Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study

Lauren M McGrath¹, Dongmei Yu², Christian Marshall³, Lea K Davis⁴, Bhooma Thiruvahindrapuram³, Bingbin Li³, Carolina Cappi⁵, Gloria Gerber⁶, Aaron Wolf⁶, Frederick A Schroeder⁶, Lisa Osiecki⁶, Colm O'Dushlaine⁷, Andrew Kirby⁶, Cornelia Illmann⁶, Stephen Haddad⁶, Patience Gallagher⁶, Jesen A Fagerness⁶, Cathy L Barr⁸, Laura Bellodi⁹, Fortu Benarroch¹⁰, O Joseph Bienvenu¹¹, Donald W Black¹², Michael H Bloch¹³, Ruth D Bruun¹⁴, Cathy L Budman¹⁵, Beatriz Camarena¹⁶, Danielle C Cath¹⁷, Maria C Cavallini¹⁸, Sylvain Chouinard¹⁹, Vladimir Coric¹³, Bernadette Cullen¹¹, Richard Delorme²⁰, Damiaan Denys²¹, Eske M Derks²², Yves Dion¹⁹, Maria C Rosário²³, Valsama Eapen²⁴, Patrick Evans⁴, Peter Falkai²⁵, Thomas V Fernandez¹³, Helena Garrido²⁶, Daniel Geller⁶, Hans J Grabe²⁷, Marco A Grados¹¹, Benjamin D Greenberg²⁸, Varda Gross-Tsur²⁹, Edna Grünblatt³⁰, Gary A Heiman³¹, Sian M J Hemmings³², Luis D Herrera³³, Ana G Hounie²³, Joseph Jankovic³⁴, James L Kennedy³⁵, Robert A King¹³, Roger Kurlan³⁶, Nuria Lanzagorta³⁷, Marion Leboyer³⁸, James F Leckman¹³, Leonhard Lennertz³⁹, Christine Lochner³², Thomas L Lowe⁴⁰, Gholson J Lyon⁴¹, Fabio Macciardi⁴², Wolfgang Maier³⁹, James T McCracken⁴³, William McMahon⁴⁴, Dennis L Murphy⁴⁵, Allan L Naarden⁴⁶, Benjamin M Neale², Erika Nurmi⁴³, Andrew J Pakstis¹³, Michele T Pato⁴⁷, Carlos N Pato⁴⁷, John Piacentini⁴³, Christopher Pittenger¹³, Yehuda Pollak²⁹, Victor I Reus⁴⁰, Margaret A Richter⁴⁸, Mark Riddle¹¹, Mary M Robertson⁴⁹, David Rosenberg⁵⁰, Guy A Rouleau⁵¹, Stephan Ruhrmann⁵², Aline S Sampaio⁵³, Jack Samuels¹¹, Paul Sandor⁸, Brooke Sheppard⁴⁰, Harvey S Singer¹¹, Jan H Smit⁵⁴, Dan J Stein⁵⁵, Jay A Tischfield³¹, Homero Vallada⁵, Jeremy Veenstra-VanderWeele⁵⁶, Susanne Walitza⁵⁷, Ying Wang¹¹, Jens R Wendland⁴⁵, Yin Yao Shugart⁴⁵, Euripedes C Miguel⁵, Humberto Nicolini³⁷, Ben A Oostra⁵⁸, Rainald Moessner³⁹, Michael Wagner³⁹, Andres Ruiz-Linares⁴⁹, Peter Heutink⁵⁹, Gerald Nestadt¹¹, Nelson Freimer⁶⁰, Tracey Petryshen², Danielle Posthuma⁶¹, Michael A Jenike⁶, Nancy J Cox⁴, Gregory L Hanna⁶², Helena Brentani⁵, Stephen W Scherer³, Paul D Arnold³, S Evelyn Stewart⁶³, Carol A Mathews⁴⁰, James A Knowles⁴⁷, Edwin H Cook⁶⁴, David L Pauls⁶, Kai Wang⁴⁷, Jeremiah M Scharf⁶⁵

