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1. Neurodevelopmental Disorders: Stereotypical Movement Disorders and Tic Disorders

Author

Vitulano, Lawrence A., Vitulano, Michael L., King, Robert A., Yazgan, M. Yanki, Leckman, James F., Ng, Chee H., Section editor, Lecic-Tosevski, Dusica, Section editor, Alfonso, César A., Section editor, Salloum, Ihsan M., Section editor, Tasman, Allan, editor, Riba, Michelle B., editor, Alarcón, Renato D., editor, Alfonso, César A., editor, Kanba, Shigenobu, editor, Lecic-Tosevski, Dusica, editor, Ndetei, David M., editor, Ng, Chee H., editor, and Schulze, Thomas G., editor

Published
2024
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2. Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability

Author

Bae, Taejeong, Fasching, Liana, Wang, Yifan, Shin, Joo Heon, Suvakov, Milovan, Jang, Yeongjun, Norton, Scott, Dias, Caroline, Mariani, Jessica, Jourdon, Alexandre, Wu, Feinan, Panda, Arijit, Pattni, Reenal, Chahine, Yasmine, Yeh, Rebecca, Roberts, Rosalinda C, Huttner, Anita, Kleinman, Joel E, Hyde, Thomas M, Straub, Richard E, Walsh, Christopher A, Urban, Alexander E, Leckman, James F, Weinberger, Daniel R, Vaccarino, Flora M, Abyzov, Alexej, Park, Peter J, Sestan, Nenad, Weinberger, Daniel, Moran, John V, Gage, Fred H, Gleeson, Joseph, Mathern, Gary, Courchesne, Eric, Roy, Subhojit, Chess, Andrew J, Akbarian, Schahram, Bizzotto, Sara, Coulter, Michael, D’Gama, Alissa, Ganz, Javier, Hill, Robert, Huang, August Yue, Khoshkhoo, Sattar, Kim, Sonia, Lee, Alice, Lodato, Michael, Maury, Eduardo A, Miller, Michael, Borges-Monroy, Rebeca, Rodin, Rachel, Zhou, Zinan, Bohrson, Craig, Chu, Chong, Cortes-Ciriano, Isidro, Dou, Yanmei, Galor, Alon, Gulhan, Doga, Kwon, Minseok, Luquette, Joe, Sherman, Maxwell, Viswanadham, Vinay, Jones, Attila, Rosenbluh, Chaggai, Cho, Sean, Langmead, Ben, Thorpe, Jeremy, Erwin, Jennifer, Jaffe, Andrew, McConnell, Michael, Narurkar, Rujuta, Paquola, Apua, Shin, Jooheon, Straub, Richard, Molitor, Cindy, Peters, Mette, Linker, Sara, Reed, Patrick, Wang, Meiyan, Urban, Alexander, Zhou, Bo, Zhu, Xiaowei, Serres Amero, Aitor, Juan, David, Lobon, Irene, Marques-Bonet, Tomas, Solis Moruno, Manuel, Garcia Perez, Raquel, Povolotskaya, Inna, Soriano, Eduardo, Antaki, Danny, and Averbuj, Dan

Subjects
Biotechnology, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Genetics, Autism, Pediatric, Mental Health, Human Genome, Underpinning research, 2.1 Biological and endogenous factors, Aetiology, 1.1 Normal biological development and functioning, Mental health, Aging, Autistic Disorder, Brain, Enhancer Elements, Genetic, Gene Expression Regulation, Humans, Mutagenesis, Mutation, Protein Binding, Transcription Factors, Whole Genome Sequencing, Brain Somatic Mosaicism Network§, General Science & Technology
Abstract

We analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic mutations after whole genome sequencing to a depth of more than 200×. Typically, brains had 20 to 60 detectable single-nucleotide mutations, but ~6% of brains harbored hundreds of somatic mutations. Hypermutability was associated with age and damaging mutations in genes implicated in cancers and, in some brains, reflected in vivo clonal expansions. Somatic duplications, likely arising during development, were found in ~5% of normal and diseased brains, reflecting background mutagenesis. Brains with autism were associated with mutations creating putative transcription factor binding motifs in enhancer-like regions in the developing brain. The top-ranked affected motifs corresponded to MEIS (myeloid ectopic viral integration site) transcription factors, suggesting a potential link between their involvement in gene regulation and autism.

