1. ¹Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA
2. ²Department of Biostatistics, Johns Hopkins University, Baltimore, MD, USA
3. ³Department of Social Medicine, University of Bristol, Bristol, UK
4. ⁴Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
5. ⁵Department of Psychiatry, Johns Hopkins University, Baltimore, MD, USA
6. ⁶The Kennedy Krieger Institute, Baltimore, MD, USA
7. ⁷Department of Psychiatry and Human Behavior, Brown Medical School, Butler Hospital, Providence, RI, USA
8. ⁸Department of Psychiatry, College of Physicians and Surgeons at Columbia University and the New York State Psychiatric Institute, New York, NY, USA
9. ⁹Department of Psychiatry and Biobehavioral Sciences, School of Medicine, University of California, Los Angeles, CA, USA
10. ¹⁰Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
11. ¹¹Laboratory of Clinical Science, NIMH, NIH, Bethesda, MD, USA
12. ¹²Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MD, USA
13. ¹³Department of Behavioral Sciences and Pediatrics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

Correspondence: Dr YY Shugart, Department of Epidemiology, Johns Hopkins University, The Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD, 21287, USA. E-mail: yyao@jhsph.edu

¹⁴Authors contributed to the manuscript equally.

Received 8 November 2005; Revised 27 March 2006; Accepted 28 April 2006; Published online 6 June 2006.

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 LOD_all 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.