Genome-wide association study of obsessive-compulsive disorder - Molecular Psychiatry

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The authors would like to express their utmost gratitude to the OCD-affected families who participated in this research. In addition, they would like to thank the International OCD Foundation (IOCDF) for their role in establishing the IOCDF Genetics Collaborative, as well as other individuals who played roles in assisting this study, including Rhonda Ellwyn, Katherine Beattie, Colm O’Dushlaine, Doug Ruderfer, Priya Moorjani and V. Guttenthaler. This work was supported primarily by a grant from the Judah Foundation (a private, non-industry related foundation established by a family affected by OCD), NIH grants MH079489 and MH073250 to DLP, American Recovery and Re-investment Act (ARRA) awards NS40024-07S1 and NS16648-29S1 to DLP, by an American Academy of Child and Adolescent Psychiatry (AACAP) Early Investigator Research Grant, an Anxiety Disorders Association of America (ADAA) Junior Investigator Research Grant, the University of British Columbia and a Michael Smith Foundation Clinical Research Scholar Award to SES, and grants from the Tourette Syndrome Association (DLP and JMS), the American Academy of Neurology Foundation (JMS) and NIH grant MH085057 to JMS. The Broad Institute Center for Genotyping and Analysis was supported by grant U54 RR020278 from the National Center for Research Resources. 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 data sets 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 related genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National 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 data sets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000092.v1.p1 through dbGaP accession number phs000092.v1.p. Frontal lobe eQTL data was provided by the North American Brain Expression Consortium and the UK Human Brain Expression Database. Funding support for generation of the eQTL data was provided by the UK Medical Research Council and the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services project Z01 AG000932-02. The North American Brain Expression Consortium comprises: Sampath Arepalli, Mark R Cookson, Allissa Dillman, Luigi Ferrucci, J Raphael Gibbs, Dena G Hernandez, Robert Johnson, Dan L Longo, Michael A Nalls, Richard O′Brien, Andrew Singleton, Bryan Traynor, Juan Troncoso, Marcel van der Brug, H Ronald Zielke and Alan Zonderman. The UK Human Brain Expression Database membership comprises: John A Hardy, Mina Ryten, Colin Smith, Daniah Trabzuni, Robert Walker and Mike Weale. None of the funding sources supporting this work had any influence or played any role in: (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.

AUTHOR CONTRIBUTIONS

Manuscript preparation: SE Stewart, JA Knowles, D Yu, JM Scharf, CA Mathews, PD Arnold, E Gamazon, PD Evans, GL Hanna, NJ Cox and DL Pauls. Study design: SE Stewart, JM Scharf, D Yu, JA Knowles, PD Arnold, CA Mathews, BM Neale, JA Fagerness, EH Cook, S Purcell, NJ Cox, G Nestadt and DL Pauls. Data analysis: D Yu, BM Neale, S Purcell, JM Scharf, PD Evans, ER Gamazon, A Tikhomirov, A Pluzhnikov, A Konkashbaev, LK Davis, D Posthuma, E Eskin, C Sabatti, CK Edlund, DV Conti, JA Knowles, NJ Cox. Project management: SE Stewart, JM Scharf, JA Fagerness, MA Jenike and DL Pauls. Sample management and processing: JA Fagerness, S Haddad, JM Scharf, J Crane, C Mayerfeld and DL Pauls. Genotyping: AT Crenshaw, MA Parkin and DB Mirel. Phenotype management: SE Stewart, L Osiecki, D Hezel, C Illmann, JM Scharf and DL Pauls. Case sample collection (ordered by numbers of submitted samples): University of Bonn, Germany: M Wagner, R Moessner (Site PI), P Falkai, W Maier, S Ruhrmann, H-J Grabe, L Lennertz. Italy: L Bellodi, MC Cavallini. Toronto, Canada/Wayne State collaborative: PD Arnold, MA Richter, EH Cook, Jr, JL Kennedy, D Rosenberg. University of Cape Town, South Africa: DJ Stein (Site PI), SMJ Hemmings, C Lochner. UCSF/ Costa Rica collaborative: CA Mathews (Site PI), A Azzam, DA Chavira, E Fournier, H Garrido, B Sheppard, P Umana. National Institute of Mental Health: DL Murphy, JR Wendland. Michigan: GL Hanna (Site PI), J Veenstra-VanderWeele. AMC, Netherlands: D Denys (Site PI), R Blom, D Deforce, F Van Nieuwerburgh, HGM Westenberg. Wurzburg Germany: S Walitza (Site PI), K Egberts, T Renner. Massachusetts General Hospital, Boston: DL Pauls (Site PI), C Illmann, SE Stewart, JM Scharf, SL Rauch. Brazil: EC Miguel (Site PI), C Cappi, AG Hounie, MC do Rosario, AS Sampaio, H Vallada. Mexico: H Nicolini (Site PI), N Lanzagorta, B Camarena. Paris, France: M Leboyer (Site PI), R Delorme. University of Southern California: MT Pato (Site PI), CN Pato, JA Knowles, E Voyiaziakis. VUMC, Netherlands: DC Cath (Site PI), P Heutink, D Posthuma, JH Smit. OCGS, Johns Hopkins collaborative: G Nestadt (Site PI), J Samuels, OJ Bienvenu, B Cullen, AJ Fyer, MA Grados, BD Greenberg, JT McCracken, MA Riddle, Y Wang. Yale University: JF Leckman (Site PI), M Bloch, C Pittenger, V Coric. United Arab Emirates: V Eapen. Iowa: DW Black. Control Sample Collection: University Medical Center, Utrecht: RA Ophoff, E Strengman. University of Bonn: R Moessner (Site PI), M Wagner, P Falkai, W Maier, S Ruhrmann, H-J Grabe, L Lennertz. Data Collection: Italian Control data: F Macciardi, D Cusi, M Turiel, F Frau. eQTL and mQTL data: C Liu. MR Cookson, JR Gibbs and A Singleton for the North American Brain Expression Consortium; J Hardy for the UK Human Brain Expression Database.

