The low-to-moderate resolution of linkage analysis in complex traits has underscored the need to identify disease phenotypes with presumed genetic homogeneity. Bipolar disorder (BP) accompanied by psychosis (psychotic BP) may be one such phenotype. We previously reported a genome-wide screen in a large bipolar pedigree sample. In this follow-up study, we reclassified the disease phenotype based on the presence or absence of psychotic features and subgrouped pedigrees according to familial load of psychosis. Evidence for significant linkage to psychotic BP (genome-wide Po0.05) was obtained on chromosomes 9q31 (lod ¼ 3.55) and 8p21 (lod ¼ 3.46). Several other sites were supportive of linkage, including 5q33 (lod, and 20q13 (lod ¼ 1.98). For most loci, the highest lod scores, including those with genome-wide significance (at 9q31 and 8p21), occurred in the subgroup of families with the largest concentration of psychotic individuals (Z3 in a family). Interestingly, all regions but six-5q33, 6q21, 8p21, 8q24, 13q32 and 18q21-appear to be novel; namely, they did not show notable linkage to BP in other genome scans, which did not employ psychosis for disease classification. Also of interest is possible overlap with schizophrenia, another major psychotic disorder: seven of the regions presumed linked in this study-5q, 6q, 8p, 13q, 15q, 17p, and 18q-are also implicated in schizophrenia, as are 2p13 and 10q26, which showed more modest support for linkage. Our results suggest that BP in conjunction with psychosis is a potentially useful phenotype that may: (1) expedite the detection of susceptibility loci for BP and (2) cast light on the genetic relationship between BP and schizophrenia.

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.