Haplotype analysis defines a 4.7Mb probable disease region for a bipolar affective disorder susceptibility locus on chromosome 4q35

We have developed a novel haplotype-based approach to define a 4q35 bipolar susceptibility region. Linkage analysis in 55 pedigrees gave a maximum two-point LOD score of 3.01 for D4S1652 and scores between 1.5 and 2.44 for several other markers. 24 linked pedigrees were selected for haplotype analysis based on having LOD scores greater than their maximum expected LOD score for multiple markers. There was no ancestral disease haplotype and no one-to-one correspondence between disease and disease haplotype. Therefore we determined a probable disease region based on the percentage of affected individuals within each pedigree sharing the same portion of the disease haplotype and pooled this data across all linked pedigrees. In each pedigree, for each 4q35 marker we calculated the number of affecteds who share the marker allele that forms part of the disease haplotype, identical-by-descent (IBD). The number of affected individuals sharing alleles IBD at each marker was pooled to generate a map of percentage of sharing. A probable disease region of 4.7Mb from D4S1540 to the telomere was defined by maximum allele sharing of affected pedigree members. Using this pedigree specific IBD allele sharing approach provides a means for focusing the candidate gene search for this complex trait.