Published
2022

3. Genome-Wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome

Author

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

Published
2024
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5. An evaluation of treatment response and remission definitions in adult obsessive-compulsive disorder: A systematic review and individual-patient data meta-analysis

Author

Ramakrishnan, Divya, Farhat, Luis C., Vattimo, Edoardo F.Q., Levine, Jessica L.S., Johnson, Jessica A., Artukoglu, Bekir B., Landeros-Weisenberger, Angeli, Zangen, Abraham, Pelissolo, Antoine, de B. Pereira, Carlos A., Rück, Christian, Costa, Daniel L.C., Mataix-Cols, David, Shannahoff-Khalsa, David, Tolin, David F., Zarean, Elham, Meyer, Elisabeth, Hawken, Emily R., Storch, Eric A., Andersson, Erik, Miguel, Euripedes C., Maina, Giuseppe, Leckman, James F., Sarris, Jerome, March, John S., Diniz, Juliana B., Kobak, Kenneth, Mallet, Luc, Vulink, Nienke C.C., Amiaz, Revital, Fernandes, Rodrigo Yacubian, Shavitt, Roseli G., Wilhelm, Sabine, Golshan, Shahrokh, Tezenas du Montcel, Sophie, Erzegovesi, Stefano, Baruah, Upasana, Greenberg, William M., Kobayashi, Yuki, and Bloch, Michael H.

Published
2024
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6. Scoping Review: Digital Mental Health Interventions for Children and Adolescents Affected by War

Author

Danese, Andrea, Martsenkovskyi, Dmytro, Remberk, Barbara, Khalil, Monika Youssef, Diggins, Emma, Keiller, Eleanor, Masood, Saba, Awah, Isang, Barbui, Corrado, Beer, Renée, Calam, Rachel, Gagliato, Marcio, Jensen, Tine K., Kostova, Zlatina, Leckman, James F., Lewis, Stephanie J., Lorberg, Boris, Myshakivska, Olha, Pfeiffer, Elisa, Rosner, Rita, Schleider, Jessica L., Shenderovich, Yulia, Skokauskas, Norbert, Tolan, Patrick H., Caffo, Ernesto, Sijbrandij, Marit, Ougrin, Dennis, Leventhal, Bennett L., and Weisz, John R.

Published
2024
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7. Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Author

Tsetsos, Fotis, Yu, Dongmei, Sul, Jae Hoon, Huang, Alden Y, Illmann, Cornelia, Osiecki, Lisa, Darrow, Sabrina M, Hirschtritt, Matthew E, Greenberg, Erica, Muller-Vahl, Kirsten R, Stuhrmann, Manfred, Dion, Yves, Rouleau, Guy A, Aschauer, Harald, Stamenkovic, Mara, Schlögelhofer, Monika, Sandor, Paul, Barr, Cathy L, Grados, Marco A, Singer, Harvey S, Nöthen, Markus M, Hebebrand, Johannes, Hinney, Anke, King, Robert A, Fernandez, Thomas V, Barta, Csaba, Tarnok, Zsanett, Nagy, Peter, Depienne, Christel, Worbe, Yulia, Hartmann, Andreas, Budman, Cathy L, Rizzo, Renata, Lyon, Gholson J, McMahon, William M, Batterson, James R, Cath, Danielle C, Malaty, Irene A, Okun, Michael S, Berlin, Cheston, Woods, Douglas W, Lee, Paul C, Jankovic, Joseph, Robertson, Mary M, Gilbert, Donald L, Brown, Lawrence W, Coffey, Barbara J, Dietrich, Andrea, Hoekstra, Pieter J, Kuperman, Samuel, Zinner, Samuel H, Wagner, Michael, Knowles, James A, Jeremy Willsey, A, Tischfield, Jay A, Heiman, Gary A, Cox, Nancy J, Freimer, Nelson B, Neale, Benjamin M, Davis, Lea K, Coppola, Giovanni, Mathews, Carol A, Scharf, Jeremiah M, Paschou, Peristera, Tourette Association of America International Consortium for Genetics, Darrow, Sabrina, Kurlan, Roger, Leckman, James F, Smit, Jan H, and Gilles de la Tourette GWAS Replication Initiative

