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.

The nature of the Reed Sternberg (RS) cell, the malignant cell of Hodgkin's disease (HD), remains unknown. Cytogenetic studies have yielded ambiguous results regarding the chromosomal profile of this cell. In an attempt to further clarify the ploidy status of the RS cell, we analyzed the DNA content of CD30-positive RS cells and RS cell variants in HD lesions from 32 patients using an image analysis system. A diploid and/or near-diploid (DNA index [DI], 1.0 +/- 0.2) and a tetraploid (2.0 +/- 0.2) RS cell population were identified in 9 and in 11 of the 32 cases examined, respectively. An aneuploid RS cell population was identified in 8 of the 32 cases examined. The remaining four cases contained two RS cell subpopulations with different DNA content, each one representing more than 15% of the total RS cell population. There was no significant correlation between the DNA content of the RS cells and the category of HD. Furthermore, analysis of multiple biopsies of an individual patient taken from different lymphoid organs at the same or different time periods showed a constant DNA profile. Our data indicate that RS cells can express variable DNA content and suggests that multiple subpopulations of RS cells with different DNA content may simultaneously coexist within the same HD lesion in some patients. In addition, the RS cell population within each patient appears to express a specific DNA content profile, possibly representing unique clones. These highly individualized profiles potentially may be useful as markers to follow the clinical course of patients with HD.