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J Am Acad Child Adolesc Psychiatry. 2014 Aug;53(8):910-9. doi: 10.1016/j.jaac.2014.04.022. Epub 2014 Jun 24.

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

McGrath LM1, Yu D2, Marshall C3, Davis LK4, Thiruvahindrapuram B3, Li B3, Cappi C5, Gerber G6, Wolf A6, Schroeder FA6, Osiecki L6, O'Dushlaine C7, Kirby A6, Illmann C6, Haddad S6, Gallagher P6, Fagerness JA6, Barr CL8, Bellodi L9, Benarroch F10, Bienvenu OJ11, Black DW12, Bloch MH13, Bruun RD14, Budman CL15, Camarena B16, Cath DC17, Cavallini MC18, Chouinard S19, Coric V13, Cullen B11, Delorme R20, Denys D21, Derks EM22, Dion Y19, Rosário MC23, Eapen V24, Evans P4, Falkai P25, Fernandez TV13, Garrido H26, Geller D6, Grabe HJ27, Grados MA11, Greenberg BD28, Gross-Tsur V29, Grünblatt E30, Heiman GA31, Hemmings SM32, Herrera LD33, Hounie AG23, Jankovic J34, Kennedy JL35, King RA13, Kurlan R36, Lanzagorta N37, Leboyer M38, Leckman JF13, Lennertz L39, Lochner C32, Lowe TL40, Lyon GJ41, Macciardi F42, Maier W39, McCracken JT43, McMahon W44, Murphy DL45, Naarden AL46, Neale BM2, Nurmi E43, Pakstis AJ13, Pato MT47, Pato CN47, Piacentini J43, Pittenger C13, Pollak Y29, Reus VI40, Richter MA48, Riddle M11, Robertson MM49, Rosenberg D50, Rouleau GA51, Ruhrmann S52, Sampaio AS53, Samuels J11, Sandor P8, Sheppard B40, Singer HS11, Smit JH54, Stein DJ55, Tischfield JA31, Vallada H5, Veenstra-VanderWeele J56, Walitza S57, Wang Y11, Wendland JR45, Shugart YY45, Miguel EC5, Nicolini H37, Oostra BA58, Moessner R39, Wagner M39, Ruiz-Linares A49, Heutink P59, Nestadt G11, Freimer N60, Petryshen T2, Posthuma D61, Jenike MA6, Cox NJ4, Hanna GL62, Brentani H5, Scherer SW3, Arnold PD3, Stewart SE63, Mathews CA40, Knowles JA47, Cook EH64, Pauls DL6, Wang K47, Scharf JM65.

Author information

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.

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

PMID:
25062598
PMCID:
PMC4218748
DOI:
10.1016/j.jaac.2014.04.022
[Indexed for MEDLINE]
Free PMC Article

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