Subjects
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, Neurons, Humans, Tourette Syndrome, Genotype, Genome-Wide Association Study, Mental Health, Genetics, Neurosciences, Human Genome, Brain Disorders, Biotechnology, Neurodegenerative, 2.1 Biological and endogenous factors, Clinical Sciences, Public Health and Health Services, Psychology
Abstract

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.

Published
2021

12. Manifesto for New Directions in Developmental Science

Author

Barbot, Baptiste, Hein, Sascha, Trentacosta, Christopher, Beckmann, Jens F., Bick, Johanna, Crocetti, Elisabetta, Liu, Yangyang, Rao, Sylvia Fernandez, Liew, Jeffrey, Overbeek, Geertjan, Ponguta, Liliana A., Scheithauer, Herbert, Super, Charles, Arnett, Jeffrey, Bukowski, William, Cook, Thomas D., Côté, James, Eccles, Jacquelynne S., Eid, Michael, Hiraki, Kazuo, Johnson, Mark, Juang, Linda, Landi, Nicole, Leckman, James, McCardle, Peggy, Mulvey, Kelly Lynn, Piquero, Alex R., Preiss, David D., Siegler, Robert, Soenens, Bart, Yousafzai, Aisha Khizar, Bornstein, Marc H., Cooper, Catherine R., Goossens, Luc, Harkness, Sara, and van IJzendoorn, Marinus H.

Abstract

Although developmental science has always been evolving, these times of fast-paced and profound social and scientific changes easily lead to disorienting fragmentation rather than coherent scientific advances. What directions should developmental science pursue to meaningfully address real-world problems that impact human development throughout the lifespan? What conceptual or policy shifts are needed to steer the field in these directions? The present manifesto is proposed by a group of scholars from various disciplines and perspectives within developmental science to spark conversations and action plans in response to these questions. After highlighting four critical content domains that merit concentrated and often urgent research efforts, two issues regarding "how" we do developmental science and "what for" are outlined. This manifesto concludes with five proposals, calling for "integrative," "inclusive," "transdisciplinary," "transparent," and "actionable" developmental science. Specific recommendations, prospects, pitfalls, and challenges to reach this goal are discussed.

Published
2020
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13. A multicenter examination and strategic revisions of the Yale Global Tic Severity Scale

Author

McGuire, Joseph F, Piacentini, John, Storch, Eric A, Murphy, Tanya K, Ricketts, Emily J, Woods, Douglas W, Walkup, John W, Peterson, Alan L, Wilhelm, Sabine, Lewin, Adam B, McCracken, James T, Leckman, James F, and Scahill, Lawrence

