A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees

Abstract

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.

Figure 1

Extent of marker coverage of each chromosome. Coverage is defined as regions for which a lod score of at least 1.6 would have been detected (in the combined data set) for markers truly linked to BP-I under the model that we employed. Areas that remain uncovered (at this threshold) are unshaded. Markers for which lod scores were obtained that exceeded the predesignated coverage thresholds in CR001, CR004, or the combined data set are shown at their approximate chromosomal position. The symbols to the right of the chromosome indicate the thresholds exceeded at that marker: • signifies that the lod score at a marker exceeded the threshold of 0.8 in CR001; ♦ signifies that the lod score exceeded the threshold of 1.2 in CR004; and ★ signifies that the lod score exceeded the threshold of 1.6 in the combined data set.

Figure 2

The lod scores for the maximum likelihood estimates (MLEs) of θ in the combined sample for the 473 microsatellite markers typed in the genome screen. The MLEs of θ are represented by different colors: red, θ < 0.10; green, 0.10 ≤ θ < 0.40; blue, θ ≥ 0.40. Note that the scale for the x-axis (distance from pter in cM) changes with chromosomes. Marker names and actual MLEs of θ are available from N.B.F. by request.