Simultaneous localization of two linked disease susceptibility genes

For diseases with complex genetic etiology, more than one susceptibility gene may exist in a single chromosomal region. Extending the work of Liang et al. ([2001] Hum. Hered. 51:64-78), we developed a method for simultaneous localization of two susceptibility genes in one region. We derived an expression for expected allele sharing of an affected sib pair (ASP) at each point across a chromosomal segment containing two susceptibility genes. Using generalized estimating equations (GEE), we developed an algorithm that uses marker identical-by-descent (IBD) sharing in affected sib pairs to simultaneously estimate the locations of the two genes and the mean IBD sharing in ASPs at these two disease loci. Confidence intervals for gene locations can be constructed based on large sample approximations. Application of the described methods to data from a genome scan for type 1 diabetes (Mein et al. [1998] Nat. Genet. 19:297-300) yielded estimates of two putative disease gene locations on chromosome 6, approximately 20 cM apart. Properties of the estimators, including bias, precision, and confidence interval coverage, were studied by simulation for a range of genetic models. The simulations demonstrated that the proposed method can improve disease gene localization and aid in resolving large peaks when two disease genes are present in one chromosomal region. Joint localization of two disease genes improves with increased excess allele sharing at the disease gene loci, increased distance between the disease genes, and increased number of affected sib pairs in the sample.