Subjects
Clinical Research, Neurodegenerative, Adolescent, Adult, Child, Child, Preschool, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Motor Activity, Psychiatric Status Rating Scales, Psychometrics, Severity of Illness Index, Tic Disorders, Tourette Syndrome, Young Adult, Clinical Sciences, Neurosciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveTo examine the internal consistency and distribution of the Yale Global Tic Severity Scale (YGTSS) scores to inform modification of the measure.MethodsThis cross-sectional study included 617 participants with a tic disorder (516 children and 101 adults), who completed an age-appropriate diagnostic interview and the YGTSS to evaluate tic symptom severity. The distributions of scores on YGTSS dimensions were evaluated for normality and skewness. For dimensions that were skewed across motor and phonic tics, a modified Delphi consensus process was used to revise selected anchor points.ResultsChildren and adults had similar clinical characteristics, including tic symptom severity. All participants were examined together. Strong internal consistency was identified for the YGTSS Motor Tic score (α = 0.80), YGTSS Phonic Tic score (α = 0.87), and YGTSS Total Tic score (α = 0.82). The YGTSS Total Tic and Impairment scores exhibited relatively normal distributions. Several subscales and individual item scales departed from a normal distribution. Higher scores were more often used on the Motor Tic Number, Frequency, and Intensity dimensions and the Phonic Tic Frequency dimension. By contrast, lower scores were more often used on Motor Tic Complexity and Interference, and Phonic Tic Number, Intensity, Complexity, and Interference.ConclusionsThe YGTSS exhibits good internal consistency across children and adults. The parallel findings across Motor and Phonic Frequency, Complexity, and Interference dimensions prompted minor revisions to the anchor point description to promote use of the full range of scores in each dimension. Specific minor revisions to the YGTSS Phonic Tic Symptom Checklist were also proposed.

Published
2018

18. Phenomenology of Tics and Sensory Urges

Author

Leckman, James F., additional, Bloch, Michael H., additional, Sukhodolsky, Denis G., additional, Artukoğlu, Bekir B., additional, Scahill, Lawrence, additional, and King, Robert A., additional

Published
2022
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23. Cognitive training for children with ADHD:composite cognitive score outcome in a randomized controlled trial

Author

Bikic, Aida, Dalsgaard, Søren, Pittman, Brian, Leckman, James Frederick, Wexler, Bruce, Bikic, Aida, Dalsgaard, Søren, Pittman, Brian, Leckman, James Frederick, and Wexler, Bruce

Abstract

Purpose of the article Cognitive training for Attention Deficit/Hyperactivity Disorder (ADHD) has shown promising, although mixed results. In post-hoc analyses, we evaluate effects of cognitive training using a novel composite cognition score as the outcome for children attending at least 16 sessions of training, dose-response of training and associations between symptoms and cognitive functioning. Materials and methods Children (age 6–13) with ADHD were randomized to intervention (n = 26) or control (n = 34). For the current analysis, we restricted the intervention group to children, who completed at least 16 sessions of cognitive training (n = 26) and examined a dose response within that group. Results Cognition improved significantly in the intervention, but not control group. Amount of the completed training sessions correlated significantly with the amount of cognitive improvement. Conclusion Variations in dose and frequency of training may be an important source of the variance in previous studies., Purpose of the article: Cognitive training for Attention Deficit/Hyperactivity Disorder (ADHD) has shown promising, although mixed results. In post-hoc analyses, we evaluate effects of cognitive training using a novel composite cognition score as the outcome for children attending at least 16 sessions of training, dose-response of training and associations between symptoms and cognitive functioning. Materials and methods: Children (age 6–13) with ADHD were randomized to intervention (n = 26) or control (n = 34). For the current analysis, we restricted the intervention group to children, who completed at least 16 sessions of cognitive training (n = 26) and examined a dose response within that group. Results: Cognition improved significantly in the intervention, but not control group. Amount of the completed training sessions correlated significantly with the amount of cognitive improvement. Conclusion: Variations in dose and frequency of training may be an important source of the variance in previous studies.

