| Assuming there is exactly one disease gene in a chromosomal region, a generalized estimating equations (GEE) approach can be used to estimate the location of the gene (Liang et al., 2001, Human Heredity 51: 64--78) using marker identical-by-descent (IBD) sharing data at multiple markers in a sample of affected sib pairs (ASPs). For diseases with complex genetic etiology, more than one susceptibility gene may exist in one chromosomal region. In such situations, linkage methods designed to detect a single locus may not successfully localize either of these two genes. We derived an expression for expected allele sharing in affected sib pairs at each point across a chromosomal segment containing two susceptibility genes, and proposed a GEE approach for localizing both disease genes simultaneously. We developed an algorithm that uses marker IBD sharing for a sample of ASPS to estimate the locations of the two genes and the expected ASP IBD sharing at these two loci. We also proposed methods to evaluate the evidence for two linked disease loci, in this GEE estimation framework, based on approximate quasi-likelihood ratio and generalized Wald and score test statistics. We evaluated the proposed estimation and testing methods by simulation, and found that the proposed estimation method can improve disease gene localization and aid in resolving large peaks when two disease genes are present in one chromosomal region. The performance of the estimation method for localizing two linked disease genes, and the power to detect the presence of two linked genes, improve with increased excess allele sharing at the disease gene loci, increased distance between the disease genes, and increased number of affected sib pairs. We applied the described methods to data from a genome scan for type 1 diabetes (Mein et al., 1998, Nature Genetics 19: 297--300) and obtained estimates of two putative disease gene locations on chromosome 6, approximately 20 cM apart. |
