Detection of expansion regions in Portuguese bipolar families

We have studied 24 families with multiple affected members with bipolar dis order to test the hypothesis that in those families clinically showing gene tic anticipation [Macedo et al., 1999] we would find large repeat expansion s. The families meeting inclusion criteria had a minimum of two affected me mbers over two generations and showed marked anticipation both in terms of age of onset and disease severity, me used the repeat expansion detection ( RED) method to test patients (n = 24) and controls from these families and unrelated controls (n = 53). me also genotyped patients and family members from two families with large expansions at the known expansion loci on chro mosomes 13, 17, and 18. The RED method revealed a higher number of large ex pansions in patients compared with controls (t-test; P < 0.0055: Mann-Whitn ey U; P = 0.02). The patients with the largest expansions were typed at the specific loci on chromosomes 13, 17, and 18 and the chromosome 18 expansio n locus segregated with disease in one family, and a second family showed s egregation with the expansion located at the SCA8 locus on chromosome 13. G enetic anticipation had been analyzed in this cohort of families, with corr ection for potential ascertainment bias, possible proband effects, cohort e ffects, regression to the mean, gender effects, and maternal vs. paternal t ransmission. None of these potential confounds appeared to account for the observed anticipation. We also identified that the presence of large expans ions in affected family members derives primarily from two families from th e genetically isolated Azores population. One family shows segregation with the chromosome 18 locus, whereas the other family segregates with expansio ns at the SGA8 locus. (C) 2000 Wiley-Liss, Inc.