Published
2024

24. Implementation Evaluation of the Mother-Child Education Program among Refugee and Other Vulnerable Communities in Lebanon

Author

Ponguta, Liliana Angelica, Issa, Ghassan, Aoudeh, Lara, Maalouf, Cosette, Nourallah, Sawsan, Khoshnood, Kaveh, Zonderman, Anna Leslie, Katsovich, Liliya, Moore, Christina, Salah, Rima, Al-Soleiti, Majd, Britto, Pia Rebello, and Leckman, James Frederick

Abstract

Despite the knowledge that quality early childhood development programs, including those that target parental knowledge and behaviors, are essential for ameliorating the negative effects of early-life adversity, robust analyses of their implementation and impact in highly vulnerable settings are scarce. To address this knowledge gap, we conducted a pilot wait-list randomized controlled trial (RCT) to assess the impact and the process of implementing and evaluating the Mother-Child Education Program (MOCEP) among refugee families and one low-income community in Beirut, Lebanon. This paper focuses on the analysis of MOCEP's implementation (i.e., key enablers of and barriers to the application and evaluation of the program). Our analysis suggests that, despite multiple challenges, implementation and robust evaluations of early childhood parenting programs in fragile contexts are feasible and urgently needed. This study illustrates how implementation evaluations are a key component of RCTs and crucial to identifying strategies to optimize program uptake and maximize impact.

Published
2019
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29. Effects of the Mother-Child Education Program on Parenting Stress and Disciplinary Practices Among Refugee and Other Marginalized Communities in Lebanon: A Pilot Randomized Controlled Trial

Author

Ponguta, Liliana A., Issa, Ghassan, Aoudeh, Lara, Maalouf, Cosette, Hein, Sascha D., Zonderman, Anna L., Katsovich, Liliya, Khoshnood, Kaveh, Bick, Johanna, Awar, Abir, Nourallah, Sawsan, Householder, Sarah, Moore, Christina C., Salah, Rima, Britto, Pia R., and Leckman, James F.

Published
2020
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30. Risk factors for obsessive–compulsive symptoms. Follow-up of a community-based youth cohort

Author

Macul Ferreira de Barros, Pedro, do Rosário, Maria Conceição, Szejko, Natalia, Polga, Natália, Requena, Guaraci de Lima, Ravagnani, Beatriz, Fatori, Daniel, Batistuzzo, Marcelo Camargo, Hoexter, Marcelo Queiroz, Rohde, Luis Augusto, Polanczyk, Guilherme Vanoni, Leckman, James Frederick, Miguel, Eurípedes Constantino, and de Alvarenga, Pedro Gomes

Published
2021
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32. Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD.

Author

Yu, Dongmei, Mathews, Carol A, Scharf, Jeremiah M, Neale, Benjamin M, Davis, Lea K, Gamazon, Eric R, Derks, Eske M, Evans, Patrick, Edlund, Christopher K, Crane, Jacquelyn, Fagerness, Jesen A, Osiecki, Lisa, Gallagher, Patience, Gerber, Gloria, Haddad, Stephen, Illmann, Cornelia, McGrath, Lauren M, Mayerfeld, Catherine, Arepalli, Sampath, Barlassina, Cristina, Barr, Cathy L, Bellodi, Laura, Benarroch, Fortu, Berrió, Gabriel Bedoya, Bienvenu, O Joseph, Black, Donald W, Bloch, Michael H, Brentani, Helena, Bruun, Ruth D, Budman, Cathy L, Camarena, Beatriz, Campbell, Desmond D, Cappi, Carolina, Silgado, Julio C Cardona, Cavallini, Maria C, Chavira, Denise A, Chouinard, Sylvain, Cook, Edwin H, Cookson, MR, Coric, Vladimir, Cullen, Bernadette, Cusi, Daniele, Delorme, Richard, Denys, Damiaan, Dion, Yves, Eapen, Valsama, Egberts, Karin, Falkai, Peter, Fernandez, Thomas, Fournier, Eduardo, Garrido, Helena, Geller, Daniel, Gilbert, Donald L, Girard, Simon L, Grabe, Hans J, Grados, Marco A, Greenberg, Benjamin D, Gross-Tsur, Varda, Grünblatt, Edna, Hardy, John, Heiman, Gary A, Hemmings, Sian MJ, Herrera, Luis D, Hezel, Dianne M, Hoekstra, Pieter J, Jankovic, Joseph, Kennedy, James L, King, Robert A, Konkashbaev, Anuar I, Kremeyer, Barbara, Kurlan, Roger, Lanzagorta, Nuria, Leboyer, Marion, Leckman, James F, Lennertz, Leonhard, Liu, Chunyu, Lochner, Christine, Lowe, Thomas L, Lupoli, Sara, Macciardi, Fabio, Maier, Wolfgang, Manunta, Paolo, Marconi, Maurizio, McCracken, James T, Mesa Restrepo, Sandra C, Moessner, Rainald, Moorjani, Priya, Morgan, Jubel, Muller, Heike, Murphy, Dennis L, Naarden, Allan L, Nurmi, Erika, Ochoa, William Cornejo, Ophoff, Roel A, Pakstis, Andrew J, Pato, Michele T, Pato, Carlos N, Piacentini, John, Pittenger, Christopher, and Pollak, Yehuda

