Sibling-based tests of linkage and association for quantitative traits

The transmission/disequilibrium test (TDT) developed by Spielman et al. can be a powerful family-based test of linkage and, in some cases, a test of association as well as linkage. It has recently been extended in several ways; these include allowance for implementation with quantitative traits, allowance for multiple alleles, and, in the case of dichotomous traits, allowance for testing in the absence of parental data. In this article, these three extensions are combined, and two procedures are developed that offer valid joint tests of linkage and (in the case of certain sibling configurations) association with quantitative traits, with use of data from siblings only, and that can accommodate biallelic or multiallelic loci. The first procedure uses a mixed-effects (i.e., random and fixed effects) analysis of variance in which sibship is the random factor, marker genotype is the fixed factor, and the continuous phenotype is the dependent variable. Covariates can easily be accommodated, and the procedure can be implemented in commonly available statistical software. The second procedure is a permutation-based procedure. Selected power studies are conducted to illustrate the relative power of each test under a variety of circumstances.