Efficient use of siblings in testing for linkage and association

Tests of linkage and association between a disease and either a candidate g ene or marker allele can be based on sibships with at least one affected an d one unaffected sibling. However, specialized techniques are required to a ccount for within-sibship correlation if some sibships contain more than on e affected or more than one unaffected sib. In this paper, we propose Withi n Sibship Paired Resampling (WSPR), a technique that is designed to test th e null hypothesis of no linkage or no association, even when sibships conta in variable numbers of sibs. One repeatedly generates data subsets based on randomly sampling one affected and one unaffected sibling from each sibshi p, and each subset is analyzed individually. Then, evidence is combined by averaging results across these resampled data sets, applying a variance exp ression that implicitly accounts for the correlation among siblings. While the general WSPR procedure allows for numerous testing strategies, we descr ibe two in detail. Simulation results for scenarios with varying degrees of population stratification demonstrate good power for the WSPR testing meth ods compared to the sib TDT (S-TDT) and the sibship disequilibrium test (SD T). (C) 2001 Wiley-Liss, Inc.