Subjects
Humans, Tourette Syndrome, Severity of Illness Index, Obsessive-Compulsive Disorder, Psychiatric Status Rating Scales, Comorbidity, Polymorphism, Single Nucleotide, Adult, Female, Male, Genome-Wide Association Study, Human Genome, Genetics, Brain Disorders, Serious Mental Illness, Neurodegenerative, Prevention, Anxiety Disorders, Mental Health, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Mental health, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

ObjectiveObsessive-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.MethodThe 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.ResultsAlthough 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=2×10(-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).ConclusionsPrevious 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 Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

Published
2015

36. Copy Number Variation in Obsessive-Compulsive Disorder and Tourette Syndrome: A Cross-Disorder Study

Author

McGrath, Lauren M, Yu, Dongmei, Marshall, Christian, Davis, Lea K, Thiruvahindrapuram, Bhooma, Li, Bingbin, Cappi, Carolina, Gerber, Gloria, Wolf, Aaron, Schroeder, Frederick A, Osiecki, Lisa, O'Dushlaine, Colm, Kirby, Andrew, Illmann, Cornelia, Haddad, Stephen, Gallagher, Patience, Fagerness, Jesen A, Barr, Cathy L, Bellodi, Laura, Benarroch, Fortu, Bienvenu, O Joseph, Black, Donald W, Bloch, Michael H, Bruun, Ruth D, Budman, Cathy L, Camarena, Beatriz, Cath, Danielle C, Cavallini, Maria C, Chouinard, Sylvain, Coric, Vladimir, Cullen, Bernadette, Delorme, Richard, Denys, Damiaan, Derks, Eske M, Dion, Yves, Rosário, Maria C, Eapen, Valsama, Evans, Patrick, Falkai, Peter, Fernandez, Thomas V, Garrido, Helena, Geller, Daniel, Grabe, Hans J, Grados, Marco A, Greenberg, Benjamin D, Gross-Tsur, Varda, Grünblatt, Edna, Heiman, Gary A, Hemmings, Sian MJ, Herrera, Luis D, Hounie, Ana G, Jankovic, Joseph, Kennedy, James L, King, Robert A, Kurlan, Roger, Lanzagorta, Nuria, Leboyer, Marion, Leckman, James F, Lennertz, Leonhard, Lochner, Christine, Lowe, Thomas L, Lyon, Gholson J, Macciardi, Fabio, Maier, Wolfgang, McCracken, James T, McMahon, William, Murphy, Dennis L, Naarden, Allan L, Neale, Benjamin M, Nurmi, Erika, Pakstis, Andrew J, Pato, Michele T, Pato, Carlos N, Piacentini, John, Pittenger, Christopher, Pollak, Yehuda, Reus, Victor I, Richter, Margaret A, Riddle, Mark, Robertson, Mary M, Rosenberg, David, Rouleau, Guy A, Ruhrmann, Stephan, Sampaio, Aline S, Samuels, Jack, Sandor, Paul, Sheppard, Brooke, Singer, Harvey S, Smit, Jan H, Stein, Dan J, Tischfield, Jay A, Vallada, Homero, Veenstra-VanderWeele, Jeremy, Walitza, Susanne, Wang, Ying, Wendland, Jens R, Shugart, Yin Yao, Miguel, Euripedes C, Nicolini, Humberto, and Oostra, Ben A