North American Brain Expression Consortium

S Arepalli¹, MR Cookson¹, A Dillman¹, L Ferrucci², JR Gibbs^1,3, DG Hernandez^1,3, R Johnson⁴, DL Longo⁵, MA Nalls¹, R O’Brien⁶, A Singleton¹, B Traynor¹, J Troncoso⁶, M van der Brug^1,7, HR Zielke⁴, A Zonderman⁸;

UK Human Brain Expression Database

JA Hardy³, M Ryten³, C Smith⁹, D Trabzuni³, R Walker⁹, Mike Weale¹⁰

¹Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; ²Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA; ³Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; ⁴NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland Medical School, Baltimore, MD, USA; ⁵Lymphocyte Cell Biology Unit, Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA; ⁶Brain Resource Center, Johns Hopkins University, Baltimore, MD, USA; ⁷ITGR Biomarker Discovery Group, Genentech, South San Francisco, CA, USA; ⁸Research Resources Branch, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; ⁹Department of Pathology, The University of Edinburgh, Edinburgh, UK and ¹⁰King’s College London, Department of Medical & Molecular Genetics, UK.

Author notes

1. S E Stewart, D Yu, J M Scharf, B M Neale, J A Fagerness, C A Mathews and P D Arnold: These authors contributed equally to this work.

2. S Purcell, G Nestadt, G L Hanna, M A Jenike, J A Knowles, N Cox and D L Pauls: These are co-senior authors.

Authors and Affiliations

1. Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Harvard Medical School, Boston, MA, USA

   S E Stewart, D Yu, J M Scharf, B M Neale, J A Fagerness, L Osiecki, L McGrath, S Haddad, J Crane, D Hezel, C Illman, C Mayerfeld, S Purcell, M A Jenike & D L Pauls

2. Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

   S E Stewart, D Yu, J M Scharf, J A Fagerness, L Osiecki, L McGrath, S Haddad, J Crane, D Hezel, C Illman, C Mayerfeld, S Purcell, M A Jenike & D L Pauls

3. British Columbia Mental Health and Addictions Research Institute, University of British Columbia, Vancouver, BC, Canada

   S E Stewart

4. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

   J M Scharf

5. Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA

   J M Scharf & S Purcell

6. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

   B M Neale

7. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA

   J M Scharf & B M Neale

8. Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA

   C A Mathews, A Azzam & B Sheppard

9. Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada

   P D Arnold

10. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    P D Arnold, M A Richter & J L Kennedy

11. Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, IL, USA

    P D Evans, E R Gamazon, A Konkashbaev, A Pluzhnikov, A Tikhomirov & N Cox

12. Department of Psychiatry, University of Chicago, Chicago, IL, USA

    C Liu

13. Department of Preventative Medicine, Division of Biostatistics, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, USA

    C K Edlund & D V Conti

14. Epigenome Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    C K Edlund & D V Conti

15. Partners Psychiatry and McLean Hospital, Boston, MA, USA

    S L Rauch

16. Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany

    R Moessner, W Maier, L Lennertz & M Wagner

17. Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany

    P Falkai

18. Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany

    S Ruhrmann

19. Department of Psychiatry and Psychotherapy, Helios-Hospital Stralsund, University Medicine Greifswald, Greifswald, Germany