Affiliations

¹ Massachusetts General Hospital, Boston; American University, Washington, DC; Harvard-MIT Broad Institute, Boston.
² Massachusetts General Hospital, Boston; Harvard-MIT Broad Institute, Boston.
³ University of Toronto and the Hospital for Sick Children, Toronto.
⁴ University of Chicago.
⁵ University of São Paulo Medical School.
⁶ Massachusetts General Hospital, Boston.
⁷ Harvard-MIT Broad Institute, Boston.
⁸ University of Toronto and the Hospital for Sick Children, Toronto; Toronto Western Research Institute, University Health Network, Toronto.
⁹ Università Vita-Salute San Raffaele, Milan.
¹⁰ Hadassah-Hebrew University Medical Center, Jerusalem.
¹¹ Johns Hopkins University School of Medicine, Baltimore.
¹² University of Iowa College of Medicine, Iowa City.
¹³ Yale University School of Medicine, New Haven, CT.
¹⁴ North Shore-Long Island Jewish Medical Center, New Hyde Park, NY; New York University Medical Center, New York.
¹⁵ North Shore-Long Island Jewish Medical Center, New Hyde Park, NY; Hofstra University School of Medicine, Hempstead, NY.
¹⁶ Instituto Nacional de Psiquiatría Ramon de la Fuente Muñiz, Mexico.
¹⁷ Utrecht University and VU Medical Center, Amsterdam.
¹⁸ Ospedale San Raffaele, Milan.
¹⁹ University of Montreal.
²⁰ Robert Debre University Hospital, Paris and the French National Science Foundation, Creteil, France; Institut Pasteur, Paris.
²¹ Netherlands Institute for Neuroscience, Amsterdam; Academic Medical Center, Amsterdam.
²² Academic Medical Center, Amsterdam.
²³ Federal University of São Paulo.
²⁴ University of New South Wales, Australia.
²⁵ University of Munich.
²⁶ Hospital Nacional de Niños, San Jose, Costa Rica; Clinica Herrera Amighetti, Avenida Escazú, San José, Costa Rica.
²⁷ University Medicine Greifswald, Greifswald, Germany.
²⁸ Brown Medical School, Providence, RI.
²⁹ Shaare Zedek Medical Center, Jerusalem.
³⁰ University of Zurich.
³¹ Rutgers University, Piscataway Township, NJ.
³² University of Stellenbosch, South Africa.
³³ Hospital Nacional de Niños, San Jose, Costa Rica.
³⁴ Baylor College of Medicine, Houston.
³⁵ Centre for Addiction and Mental Health, Toronto.
³⁶ Atlantic Neuroscience Institute, Summit, NJ.
³⁷ Carracci Medical Group, Mexico City.
³⁸ Robert Debre University Hospital, Paris and the French National Science Foundation, Creteil, France; Institut Mondor de Recherche Biomédicale, Créteil, France.
³⁹ University of Bonn, Germany.
⁴⁰ University of California at San Francisco School of Medicine.
⁴¹ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
⁴² University of California, Irvine.
⁴³ University of California, Los Angeles (UCLA) School of Medicine.
⁴⁴ University of Utah, Salt Lake City.
⁴⁵ National Institute of Mental Health (NIMH) Intramural Research Program, Bethesda, MD.
⁴⁶ Medical City Dallas Hospital.
⁴⁷ Zilkha Neurogenetic Institute, Los Angeles.
⁴⁸ University of Toronto and the Hospital for Sick Children, Toronto; Sunnybrook Health Sciences Centre, Toronto.
⁴⁹ University College London.
⁵⁰ Wayne State University and Detroit Medical Center, Detroit.
⁵¹ Montreal Neurological Institute.
⁵² University of Cologne, Germany.
⁵³ Federal University of São Paulo; Universidade Federal da Bahia, Salvador, Bahia, Brazil.
⁵⁴ VU Amsterdam and Erasmus University Medical Centre, Rotterdam; VU University Amsterdam; VU Medical Center, Amsterdam.
⁵⁵ University of Cape Town, South Africa.
⁵⁶ Vanderbilt University, Nashville, TN.
⁵⁷ University of Zurich; University of Würzburg.
⁵⁸ Erasmus Medical Center Rotterdam, the Netherlands.
⁵⁹ German Center for Neurodegenerative Diseases, Bonn and VU Medical Center Amsterdam.
⁶⁰ University of California, Los Angeles (UCLA) School of Medicine; Semel Institute for Neuroscience and Human Behavior, UCLA.
⁶¹ VU Amsterdam and Erasmus University Medical Centre, Rotterdam.
⁶² University of Michigan, Ann Arbor, MI.
⁶³ Massachusetts General Hospital, Boston; University of British Columbia, Vancouver.
⁶⁴ University of Illinois at Chicago.
⁶⁵ Massachusetts General Hospital, Boston; Brigham and Womens Hospital, Boston; Harvard-MIT Broad Institute, Boston. Electronic address: jscharf@partners.org.

