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

 Supplemental material cited in this article is available online.

 This article was reviewed under and accepted by ad hoc editor Robert R. Althoff, MD, PhD

 Drs. McGrath, Illmann, Fagerness, Geller, Jenike, Neale, Petryshen, Pauls, Scharf, Schroeder, Stewart, Mss.Yu, Gerber, Osiecki, Gallagher, and Messrs. Wolf, Haddad, and Kirby are with Massachusetts General Hospital. Dr. Stewart is also with the University of British Columbia. Dr. McGrath is also with American University. Dr. Scharf is also with Brigham and Womens Hospital, Boston, MA. Drs. O’Dushlaine, McGrath, Neale, Petryshen, Scharf, and Ms. Yu are also with the Harvard-MIT Broad Institute. Drs. Marshall, Scherer, Barr, Richter, Arnold, Sandor, Ms. Thiruvahindrapuram and Mr. Li are with the University of Toronto and the Hospital for Sick Children. Drs. Sandor and Barr are also with the Toronto Western Research Institute, University Health Network, Toronto. Dr. Kennedy is with the Centre for Addiction and Mental Health. Drs. Davis, Evans, and Cox are with the University of Chicago. Drs. Vallada, Miguel, and Brentani and Ms. Cappi are with the University of São Paulo Medical School. Dr. Bellodi is with the Università Vita-Salute San Raffaele. Dr. Benarroch is with Hadassah-Hebrew University Medical Center. Drs. Bienvenu, Cullen, Grados, Samuels, Singer, Nestadt, Riddle, and Ms. Wang are with Johns Hopkins University School of Medicine. Dr. Black is with the University of Iowa College of Medicine. Drs. Bloch, Coric, Fernandez, Leckman, Pakstis, Pittenger, and King are with the Yale University School of Medicine. Drs. Bruun and Budman are with North Shore-Long Island Jewish Medical Center. Dr. Budman is also with Hofstra University School of Medicine, Hempstead, NY. Dr. Bruun is also with New York University Medical Center, New York. Ms. Camarena is with the Instituto Nacional de Psiquiatría Ramon de la Fuente Muñiz. Dr. Cath is with Utrecht University and VU University Medical Center, Amsterdam. Dr. Cavallini is with the Ospedale San Raffaele. Drs. Chouinard and Dion are with the University of Montreal. Drs. Delorme and Leboyer are with the Robert Debre University Hospital and the French National Science Foundation. Dr. Delorme is also with Institut Pasteur, Paris. Dr. Leboyer is also with Institut Mondor de Recherche Biomédicale, Créteil, France. Dr. Denys is with the Netherlands Institute for Neuroscience. Drs. Denys and Derks are with the Academic Medical Center, Amsterdam. Drs. Rosário, Hounie, and Sampaio are with the Federal University of São Paulo. Dr. Sampaio is also with Universidade Federal da Bahia, Salvador, Bahia, Brazil. Dr. Eapen is with the University of New South Wales. Dr. Falkai is with the University of Munich. Dr. Herrera and Ms. Garrido are with the Hospital Nacional de Niños. Ms. Garrido is also with Clinica Herrera Amighetti, Avenida Escazú, San José, Costa Rica. Dr. Grabe is with the University Medicine Greifswald. Dr. Greenberg is with Brown Medical School. Drs. Gross-Tsur and Pollak are with Shaare Zedek Medical Center. Drs. Grünblatt and Walitza are with the University of Zurich. Dr. Walitza is also with the University of Würzburg. Drs. Heiman and Tischfield are with Rutgers University. Dr. Jankovic is with Baylor College of Medicine. Dr. Kurlan is with the Atlantic Neuroscience Institute. Drs. Lanzagorta and Nicolini are with the Carracci Medical Group. Mr. Lennertz and Drs. Maier, Moessner, and Wagner are with the University of Bonn.

 Drs. Lochner and Hemmings are with the University of Stellenbosch. Drs. Lowe, Reus, Mathews and Ms. Sheppard are with the University of California at San Francisco School of Medicine. Dr. Lyon is with the Cold Spring Harbor Laboratory. Dr. Macciardi is with University of California Irvine. Drs. McCracken, Piacentini, Nurmi, and Freimer are with the UCLA School of Medicine. Dr. Freimer is also with Semel Institute for Neuroscience and Human Behavior, UCLA. Dr. McMahon is with the University of Utah. Drs. Murphy, Wendland and Shugart are with the NIMH Intramural Research Program. Dr. Naarden is with Medical City Dallas Hospital. Drs. M. Pato, C. Pato, Knowles, and Wang are with the Zilkha Neurogenetic Institute. Dr. Richter is with Sunnybrook Health Sciences Centre. Drs. Robertson and Ruiz-Linares are with University College London. Dr. Rosenberg is with Wayne State University and Detroit Medical Center. Dr. Rouleau is with the Montreal Neurological Institute. Dr. Ruhrmann is with the University of Cologne. Dr. Stein is with the University of Cape Town. Dr. Veenstra-VanderWeele is with Vanderbilt University. Dr. Oostra is with Erasmus Medical Center. Dr. Heutink is with the German Center for Neurodegenerative Diseases and VU University Medical Center Amsterdam. Dr. Posthuma is with VU University Amsterdam and Erasmus University Medical Centre, Rotterdam. Dr. Hanna is with the University of Michigan. Dr. Cook is with the University of Illinois at Chicago.