Subjects
Human Genome, Genetics, Brain Disorders, Serious Mental Illness, Neurodegenerative, Mental Health, Tourette Syndrome, Neurosciences, Intellectual and Developmental Disabilities (IDD), Aetiology, 2.1 Biological and endogenous factors, Mental health, Adolescent, DNA Copy Number Variations, Diagnostic and Statistical Manual of Mental Disorders, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Obsessive-Compulsive Disorder, Polymorphism, Single Nucleotide, Tourette syndrome, obsessive-compulsive disorder, copy number variation, genetics, 16p13.11, Medical and Health Sciences, Psychology and Cognitive Sciences, Developmental & Child Psychology
Abstract

ObjectiveObsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (

Published
2014

39. Tics and Tourette Syndrome

Author

Sukhodolsky, Denis G., Gladstone, Theresa R., Kaushal, Shivani A., Piasecka, Justyna B., Leckman, James F., and Matson, Johnny L., Series Editor

Published
2017
Full Text
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43. Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

Author

Davis, Lea K, Yu, Dongmei, Keenan, Clare L, Gamazon, Eric R, Konkashbaev, Anuar I, Derks, Eske M, Neale, Benjamin M, Yang, Jian, Lee, S. Hong, Evans, Patrick, Barr, Cathy L, Bellodi, Laura, Benarroch, Fortu, Berrio, Gabriel Bedoya, Bienvenu, Oscar J, Bloch, Michael H, Blom, Rianne M, Bruun, Ruth D, Budman, Cathy L, Camarena, Beatriz, Campbell, Desmond, Cappi, Carolina, Cardona Silgado, Julio C, Cath, Danielle C, Cavallini, Maria C, Chavira, Denise A, Chouinard, Sylvain, Conti, David V, Cook, Edwin H, Coric, Vladimir, Cullen, Bernadette A, Deforce, Dieter, Delorme, Richard, Dion, Yves, Edlund, Christopher K, Egberts, Karin, Falkai, Peter, Fernandez, Thomas V, Gallagher, Patience J, Garrido, Helena, Geller, Daniel, Girard, Simon L, Grabe, Hans J, Grados, Marco A, Greenberg, Benjamin D, Gross-Tsur, Varda, Haddad, Stephen, Heiman, Gary A, Hemmings, Sian M. J, Hounie, Ana G, Illmann, Cornelia, Jankovic, Joseph, Jenike, Michael A, Kennedy, James L, King, Robert A, Kremeyer, Barbara, Kurlan, Roger, Lanzagorta, Nuria, Leboyer, Marion, Leckman, James F, Lennertz, Leonhard, Liu, Chunyu, Lochner, Christine, Lowe, Thomas L, Macciardi, Fabio, McCracken, James T, McGrath, Lauren M, Mesa Restrepo, Sandra C, Moessner, Rainald, Morgan, Jubel, Muller, Heike, Murphy, Dennis L, Naarden, Allan L, Ochoa, William Cornejo, Ophoff, Roel A, Osiecki, Lisa, Pakstis, Andrew J, Pato, Michele T, Pato, Carlos N, Piacentini, John, Pittenger, Christopher, Pollak, Yehuda, Rauch, Scott L, Renner, Tobias J, Reus, Victor I, Richter, Margaret A, Riddle, Mark A, Robertson, Mary M, Romero, Roxana, Rosàrio, Maria C, Rosenberg, David, Rouleau, Guy A, Ruhrmann, Stephan, Ruiz-Linares, Andres, Sampaio, Aline S, Samuels, Jack, Sandor, Paul, Sheppard, Brooke, Singer, Harvey S, and Smit, Jan H