    H-J Grabe

20. Psychiatry Universita Vita-Salute San Raffaele, Milano, Italy

    L Bellodi

21. Fondazione Centro San Raffaele del Monte Tabor, Milano, Italy

    M C Cavallini

22. Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

    M A Richter

23. Department of Psychiatry, Institute for Juvenile Research, University of Illinois at Chicago, Chicago, IL, USA

    E H Cook Jr

24. Centre for Addiction and Mental Health, Toronto, ON, Canada

    J L Kennedy

25. Child Psychiatry and Psychology, Wayne State University, Detroit, MI, USA

    D Rosenberg

26. Children's Hospital of Michigan, Detroit, MI, USA

    D Rosenberg

27. University of Cape Town, Cape Town, South Africa

    D J Stein

28. University of Stellenbosch, Stellenbosch, South Africa

    S M J Hemmings & C Lochner

29. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

    D A Chavira

30. Hospital Nacional de Niños, San José, Costa Rica

    E Fournier, H Garrido & P Umaña

31. Laboratory of Clinical Science, NIMH Intramural Research Program, Bethesda, MD, USA

    D L Murphy & J R Wendland

32. CNS Clinical Biomarker Group, Pharma Research and Early Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland

    J R Wendland

33. Departments of Psychiatry, Pediatrics, and Pharmacology, Kennedy Center for Research on Human Development, and Brain Institute, Vanderbilt University, Nashville, TN, USA

    J Veenstra-VanderWeele

34. Department of Psychiatry, Academic Medical Center and Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences (NIN-KNAW), Amsterdam, The Netherlands

    D Denys, R Blom & H G M Westenberg

35. Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium

    D Deforce & F Van Nieuwerburgh

36. Department of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland

    S Walitza

37. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany

    K Egberts & T Renner

38. Department of Psychiatry, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil

    E C Miguel, C Cappi, A G Hounie, M Conceição do Rosário, A S Sampaio & H Vallada

39. University Health Care Services - SMURB, Federal University of Bahia, Salvador, Brazil

    A S Sampaio

40. Centre for Genomic Sciences, University of Mexico City, Mexico City, Mexico

    H Nicolini

41. Carracci Medical Group, Mexico City, Mexico

    H Nicolini & N Lanzagorta

42. Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Depto. de Genética Psiquiátrica, Mexico City, Mexico

    B Camarena

43. Department of Child and Adolescent Psychiatry, AP-HP, Robert Debré Hospital, INSERM U955, Paris, France

    R Delorme & M Leboyer

44. Institut Mondor de Recherche Biomédicale, Psychiatric Genetics, Créteil, France

    R Delorme & M Leboyer

45. Foundation Fondamental, French National Science Foundation, Créteil, France

    R Delorme & M Leboyer

46. Department of Psychiatry and The Behavioral Sciences, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    C N Pato, M T Pato, E Voyiaziakis & J A Knowles

47. Department of Clinical Genetics, Section of Medical Genomics, VU University Medical Center Amsterdam, Amsterdam, The Netherlands

    P Heutink & D Posthuma

48. Department of Psychiatry, VU University Medical Center and Department of Clinical and Health Psychology, Utrecht University, Utrecht, The Netherlands

    D C Cath

49. Department of Psychiatry, EMGO Institute, VU University Medical Center, Utrecht, The Netherlands

    D C Cath & J H Smit

50. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    J Samuels, O J Bienvenu, B Cullen, M A Grados, M A Riddle, Y Wang & G Nestadt

51. Department of Psychiatry, College of Physicians and Surgeons at Columbia University, New York City, NY, USA

    A J Fyer

52. New York State Psychiatric Institute, New York City, NY, USA

    A J Fyer

53. Department of Psychiatry and Human Behavior, Brown Medical School, Butler Hospital, Providence, RI, USA

    B D Greenberg

54. Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, School of Medicine, Los Angeles, CA, USA

    J T McCracken

55. Child Study Centre and Department of Psychiatry, Yale University, New Haven, CT, USA

    V Coric, M Bloch & C Pittenger

56. Child Study Centre, Pediatrics and Psychology, Yale University, New Haven, CT, USA

    J F Leckman

57. Infant, Child and Adolescent Psychiatry, University of New South Wales, Academic Unit of Child Psychiatry South West Sydney (AUCS), Sydney, NSW, Australia

