ, Inst Nacl Psiquiatria Ramon de la Fuente Muniz, UCL, Univ Hong Kong, Universidade de São Paulo (USP), Vrije Univ Amsterdam, Univ Utrecht, Altrecht Acad Anxiety Ctr, Univ Milan, Univ Calif Los Angeles, Univ Calif San Diego, Univ Montreal, Univ Illinois, Univ Ghent, Inst Pasteur, French Natl Sci Fdn, Hop Robert Debre, Univ Wurzburg, Univ Munich, Univ Med Greifswald, Butler Hosp, Shaare Zedek Med Ctr, Rutgers State Univ, Univ Stellenbosch, Baylor Coll Med, Ctr Addict & Mental Hlth, Univ Toronto, Overlook Hosp, Carracci Med Grp, Inst Mondor Rech Biomed, Univ Bonn, Univ Calif San Francisco, UCI, Univ Utah, NIMH Intramural Res Program, Med City Dallas Hosp, Univ Med Ctr, Univ So Calif, Partners Psychiat & McLean Hosp, Sunnybrook Hlth Sci Ctr, St George Hosp, Sch Med, Hosp Nacl Ninos Dr Carlos Saenz Herrera, Universidade Federal de São Paulo (UNIFESP), Wayne State Univ, Detroit Med Ctr, McGill Univ, Univ Cologne, Universidade Federal da Bahia (UFBA), Youthdale Treatment Ctr, Johns Hopkins Univ Sch Med, Univ Cape Town, Univ Med Ctr Utrecht, Vanderbilt Univ, Univ Zurich, Inst Royal Netherlands Acad Arts & Sci NIN KNAW, Natl Inst Genom Med SAP, Vrije Univ Amsterdam Med Ctr, Erasmus Univ, Univ Michigan, German Ctr Neurodegenerat Dis, Erasmus MC, Univ British Columbia, Brigham & Womens Hosp, Davis, Lk, Yu, D, Keenan, Cl, Gamazon, Er, Konkashbaev, Ai, Derks, Em, Neale, Bm, Yang, J, Lee, Sh, Evans, P, Barr, Cl, Bellodi, Laura, Benarroch, F, Berrio, Gb, Bienvenu, Oj, Bloch, Mh, Blom, Rm, Bruun, Rd, Budman, Cl, Camarena, B, Campbell, D, Cappi, C, Cardona Silgado, Jc, Cath, Dc, Cavallini, Mc, Chavira, Da, Chouinard, S, Conti, Dv, Cook, Eh, Coric, V, Cullen, Ba, Deforce, D, Delorme, R, Dion, Y, Edlund, Ck, Egberts, K, Falkai, P, Fernandez, Tv, Gallagher, Pj, Garrido, H, Geller, D, Girard, Sl, Grabe, Hj, Grados, Ma, Greenberg, Bd, Gross Tsur, V, Haddad, S, Heiman, Ga, Hemmings, Sm, Hounie, Ag, Illmann, C, Jankovic, J, Jenike, Ma, Kennedy, Jl, King, Ra, Kremeyer, B, Kurlan, R, Lanzagorta, N, Leboyer, M, Leckman, Jf, Lennertz, L, Liu, C, Lochner, C, Lowe, Tl, Macciardi, F, Mccracken, Jt, Mcgrath, Lm, Mesa Restrepo, Sc, Moessner, R, Morgan, J, Muller, H, Murphy, Dl, Naarden, Al, Ochoa, Wc, Ophoff, Ra, Osiecki, L, Pakstis, Aj, Pato, Mt, Pato, Cn, Piacentini, J, Pittenger, C, Pollak, Y, Rauch, Sl, Renner, Tj, Reus, Vi, Richter, Ma, Riddle, Ma, Robertson, Mm, Romero, R, Rosàrio, Mc, Rosenberg, D, Rouleau, Ga, Ruhrmann, S, Ruiz Linares, A, Sampaio, A, Samuels, J, Sandor, P, Sheppard, B, Singer, H, Smit, Jh, Stein, Dj, Strengman, E, Tischfield, Ja, Valencia Duarte, Av, Vallada, H, Van Nieuwerburgh, F, Veenstra Vanderweele, J, Walitza, S, Wang, Y, Wendland, Jr, Westenberg, Hg, Shugart, Yy, Miguel, Ec, Mcmahon, W, Wagner, M, Nicolini, H, Posthuma, D, Hanna, Gl, Heutink, P, Denys, D, Arnold, Pd, Oostra, Ba, Nestadt, G, Freimer, Nb, Pauls, Dl, Wray, Nr, Stewart, Se, Mathews, Ca, Knowles, Ja, Cox, Nj, Scharf, Jm, Functional Genomics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Davis, Lea K, Yu, Dongmei, Keenan, Clare L, Gamazon, Eric R, Lee, S Hong, Scharf, Jeremiah M, Child and Adolescent Psychiatry / Psychology, Clinical Genetics, Other departments, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Adult Psychiatry, and Graduate School

