RESUMEN
Bipolar mood disorder (BP) is a debilitating syndrome characterized by episodes of mania and depression. We designed a multistage study to detect all major loci predisposing to severe BP (termed BP-I) in two pedigrees drawn from the Central Valley of Costa Rica, where the population is largely descended from a few founders in the 16th-18th centuries. We considered only individuals with BP-I as affected and screened the genome for linkage with 473 microsatellite markers. We used a model for linkage analysis that incorporated a high phenocopy rate and a conservative estimate of penetrance. Our goal in this study was not to establish definitive linkage but rather to detect all regions possibly harboring major genes for BP-I in these pedigrees. To facilitate this aim, we evaluated the degree to which markers that were informative in our data set provided coverage of each genome region; we estimate that at least 94% of the genome has been covered, at a predesignated threshold determined through prior linkage simulation analyses. We report here the results of our genome screen for BP-I loci and indicate several regions that merit further study, including segments in 18q, 18p, and 11p, in which suggestive lod scores were observed for two or more contiguous markers. Isolated lod scores that exceeded our thresholds in one or both families also occurred on chromosomes 1, 2, 3, 4, 5, 7, 13, 15, 16, and 17. Interesting regions highlighted in this genome screen will be followed up using linkage disequilibrium (LD) methods.
Asunto(s)
Trastorno Bipolar/genética , Cromosomas Humanos Par 18 , Genoma Humano , Mapeo Cromosómico , Costa Rica , Femenino , Genes Dominantes , Ligamiento Genético , Marcadores Genéticos , Humanos , Escala de Lod , Masculino , Repeticiones de Microsatélite , Modelos Genéticos , LinajeRESUMEN
Linkage disequilibrium (LD) analysis provides a powerful means for screening the genome to map the location of disease genes, such as those for bipolar disorder (BP). As described in this paper, the population of the Central Valley of Costa Rica, which is descended from a small number of founders, should be suitable for LD mapping; this assertion is supported by reconstruction of extended haplotypes shared by distantly related individuals in this population suffering low-frequency hearing loss (LFHL1), which has previously been mapped by linkage analysis. A sampling strategy is described for applying LD methods to map genes for BP, and clinical and demographic characteristics of an initially collected sample are discussed. This sample will provide a complement to a previously collected set of Costa Rican BP families which is under investigation using standard linkage analysis.
Asunto(s)
Trastorno Bipolar/genética , Mapeo Cromosómico , Desequilibrio de Ligamiento , Adulto , Trastorno Bipolar/epidemiología , Costa Rica/epidemiología , Femenino , Haplotipos , Pérdida Auditiva/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Manic depressive illness, or bipolar disorder (BP), is characterized by episodes of elevated mood (mania) and depression. We designed a multistage study in the genetically isolated population of the Central Valley of Costa Rica to identify genes that promote susceptibility to severe BP (termed BPI), and screened the genome ot two Costa Rican BPI pedigrees (McInnes et al., submitted). We considered only individuals who fulfilled very stringent diagnostic criteria for BPI to be affected. The strongest evidence for a BPI locus was observed in 18q22-q23. We tested 16 additional markers in this region and seven yielded peak lod scores over 1.0. These suggestive lod scores were obtained over a far greater chromosomal length (about 40 cM) than in any other genome region. This localization is supported by marker haplotypes shared by 23 of 26 BPI affected individuals studied. Additionally, marker allele frequencies over portions of this region are significantly different in the patient sample from those of the general Costa Rican population. Finally, we performed an analysis which made use of both the evidence for linkage and for association in 18q23, and we observed significant lod scores for two markers in this region.
Asunto(s)
Trastorno Bipolar/genética , Cromosomas Humanos Par 18/genética , Alelos , Mapeo Cromosómico , Costa Rica , Femenino , Ligamiento Genético , Marcadores Genéticos , Genética de Población , Genotipo , Haplotipos , Humanos , Escala de Lod , Masculino , Repeticiones de Microsatélite , LinajeRESUMEN
A review of the surgical and autopsy records from two general hospitals in La Paz, Bolivia, discloses an incidence of colon and rectal disease, excluding hemorrhoids, of 0.6 per cent (138 of 22,361 surgical cases) and 2.5 per cent (16 of 640 consecutive autopsies). Acquired megacolon complicated by volvulus represented more than half of all cases in the surgical series. Ulcerative colitis, diverticular disease, and neoplastic polyps represented less than 10 per cent of the cases of colonic disease. Only ten cases of carcinoma of the colon were seen, whereas five cases of granulomatous colitis or ileocolitis were detected in the same surgical material. Among sixty-four lesions of the rectum, so-called retention polyps accounted for 54.5 per cent of the cases, with carcinoma next in frequency (25 per cent), and the remainder being different varieties of inflammatory conditions. In the autopsy material almost half of the cases were infectious conditions, followed by congenital malformations and complicated acquired megacolon. No case of diverticular disease of the colon or neoplastic polyps was seen, and there was only one case of cancer of the large bowel. Because of the high incidence of acquired megacolon and the low incidence of cancer, ulcerative colitis, adenomatous polyps, and diverticular disease of the colon, possible etiopathogenic factors of these conditions are discussed in comparison with their incidence in other developed and developing countries of the world.