Affected sibpair linkage tests for multiple linked susceptibility genes

Genome-wide searches for susceptibility genes using pairs of affected siblings are being undertaken to dissect out individual polygenes that contribute to human multifactorial disease. Efficient identity-by-descent (IBD)-based sibpair linkage tests are available that test individual markers or maps of linked markers for linkage to a single putative susceptibility gene. In order to assess the support for linkage to a second putative susceptibility gene that happens to map close to an established susceptibility gene, it is necessary to use a method that correctly allows for the IBD distortion that directly results from the linkage between the two genes. A maximum likelihood-based, multilocus linkage test is proposed, which accounts for this interdependency and evaluates the support for an interaction between constituent susceptibility genes. The size and power of a test for a second linked susceptibility gene is investigated by simulation studies.