PMID: 25062598
PMCID: PMC4218748
DOI: 10.1016/j.jaac.2014.04.022

Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study

Lauren M McGrath et al. J Am Acad Child Adolesc Psychiatry. 2014 Aug.

. 2014 Aug;53(8):910-9.

doi: 10.1016/j.jaac.2014.04.022. Epub 2014 Jun 24.

Authors

Affiliations

¹ Massachusetts General Hospital, Boston; American University, Washington, DC; Harvard-MIT Broad Institute, Boston.
² Massachusetts General Hospital, Boston; Harvard-MIT Broad Institute, Boston.
³ University of Toronto and the Hospital for Sick Children, Toronto.
⁴ University of Chicago.
⁵ University of São Paulo Medical School.
⁶ Massachusetts General Hospital, Boston.
⁷ Harvard-MIT Broad Institute, Boston.
⁸ University of Toronto and the Hospital for Sick Children, Toronto; Toronto Western Research Institute, University Health Network, Toronto.
⁹ Università Vita-Salute San Raffaele, Milan.
¹⁰ Hadassah-Hebrew University Medical Center, Jerusalem.
¹¹ Johns Hopkins University School of Medicine, Baltimore.
¹² University of Iowa College of Medicine, Iowa City.
¹³ Yale University School of Medicine, New Haven, CT.
¹⁴ North Shore-Long Island Jewish Medical Center, New Hyde Park, NY; New York University Medical Center, New York.
¹⁵ North Shore-Long Island Jewish Medical Center, New Hyde Park, NY; Hofstra University School of Medicine, Hempstead, NY.
¹⁶ Instituto Nacional de Psiquiatría Ramon de la Fuente Muñiz, Mexico.
¹⁷ Utrecht University and VU Medical Center, Amsterdam.
¹⁸ Ospedale San Raffaele, Milan.
¹⁹ University of Montreal.
²⁰ Robert Debre University Hospital, Paris and the French National Science Foundation, Creteil, France; Institut Pasteur, Paris.
²¹ Netherlands Institute for Neuroscience, Amsterdam; Academic Medical Center, Amsterdam.
²² Academic Medical Center, Amsterdam.
²³ Federal University of São Paulo.
²⁴ University of New South Wales, Australia.
²⁵ University of Munich.
²⁶ Hospital Nacional de Niños, San Jose, Costa Rica; Clinica Herrera Amighetti, Avenida Escazú, San José, Costa Rica.
²⁷ University Medicine Greifswald, Greifswald, Germany.
²⁸ Brown Medical School, Providence, RI.
²⁹ Shaare Zedek Medical Center, Jerusalem.
³⁰ University of Zurich.
³¹ Rutgers University, Piscataway Township, NJ.
³² University of Stellenbosch, South Africa.
³³ Hospital Nacional de Niños, San Jose, Costa Rica.
³⁴ Baylor College of Medicine, Houston.
³⁵ Centre for Addiction and Mental Health, Toronto.
³⁶ Atlantic Neuroscience Institute, Summit, NJ.
³⁷ Carracci Medical Group, Mexico City.
³⁸ Robert Debre University Hospital, Paris and the French National Science Foundation, Creteil, France; Institut Mondor de Recherche Biomédicale, Créteil, France.
³⁹ University of Bonn, Germany.
⁴⁰ University of California at San Francisco School of Medicine.
⁴¹ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
⁴² University of California, Irvine.
⁴³ University of California, Los Angeles (UCLA) School of Medicine.
⁴⁴ University of Utah, Salt Lake City.
⁴⁵ National Institute of Mental Health (NIMH) Intramural Research Program, Bethesda, MD.
⁴⁶ Medical City Dallas Hospital.
⁴⁷ Zilkha Neurogenetic Institute, Los Angeles.
⁴⁸ University of Toronto and the Hospital for Sick Children, Toronto; Sunnybrook Health Sciences Centre, Toronto.
⁴⁹ University College London.
⁵⁰ Wayne State University and Detroit Medical Center, Detroit.
⁵¹ Montreal Neurological Institute.
⁵² University of Cologne, Germany.
⁵³ Federal University of São Paulo; Universidade Federal da Bahia, Salvador, Bahia, Brazil.
⁵⁴ VU Amsterdam and Erasmus University Medical Centre, Rotterdam; VU University Amsterdam; VU Medical Center, Amsterdam.
⁵⁵ University of Cape Town, South Africa.
⁵⁶ Vanderbilt University, Nashville, TN.
⁵⁷ University of Zurich; University of Würzburg.
⁵⁸ Erasmus Medical Center Rotterdam, the Netherlands.
⁵⁹ German Center for Neurodegenerative Diseases, Bonn and VU Medical Center Amsterdam.
⁶⁰ University of California, Los Angeles (UCLA) School of Medicine; Semel Institute for Neuroscience and Human Behavior, UCLA.
⁶¹ VU Amsterdam and Erasmus University Medical Centre, Rotterdam.
⁶² University of Michigan, Ann Arbor, MI.
⁶³ Massachusetts General Hospital, Boston; University of British Columbia, Vancouver.
⁶⁴ University of Illinois at Chicago.
⁶⁵ Massachusetts General Hospital, Boston; Brigham and Womens Hospital, Boston; Harvard-MIT Broad Institute, Boston. Electronic address: jscharf@partners.org.