    V Eapen

58. University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA

    D W Black

59. UCLA Center for Neurobehavioral Genetics, Los Angeles, CA, USA

    R A Ophoff & E Strengman

60. University Medical Center Utrecht, Utrecht, The Netherlands

    R A Ophoff & E Strengman

61. Department of Medicine, Surgery and Dentistry, Graduate School of Nephrology, University of Milano, Milano, Italy

    D Cusi & F Frau

62. Division of Nephrology, San Paolo Hospital, Milano, Italy

    D Cusi

63. Department of Health Technologies, University of Milano, Milano, Italy

    M Turiel

64. Filarete Foundation, Milano, Italy

    F Frau

65. Department of Psychiatry and Human Behavior, School of Medicine, University of California Irvine (UCI), Irvine, CA, USA

    F Macciardi

66. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

    J R Gibbs, M R Cookson & A Singleton

67. Department of Molecular Neuroscience, University College of London, Institute of Neurology, London, UK

    J Hardy

68. The Broad Institute of Harvard-MIT, Cambridge, MA, USA

    A T Crenshaw, M A Parkin, D B Mirel & S Purcell

69. Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA

    G L Hanna

Consortia

Corresponding authors

Correspondence to S E Stewart or D L Pauls.

Competing interests

SE Stewart has received funding from the International OCD Foundation (IOCDF) and is a member of the IOCDF Scientific Advisory Committee. PD Arnold reports funding sources including the CIHR, NIH, Ontario Research Foundation, Ontario Brain Institute, DNA Genotek, and the McLaughlin Centre. AB Singleton served as an unpaid consultant to Teva Pharmaceuticals. HJ Grabe has received funds from the German Research Foundation; Federal Ministry of Education and Research Germany; speakers honoraria from Bristol-Myers Squibb, Eli Lilly, Novartis, Eisai, Boehringer Ingelheim; speaker and travel funds from Janssen-Cilag, Eli Lilly, Novartis, AstraZeneca, Lundbeck and SALUS-Institute for Trend-Research and Therapy Evaluation in Mental Health. R Moessner has been supported by the German Research Foundation (DFG) (grants Wa 731/6 and 731/4), and by the German Federal Ministry for Education and Research (BMBF grant 01GV0907). M Wagner has been supported by the German Research Foundation (DFG) (grants Wa 731/6 and 731/4), and by the German Federal Ministry for Education and Research (BMBF grant 01GV0907). MA Richter has received honoraria from Lundbeck and she is recipient of grant funding from Eli Lilly Canada, Ontario Mental Health Foundation and the Obsessive-Compulsive Foundation. DJ Stein has received research grants and/or consultancy honoraria from Abbott, Astrazeneca, Eli-Lilly, GlaxoSmithKline, Jazz Pharmaceuticals, Johnson & Johnson, Lundbeck, Orion, Pfizer, Pharmacia, Roche, Servier, Solvay, Sumitomo, Takeda and Tikvah. JR Wendland is now a full-time employee of F Hoffmann-La Roche J Veenstra-VanderWeele receives research funding from Seaside Therapeutics, Roche Pharmaceuticals and Novartis. GL Hanna, MT Pato and CN Pato receive NIH funding. K Egberts, T Renner and S Walitza received sample collection funding by DFG WA168/1-1. SL Rauch has received research funding from Cyberonics and Medtronic. JA Knowles is a recipient of grant funding from NIH and from NARSAD; he sits on the Scientific Advisory Committee for Next-Generation Sequencing of Life Technologies and is a technical advisor to SoftGenetics; he is on the Scientific Advisory Committee for Next-Generation Sequencing of Life Technologies and is a technical advisor to SoftGenetics. JF Leckman has been funded by the NIH, the TSA, Talecris Biotherapeutics, Klingenstein Third Generation Foundation, John Wiley and Sons, McGraw Hill and Oxford University Press. V Coric works for Bristol Myers-Squibb. DW Black has received NIH funding and support from AstraZeneca and Psysadon in addition to royalties from American Psychiatric Publishing and Oxford University Press. The remaining authors declare no conflicts of interest.

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Cite this article

Stewart, S., Yu, D., Scharf, J. et al. Genome-wide association study of obsessive-compulsive disorder. Mol Psychiatry 18, 788–798 (2013). https://doi.org/10.1038/mp.2012.85

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• Received: 04 January 2012

• Revised: 03 May 2012

• Accepted: 07 May 2012

• Published: 14 August 2012

• Issue Date: July 2013

• DOI: https://doi.org/10.1038/mp.2012.85

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