A discordant-sibship test for disequilibrium and linkage: No need for parental data

The sibship disequilibrium test (SDT) is designed to detect both linkage in the presence of association and association in the presence of linkage (li nkage disequilibrium). The test does not require parental data but requires discordant sibships with at least one affected and one unaffected sibling. The SDT has many desirable properties: it uses all the siblings in the sib ship; it remains valid if there are misclassifications of the affectation s tatus; it does not detect spurious associations due to population stratific ation; asymptotically it has a chi(2) distribution under the null hypothesi s; and exact P values can be easily computed for a biallelic marker. We sho w how to extend the SDT to markers with multiple alleles and how to combine families with parents and data from discordant sibships. We discuss the po wer of the test by presenting sample-size calculations involving a complex disease model, and we present formulas for the asymptotic relative efficien cy (which is approximately the ratio of sample sizes) between SDT and the t ransmission/disequilibrium test (TDT) for special family structures. For si b pairs, we compare the SDT to a test proposed both by Curtis and, independ ently, by Spielman and Ewens. We show that, for discordant sib pairs, the S DT has good power for testing linkage disequilibrium relative both to Curti s's tests and to the TDT using trios comprising an affected sib and its par ents. With additional sibs, we show that the SDT can be more powerful than the TDT for testing linkage disequilibrium, especially for disease prevalen ce >.3.