Subjects
Cancer Research, Obsessive-Compulsive Disorder, COMPLEX DISEASES, Genome-wide association study, heritability, Genome-wide association studies, neurobehavioral disorders, COMMON SNPS, 0302 clinical medicine, Gene Frequency, Missing heritability problem, MISSING HERITABILITY, Cerebellum, Heritability of autism, BRAIN, Genetics (clinical), Genetics, ddc:616, Genetics & Heredity, 0303 health sciences, Chromosome 15, humanities, FAMILY, obsessive-compulsive disorder, genetics [Tourette Syndrome], Phenotype, NEUROPSYCHIATRIC DISORDERS, GENÔMICA, Research Article, EXPRESSION, lcsh:QH426-470, SNP, Biology, Quantitative trait locus, Genome-wide Complex Trait Analysis, Genetic correlation, behavioral disciplines and activities, Polymorphism, Single Nucleotide, Chromosomes, TIC DISORDERS, 03 medical and health sciences, Quantitative Trait, Heritable, mental disorders, genetic risk factors, Humans, ddc:610, AUTISM, Variant genotypes, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, genetics [Obsessive-Compulsive Disorder], Tourette syndrome, Parietal lobe, Biology and Life Sciences, Heritability, Genetic architecture, Minor allele frequency, Trastorno Obsesivo Compulsivo, lcsh:Genetics, pathology [Obsessive-Compulsive Disorder], genetic variation, pathology [Tourette Syndrome], Síndrome de Tourette, 030217 neurology & neurosurgery, GILLES, Genome-Wide Association Study, Tourette Syndrome
Abstract

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures., Author Summary Family and twin studies have shown that genetic risk factors are important in the development of Tourette Syndrome (TS) and obsessive compulsive disorder (OCD). However, efforts to identify the individual genetic risk factors involved in these two neuropsychiatric disorders have been largely unsuccessful. One possible explanation for this is that many genetic variations scattered throughout the genome each contribute a small amount to the overall risk. For TS and OCD, the genetic architecture (characterized by the number, frequency, and distribution of genetic risk factors) is presently unknown. This study examined the genetic architecture of TS and OCD in a variety of ways. We found that rare genetic changes account for more genetic risk in TS than in OCD; certain chromosomes contribute to OCD risk more than others; and variants that influence the level of genes expressed in two regions of the brain can account for a significant amount of risk for both TS and OCD. Results from this study might help in determining where, and what kind of variants are individual risk factors for TS and OCD and where they might be located in the human genome.

Published
2013

16. Family-Based Genetic Association Study of DLGAP3 in Tourette Syndrome

Author

Peter Heutink, Jeremiah M. Scharf, Lisa Osiecki, Jacquelyn Crane, Jesen Fagerness, B. Gunnell, David L. Pauls, S. E. Stewart, Human genetics, and NCA - Anxiety & Depression

Subjects
Genetic Markers, Genetics, Candidate gene, Linkage disequilibrium, Haplotype, Nerve Tissue Proteins, Single-nucleotide polymorphism, Biology, medicine.disease, Polymorphism, Single Nucleotide, Tourette syndrome, Article, Linkage Disequilibrium, Genetic determinism, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Haplotypes, Genetic marker, medicine, Humans, Family, Genetic Association Studies, Genetics (clinical), Tourette Syndrome, Genetic association
Abstract

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder that is familial and highly heritable. Although genetic influences are thought to play a significant role in the development of TS, no definite TS susceptibility genes have been identified to date. TS is believed to be genetically related to both obsessive-compulsive disorder (OCD) and grooming disorders (GD) such as trichotillomania (TTM). SAP90/PSD95-associated protein 3 (SAPAP3/DLGAP3) is a post-synaptic scaffolding protein that is highly expressed in glutamatergic synapses in the striatum and has recently been investigated as a candidate gene in both OCD and GD studies. Given the shared familial relationship between TS, OCD and TTM, DLGAP3 was evaluated as a candidate TS susceptibility gene. In a family-based sample of 289 TS trios, 22 common single nucleotide polymorphisms (SNPs) in the DLGAP3 region were analyzed. Nominally significant associations were identified between TS and rs11264126 and two haplotypes containing rs11264126 and rs12141243. Secondary analyses demonstrated that these results cannot be explained by the presence of comorbid OCD or TTM in the sample. Although none of these results remained significant after correction for multiple hypothesis testing, DLGAP3 remains a promising candidate gene for TS.

Published
2011

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