Subjects
Missing Heritability, Tic Disorders, Neuropsychiatric Disorders, Complex Diseases, Common Snps, Gilles, Family, Brain, Expression, Autism
Published
2013

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

Author

Chouinard, Sylvain, Conti, David, Cook, Edwin, Coric, Vladimir, Cullen, Bernadette, Deforce, Dieter, Delorme, Richard, Dion, Yves, Edlund, Christopher, Egberts, Karin, Falkai, Peter, Fernandez, Thomas, Gallagher, Patience, Garrido, Helena, Geller, Daniel, Girard, Simon, Grabe, Hans, Grados, Marco, Greenberg, Benjamin, Gross-Tsur, Varda, Haddad, Stephen, Heiman, Gary, Hemmings, Sian, Hounie, Ana, Illmann, Cornelia, Jankovic, Joseph, Jenike, Michael, Kennedy, James, King, Robert, Kremeyer, Barbara, Kurlan, Roger, Lanzagorta, Nuria, Leboyer, Marion, Leckman, James, Lennertz, Leonhard, Liu, Chunyu, Lochner, Christine, Davis, Lea, Yu, Dongmei, Keenan, Clare, Gamazon, Eric, Konkashbaev, Anuar, Derks, Eske, Neale, Benjamin, Yang, Jian, Lee, S, Evans, Patrick, Barr, Cathy, Bellodi, Laura, Benarroch, Fortu, Berrio, Gabriel, Bienvenu, Oscar, Bloch, Michael, Blom, Rianne, Bruun, Ruth, Budman, Cathy, Camarena, Beatriz, Campbell, Desmond, Cappi, Carolina, Cardona Silgado, Julio, Cath, Danielle, Cavallini, Maria, McCracken, James, McGrath, Lauren, Mesa Restrepo, Sandra, Moessner, Rainald, Morgan, Jubel, Muller, Heike, Murphy, Dennis, Naarden, Allan, Ochoa, William, Osiecki, Lisa, Pakstis, Andrew, Pato, Michele, Pato, Carlos, Pittenger, Christopher, Pollak, Yehuda, Rauch, Scott, Renner, Tobias, Richter, Margaret, Riddle, Mark, Robertson, Mary, Romero, Roxana, Rosàrio, Maria, Rosenberg, David, Rouleau, Guy, Ruhrmann, Stephan, Ruiz-Linares, Andres, Sampaio, Aline, Samuels, Jack, Sandor, Paul, Sheppard, Brooke, Singer, Harvey, Smit, Jan, Stein, Dan, Strengman, E, Tischfield, Jay, Valencia Duarte, Ana, Vallada, Homero, and Van Nieuwerburgh, Filip

Subjects
Gene Frequency, Genome-Wide Association Study, Humans, Obsessive-Compulsive Disorder, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, 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.

Published
2013

46. Sequence Variants in SLITRK1 Are Associated with Tourette's Syndrome

Author

Abelson, Jesse F., Kwan, Kenneth Y., O'Roak, Brian J., Baek, Danielle Y., Stillman, Althea A., Morgan, Thomas M., Mathews, Carol A., Pauls, David L., Rašin, Mladen-Roko, Gunel, Murat, Davis, Nicole R., Ercan-Sencicek, A. Gulhan, Guez, Danielle H., Spertus, John A., Leckman, James F., Dure, Leon S., Kurlan, Roger, Singer, Harvey S., Gilbert, Donald L., Farhi, Anita, Louvi, Angeliki, Lifton, Richard P., Šestan, Nenad, and State, Matthew W.

Published
2005

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