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Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q

Molecular Psychiatry volume 11, pages 763–770 (2006)Cite this article

Abstract

Obsessive-compulsive disorder (OCD) is the tenth most disabling medical condition worldwide. Twin and family studies implicate a genetic etiology for this disorder, although specific genes have yet to be identified. Here, we present the first large-scale model-free linkage analysis of both extended and nuclear families using both ‘broad’ (definite and probable diagnoses) and ‘narrow’ (definite only) definitions of OCD. We conducted a genome-scan analysis of 219 families collected as part of the OCD Collaborative Genetics Study. Suggestive linkage signals were revealed by multipoint analysis on chromosomes 3q27–28 (P=0.0003), 6q (P=0.003), 7p (P=0.001), 1q (P=0.003), and 15q (P=0.006). Using the ‘broad’ OCD definition, we observed the strongest evidence for linkage on chromosome 3q27-28. The maximum overall Kong and Cox LODall score (2.67) occurred at D3S1262 and D3S2398, and simulation based P-values for these two signals were 0.0003 and 0.0004, respectively, although for both signals, the simulation-based genome-wide significance levels were 0.055. Covariate-linkage analyses implicated a possible role of gene(s) on chromosome 1 in increasing the risk for an earlier onset form of OCD. We are currently pursuing fine mapping in the five regions giving suggestive signals, with a particular focus on 3q27–28. Given probable etiologic heterogeneity in OCD, mapping gene(s) involved in the disorder may be enhanced by replication studies, large-scale family-based linkage studies, and the application of novel statistical methods.

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Acknowledgements

Genotyping services at CIDR was funded through the National Institutes of Health via The Johns Hopkins University, Contract Number N01-HG-65403. We are grateful to the numerous individuals and families who generously donated their time and resources, and to the Obsessive Compulsive Foundation. We thank David Houseman, MD, Kathleen Merikangas, PhD, Ann Pulver, PhD, and Alec Wilson, PhD, for consultation; and clinicians and coordinators at each site: Providence (Maria Mancebo, PhD, Richard Marsland, RN, Shirley Yen, PhD); New York (Renee Goodwin, PhD, Joshua Lipsitz, PhD); Baltimore (Laura Eisen, BS; Karan Lamb, PsyD, Tracey Lichner, PhD, Yung-mei Leong, PhD; Krista Vermillion, BA, Ying Wang, MS); Boston (Dan Geller, MD, Anne Chosak, PhD, Michelle Wedig, BS, Evelyn Stewart, MD, Michael Jenike, MD, Beth Gershuny, PhD, Sabine Wilhelm, PhD); Bethesda (Lucy Justement, Diane Kazuba, V Holland LaSalle-Ricci, Theresa B DeGuzman); Los Angeles (R Lindsey Bergman, PhD, Susanna Chang, PhD, Audra Langley, PhD, Amanda Pearlman, BA). This study is supported by NIMH R01 MH50214 to GN, K23-MH64543 to OJB, and 7K23MH066284 to MAG from the National Institute of Mental Health, and NIH, NCRR, OPD-GCRC RR 00052 from the National Institutes of Health. YYS is, in part, supported by the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health.

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Author notes

  1. Y Y Shugart and J Samuels: Authors contributed to the manuscript equally.

Authors and Affiliations

  1. Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA

    Y Y Shugart

  2. Department of Biostatistics, Johns Hopkins University, Baltimore, MD, USA

    Y Y Shugart & K-Y Liang

  3. Department of Social Medicine, University of Bristol, Bristol, UK

    Y Y Shugart

  4. Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    J Samuels & G Nestadt

  5. Department of Psychiatry, Johns Hopkins University, Baltimore, MD, USA

    J Samuels, V L Willour, M A Grados, Y Wang, B Cullen, O J Bienvenu, R Hoehn-Saric, M A Riddle & G Nestadt

  6. The Kennedy Krieger Institute, Baltimore, MD, USA

    M A Grados

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

    B D Greenberg, A Pinto & S A Rasmussen

  8. Department of Psychiatry, College of Physicians and Surgeons at Columbia University and the New York State Psychiatric Institute, New York, NY, USA

    J A Knowles, A J Fyer & J Page

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

    J T McCracken & J Piacentini

  10. Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    S L Rauch & D L Pauls

  11. Laboratory of Clinical Science, NIMH, NIH, Bethesda, MD, USA

    D L Murphy

  12. Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MD, USA

    D L Pauls

  13. Department of Behavioral Sciences and Pediatrics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    D Valle & M A Riddle

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  1. Y Y Shugart
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  2. J Samuels
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  4. M A Grados
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  10. Y Wang
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  11. A Pinto
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  13. J Piacentini
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  14. D L Pauls
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  15. B Cullen
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  16. J Page
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  17. S A Rasmussen
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  18. O J Bienvenu
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  19. R Hoehn-Saric
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  20. D Valle
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  21. K-Y Liang
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  22. M A Riddle
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  23. G Nestadt
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Correspondence to Y Y Shugart.

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Shugart, Y., Samuels, J., Willour, V. et al. Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q. Mol Psychiatry 11, 763–770 (2006). https://doi.org/10.1038/sj.mp.4001847

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  • DOI: https://doi.org/10.1038/sj.mp.4001847

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