Genetic association mapping based on discordant sib pairs: the discordant-alleles test

Family-based tests of association provide the opportunity to test for an association between a disease and a genetic marker. Such tests avoid false-positive results produced by population stratification, so that evidence for association may be interpreted as evidence for linkage or causation. Several methods that use family-based controls have been proposed, including the haplotype relative risk, the transmission-disequilibrium test, and affected family-based controls. However, because these methods require genotypes on affected individuals and their parents, they are not ideally suited to the study of late-onset diseases. In this paper, we develop several family-based tests of association that use discordant sib pairs (DSPs) in which one sib is affected with a disease and the other sib is not. These tests are based on statistics that compare counts of alleles or genotypes or that test for symmetry in tables of alleles or genotypes. We describe the use of a permutation framework to assess the significance of these statistics. These DSP-based tests provide the same general advantages as parent-offspring trio-based tests, while being applicable to essentially any disease; they may also be tailored to particular hypotheses regarding the genetic model. We compare the statistical properties of our DSP-based tests by computer simulation and illustrate their use with an application to Alzheimer disease and the apolipoprotein E polymorphism. Our results suggest that the discordant-alleles test, which compares the numbers of nonmatching alleles in DSPs, is the most powerful of the tests we considered, for a wide class of disease models and marker types. Finally, we discuss advantages and disadvantages of the DSP design for genetic association mapping.