ORIGINAL RESEARCH ARTICLE Evidence for a putative bipolar disorder locus on 2p13–16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21– 24, 13q32, 14q21 and 17q11–12 J Liu 1,2 , SH Juo 1,3 , A Dewan 5 , A Grunn 1 , X Tong 1 , M Brito 1 , N Park 1 , JE Loth 2 , K Kanyas 6 , B Lerer 6 , J Endicott 2 , G Penchaszadeh 1 , JA Knowles 2 , J Ott 5 , TC Gilliam 1,2,4 and M Baron 1,2 1 Columbia Genome Center, Columbia University, New York, NY, USA; 2 Department of Psychiatry, Columbia University, New York, NY, USA; 3 Department of Epidemiology, Columbia University, New York, NY10032, USA; 4 Department of Genetics and Development, Columbia University, New York, NY USA; 5 Laboratory of Statistical Genetics, The Rockefeller University, New York, NY, USA; 6 Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Bipolar disorder (BP) is a severe and common psychiatric disorder characterized by extreme mood swings. Family, twin and adoption studies strongly support a genetic component. The mode of inheritance is complex and likely involves multiple, as yet unidentified genes. To identify susceptibility loci, we conducted a genome-wide scan with 343 microsatellite markers in one of the largest, well-characterized pedigree samples assembled to date (373 individuals in 40 pedigrees). To increase power to detect linkage, scan statistics were used to examine the logarithm of odds (lod) scores based on evidence at adjacent chromosomal loci. This analysis yielded significant evidence of linkage (genome-wide Po0.05) for markers on 2p13–16. Standard linkage analysis was also supportive of linkage to 2p13–16 (lod ¼ 3.20), and identified several other interesting regions: 4q31 (lod ¼ 3.16), 7q34 (lod ¼ 2.78), 8q13 (lod ¼ 2.06), 9q31 (lod ¼ 2.07), 10q24 (lod ¼ 2.79), 13q32 (lod ¼ 2.2), 14q21 (lod ¼ 2.36) and 17q11–12 (lod ¼ 2.75). In this systematic, large-scale study, we identified novel putative loci for BP (on 2p13–16, 8q13 and 14q21) and found support for previously proposed loci (on 4q31, 7q34, 9q31, 10q21–24, 13q32 and 17q11–12). Two of the regions implicated in our study, 2p13–14 and 13q32, have also been linked to schizophrenia, suggesting that the two disorders may have susceptibility genes in common. Molecular Psychiatry (2003) 8, 333–342. doi:10.1038/sj.mp.4001254 Keywords: manic depression; genetic linkage; genome scan; susceptibility loci Introduction Bipolar affective disorder (BP), or manic depression, is a major psychiatric disorder characterized by mania (BPI) or hypomania (BPII) alternating with periods of depression. BP is a major public health concern owing to high lifetime prevalence (0.5–1.5%) and substantial morbidity and mortality: if untreated, the disease can lead to frequent hospitalizations, sub- stance abuse, psychosocial impairment and suicide. Little is known about the etiology of BP, but genetic– epidemiological studies support a strong genetic component. Susceptibility to BP is likely governed by multiple genes together with nongenetic influ- ences. Early linkage studies produced negative or incon- sistent results, underscoring pitfalls in linkage analy- sis of complex psychiatric traits. 1–4 Recent data generated with improved methodologies and exten- sive genome coverage have implicated several chro- mosomal regions as potential sites for BP genes, most notably 1q31–32, 5 4p16, 6 6pter–p24, 7 10p14, 8 10q21– 26, 9 12q23–24, 10 13q31–33, 5 18p11, 11 18q21–23, 12,13 21q22, 14 22q11–13 15 and Xq24–27. 16 Even with these improvements, conflicting reports and methodologi- cal uncertainties indicate that these are not con- firmed, compelling findings. 3,17 In previous, more limited studies, we reported evidence of linkage to 21q 22 14,18,19 and nonreplica- tion of proposed loci on 18p11 20 and Xq27–28. 21,22 Here, we report a comprehensive, whole-genome scan in a large series of pedigrees with high density of BP and other mood disorders. This sample includes the families studied in our previous 21q 18 and Xq 21,22 studies, and 40 of the pedigrees reported in our 18p study 20 (as determined by power to detect linkage; see Methods). We present evidence for novel, un- reported BP susceptibility loci, support for previously Received 26 April 2002 and 22 June 2002 and 5 August 2002; accepted 6 August 2002 Correspondence: Dr M Baron, MD, Columbia University–NYS Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, USA. E-mail: mb17@columbia.edu or TC Gilliam, E-mail: tcg1@columbia.edu Molecular Psychiatry (2003) 8, 333–342 & 2003 Nature Publishing Group All rights reserved 1359-4184/03 $25.00 www.nature.com/mp