 ^∞Deceased

 This work was supported by grants from the David Judah Fund, the Tourette Syndrome Association, the International OCD Foundation, and NIH (U01NS40024: DLP/JMS/TSA International Consortium for Genetics; R01NS16648, R01MH079489, and MH073250 ([DLP]; K23MH085057 [JMS]; T32MH16259 [LMM]; NS037484 and P30NS062691 [NBF]; K20MH01065 and R01MH58376 [GLH]; R01MH092293 [GAH/RAK/JAT]). Additional support came from American Recovery and Re-investment Act (ARRA) awards NS40024-07S1 and NS16648-29S1 (DLP). This work was also supported by grants from the New Jersey Center for Tourette Syndrome and Associated Disorders, NIMH (R01MH092293; GAH/RAK/JAT), the German Research Foundation (Fa 241/6-1; DFG), the Ontario Mental Health Foundation (MAR and JLK), and T32MH018268 (JFL). Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative (GEI; U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392), and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the Nation al Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease" (HHSN268200782096C). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgibin/study.cgi?study_id=phs000092.v1.p1_throughdbGaP a_ccession number phs000092.v1.p. None of the funding agencies for this project had any influence on a) the design or conduct of the study; b) management, analysis or interpretation of the data; or c) preparation, review or approval of the manuscript.

 Dr. K. Wang served as the statistical expert for this research.

 The authors thank the families, patients, and control volunteers who participated in this research. The authors would like to acknowledge additional members of the Tourette Syndrome Association International Consortium for Genetics (TSAICG) and the International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC), including Denise A. Chavira, PhD, Karin Egberts, MD, Eduardo Fournier, MS, Simon L. Girard, MSc, Jubel Morgan, RN, Tobias Renner, MD, Roxana Romero, MA, John Walkup, MD, and Herman G. Westenberg, PhD (deceased), for their contributions to this research.

