A Discordant-Sibship Test for Disequilibrium and Linkage: No Need for Parental Data

Abstract

The sibship disequilibrium test (SDT) is designed to detect both linkage in the presence of association and association in the presence of linkage (linkage 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 sibship; it remains valid if there are misclassifications of the affectation status; it does not detect spurious associations due to population stratification; asymptotically it has a chi2 distribution under the null hypothesis; and exact P values can be easily computed for a biallelic marker. We show 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 power of the test by presenting sample-size calculations involving a complex disease model, and we present formulas for the asymptotic relative efficiency (which is approximately the ratio of sample sizes) between SDT and the transmission/disequilibrium test (TDT) for special family structures. For sib pairs, we compare the SDT to a test proposed both by Curtis and, independently, by Spielman and Ewens. We show that, for discordant sib pairs, the SDT has good power for testing linkage disequilibrium relative both to Curtis's tests and to the TDT using trios comprising an affected sib and its parents. With additional sibs, we show that the SDT can be more powerful than the TDT for testing linkage disequilibrium, especially for disease prevalence >.3.