A comprehensive linkage analysis of chromosome 21q22 supports prior evidence for a putative bipolar affective disorder locus

Previously, we demonstrated evidence of linkage to bipolar affective disord er (BP) in a single large, multigenerational family with a LOD score of 3.4 1 at the PFKL locus on chromosome 21q22.3. Additional families showed littl e support for linkage to PFKL under homogeneity or heterogeneity, in that s tudy We I-rave expanded on that analysis, with 31 microsatellite markers at an average marker spacing of less than or equal to 2 cM, in the largest mu ltigenerational BP pedigree series reported to date. A two-point heterogene ity (alpha=0.5) LOD score of 3.35 (P <.000156) was found at the D21S1260 lo cus, 5 cM proximal to PFKL. Polylocus analysis with a cluster of three neig hboring markers was consistent with these results (PL-HetLOD = 3.25). In th e design of this study, 373 individuals from 40 families (from a total set of 1,508 individuals in 57 families) were chosen, as a cost-effective appro ach to genotyping this large sample set. Linkage analyses were performed wi th an "affecteds-only" method. As such, our results are based solely on gen etic information from affected individuals, without assumptions about the d isease-locus genotypes of the unaffecteds. Furthermore, for ease of compari son, this study was performed with the same approach as a 10cM genome scan for BP loci, the results of which will be reported elsewhere.