 Disclosure: Dr. O'Dushlaine has received funding from the Stanley Center for Psychiatric Research. Dr. Black has received a research grant from AstraZeneca and has received royalties from American Psychiatric Publishing, UpToDate, and Oxford University Press. Dr. Bloch has received grant or research support from the National Institutes of Health (NIH) K23 Award, the Trichotillomania Learning Center, TSA, the Patterson Foundation, the National Alliance for Research on Schizophrenia and Depression, the Rembrandt Foundation, and the American Academy of Child and Adolescent Psychiatry Research Initiative Junior Investigator Award. Dr. Budman is currently receiving funding for Tourette syndrome clinical trials from Otsuka Pharmaceutical and has received research funding in the past year from Psyadon Pharmaceuticals. She is also a speaker for the TSA-CDC partnership and was on the National Medical Advisory Board for TSA in the past year. Dr. Cath has received speaker's honoraria from Pfizer pharmaceuticals and a research grant from the TSA foundation. Dr. Denys is a member of the advisory board of Lundbeck and has received occasional consultant fees from Medtronic for educational purposes. Dr. Rosário has received a grant from CNPq (Brazilian National Council) and has received research grants and/or consultancy honoraria from Novartis and Shire. Dr. Fernandez has received research funding from NIMH (K08 MH099424-01), the Simons Foundation, Allison Foundation, and Shire. Dr. Geller has received research support from NIMH and teaching honorarium from the American Academy of Child and Adolescent Psychiatry. Dr. Grabe has received research grants from the German Research Foundation and the Federal Ministry of Education and Research Germany. He has also received speakers’ honoraria from Bristol-Myers Squibb, Eli Lilly and Co., and Servier, and travel funds from Eli Lilly and Co., AstraZeneca, and Servier. Dr. Greenberg has received research funding from F. Hoffman la Roche Pharmaceuticals, Ltd. Dr. Kennedy has received honoraria from Roche, Eli Lilly and Co., and Novartis. Dr. King has received research support from NIH and Grifols, LLC. Dr. Leckman has received grant or research support from the National Institute of Mental Health (NIMH), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), TSA, GRIFOLS (formerly Talecris Biotherapeutics), and the Klingenstein Third Generation Foundation. He has served on the speakers’ bureau of TSA. He has received royalties from John Wiley and Sons, McGraw Hill, and Oxford University Press. He has received donations to clinical and research programs by the Associates of the Yale Child Study Center. Dr. Macciardi has received payments and travel refunds from Pharma Company TEVA for a couple of meetings in 2012. Dr. McCracken has received speaker honoraria from the TSA and research grants from Otsuka, Roche, Seaside Therapeutics, NICHD, and NIMH. He has served as a consultant to Roche. Dr. Piacentini has received grant or research support from NIMH, Pfizer Pharmaceuticals through the Duke Clinical Research Institute CAPTN Network, and TSA. He has served as a consultant to the Coleman Research Group and NIMH. He has served on the speakers’ bureau of TSA and the International Obsessive Compulsive Disorder Foundation. He has received book royalties from Guilford Press and Oxford University Press. He is a co-author of the Child OCD Impact Scale-Revised (COIS-R), the Child Anxiety Impact Scale (CAIS), the Parent Tic Questionnaire (PTQ), and the Premonitory Urge for Tics Scale (PUTS) assessment tools, all of which are in the public domain, therefore no royalties are received. He has received financial support from the Furlotti Family Foundation to develop a computerized child OCD treatment program. Dr. Pittenger has received honoraria for consulting from F. Hoffman la Roche Pharmaceuticals, Ltd. Dr. Richter has received honoraria from Lundbeck and has received research funding from Great-West Life Assurance Company of Canada and Eli Lilly Canada Ltd. Dr. Robertson has received grants from Tourette’s Action-UK, TSA-USA. She has received honoraria from Janssen-Cilag, and book royalties from Wiley-Blackwell, David Fulton/Granada/Taylor Francis, Oxford University Press, and Jessica Kingsley Publishers. She is a patron of Tourette's Action (UK), sits on the medical advisory boards of the Italian Tourette Syndrome Association and the Tourette Syndrome Foundation of Canada, and is Honorary Life President of ESSTS (European Society for the Study of Tourette's Syndrome). Dr. Rosenberg has received consulting fees from Shire and research support from Children’s Hospital of Michigan Foundation and NIH. Dr. Sandor has received honoraria and research support from GlaxoSmithKline, Astra, Solway, Otsuka, Psyadon, TSA, Tourette Syndrome Foundation of Canada, and NIH. Dr. Stein has received research grants and/or consultancy honoraria from AMBRF, Biocodex, Lundbeck, National Responsible Gambling Foundation, Novartis, Servier, and Sun. Dr. Veenstra-VanderWeele has consulted with Novartis and Roche Pharmaceuticals. He has received research funding from Novartis, Roche, Seaside Therapeutics, Forest, Sunovion, and SynapDx. Dr. Walitza has received lecture honoraria from Janssen Cilag, AstraZeneca, and Eli Lilly and Co. She has received research support from the Swiss National Science Foundation (SNF), Deutsche Forschungsgemeinschaft, EU FP7, and HSM Hochspezialisierte Medizin of the Kanton, Zurich, Switzerland. Dr. Wendland is a past employee of F. Hoffmann-La Roche and a current employee of Pfizer. Dr. Nicolini has received grant/research support from Servier, Transcept, and Pherin. He has served as a consultant or on advisory boards for Servier, Transcept, Sanofi, and MSD. He has also served on speakers' bureaus for MSD. Dr. Scherer has received funding from the government of Ontario. Dr. Arnold has received an unrestricted research grant from DNA Genotek. Dr. Stewart has received research support from the International OCD Foundation, the Anxiety Disorder Association of America, a Harvard Scholar Award, the Canadian Institutes of Health Research, the University of British Columbia, the Child and Family Research Institute, the British Columbia Mental Health and Addictions Research Institute, and the Michael Smith Foundation for Health Research. Dr. Mathews has received speaker honoraria and a research grant from the TSA and a research grant from the International OCD Foundation. Dr. Knowles has received research support from NIH, the International OCD Foundation, and Della Martin Foundation, and speaker's honoraria from Illumina, Inc. Dr. Cook has served as a consultant for and has had a research contract with Seaside Therapeutics. Dr. K. Wang is co-founder and shareholder of Tute Genomics, a bioinformatics consulting company. Dr. Scharf has received research support, honoraria, and travel support from TSA. He is also a member of the TSA Scientific Advisory Board. Ms. Yu has received research support from TSA and NIH. Mr. Fagerness was employed by Genomind. Drs. McGrath, Marshall, Davis, Schroeder, Illmann, Barr, Bellodi, Benarroch, Bienvenu, Bruun, Cavallini, Chouinard, Coric, Cullen, Delorme, Derks, Dion, Eapen, Evans, Falkai, Grados, Gross-Tsur, Grünblatt, Heiman, Hemmings, Herrera, Hounie, Jankovic, Kurlan, Lanzagorta, Leboyer, Lochner, Lowe, Lyon, Maier, McMahon, Murphy, Naarden, Neale, Nurmi, Pakstis, M. Pato, C. Pato, Pollak, Reus, Riddle, Rouleau, Ruhrmann, Sampaio, Samuels, Singer, Smit, Tischfield, Vallada, Shugart, Miguel, Oostra, Moessner, Wagner, Ruiz-Linares, Heutink, Nestadt, Freimer, Petryshen, Posthuma, Jenike, Cox, Hanna, Brentani, Pauls, and Mr. Thiruvahindrapuram, Mr. Li, Ms. Cappi, Ms. Gerber, Mr. Wolf, Ms. Osiecki, Mr. Kirby, Mr. Haddad, Ms. Gallagher, Ms. Camarena, Ms. Garrido, Mr. Lennertz, Ms. Sheppard, and Ms. Y. Wang report no biomedical financial interests or potential conflicts of interest.

PII: S0890-8567(14)00404-3

doi:10.1016/j.jaac.2014.04.022

© 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.