PMID: 25062598
PMCID: PMC4218748
DOI: 10.1016/j.jaac.2014.04.022

Abstract

Objective: Obsessive-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 (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date.

Method: The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios.

Results: Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p = .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p = .08 in the current study, p = .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%).

Conclusion: Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes.

Keywords: 16p13.11; Tourette syndrome; copy number variation; genetics; obsessive-compulsive disorder.

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Figures

**Figure 1**
16p13.11 region with 8 patient and 1 control copy number variants (CNVs). Note: red denotes deletions; blue, duplications. Gray denotes the de novo deletion that did not survive strict quality control (QC) filters but was validated in silico and by qPCR.

See this image and copyright information in PMC

References

1. Grados MA. The genetics of obsessive-compulsive disorder and Tourette’s syndrome: what are the common factors? Curr Psychiatry Rep. 2009;11:162–166. - PubMed
1. Davis LK, Yu D, Keenan CL, et al. Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture. PLoS genetics. 2013 Oct;9(10):e1003864. - PMC - PubMed
1. Cook EH, Jr, Scherer SW, Cook EH. Copy-number variations associated with neuropsychiatric conditions. Nature. 2008;455:919–923. - PubMed
1. Malhotra D, Sebat J. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell. 2012;148:1223–1241. - PMC - PubMed
1. Thapar A, Cooper M. Copy number variation: what is it and what has it told us about child psychiatric disorders? Journal of the American Academy of Child and Adolescent Psychiatry. 2013;52:772–774. - PMC - PubMed

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Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study

Affiliations

Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study

Authors

Affiliations

Abstract

Figures

References

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MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical