Assessing whether an allele can account in part for a linkage signal: The Genotype-IBD Sharing Test (GIST)

To fine map genes, investigators often test for disease-marker association in chromosomal regions with evidence for linkage. Given a marker allele tentatively associated with disease, one would ask if this allele, or one in linkage disequilibrium (LD) with it, could account in part for the observed linkage signal. This question can be addressed by determining if families selected on the basis of the presence of the tentatively associated allele show stronger evidence of linkage as measured by increased allele sharing identical by descent (IBD) by affected family members. However, common selection strategies can be biased for or against linkage in the marker region, even given no disease-marker association. We define unbiased selection schemes and extend the definition to allow weighted selection on the basis of all genotyped family members. For affected-sibship data, we describe three genotype-based weight variables, corresponding to dominant, recessive, and additive models. We then introduce a test for association of a family weight variable with excess IBD sharing. This test allows us to determine if the linkage signal in a region can be attributed in part to the presence of a marker allele, either because of direct involvement in disease etiology or because of LD with a predisposing genetic variant. For samples of 500 affected sib pairs, the tests are powerful in detection of genotype-IBD sharing association, even for disease models with sib relative risk as low as lambda(s) = 1.1, or when evidence for linkage is absent because of sampling variation. This makes our method a new tool for detecting linkage as well as association, especially in regions harboring a candidate gene. We have implemented these methods in the software package GIST (Genotype-IBD Sharing Test).