1. ¹Columbia Genome Center, Columbia University, New York, NY, USA
2. ²Department of Epidemiology, Columbia University, New York, NY, USA
3. ³Graduate Institute of Medical Genetics, Kaohsiung Medical University, Kaohsiung, Taiwan
4. ⁴Department of Psychiatry, Columbia University, New York, NY, USA
5. ⁵Department of Biomedical Informatics, Columbia University, New York, NY, USA
6. ⁶Department of Psychiatry, Hadassah-Hebrew University, Jerusalem, Israel

Correspondence: Dr M Baron, Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA. E-mail: mb17@columbia.edu

⁷Current address: Department of Human Genetics, University of Chicago, Chicago, IL, USA

Received 13 July 2005; Revised 1 October 2005; Accepted 7 November 2005; Published online 10 January 2006.

Abstract

We conducted a 9-cM genome scan in a large bipolar pedigree sample from the National Institute of Mental Health genetics initiative (1060 individuals from 154 multiplex families). We performed parametric and nonparametric analyses using both standard diagnostic models and comorbid conditions thought to identify phenotypic subtypes: psychosis, suicidal behavior, and panic disorder. Our strongest linkage signals (genome-wide significance) were observed on chromosomes 10q25, 10p12, 16q24, 16p13, and 16p12 using standard diagnostic models, and on 6q25 (suicidal behavior), 7q21 (panic disorder) and 16p12 (psychosis) using phenotypic subtypes. Several other regions were suggestive of linkage, including 1p13 (psychosis), 1p21 (psychosis), 1q44, 2q24 (suicidal behavior), 2p25 (psychosis), 4p16 (psychosis, suicidal behavior), 5p15, 6p25 (psychosis), 8p22 (psychosis), 8q24, 10q21, 10q25 (suicidal behavior), 10p11 (psychosis), 13q32 and 19p13 (psychosis). Over half the implicated regions were identified using phenotypic subtypes. Several regions – 1p, 1q, 6q, 8p, 13q and 16p – have been previously reported to be linked to bipolar disorder. Our results suggest that dissection of the disease phenotype can enrich the harvest of linkage signals and expedite the search for susceptibility genes. This is the first large-scale linkage scan of bipolar disorder to analyze simultaneously bipolar disorder, psychosis, suicidal behavior, and panic disorder.