LINKAGE ANALYSIS OF COMPLEX TRAITS USING AFFECTED SIBPAIRS - EFFECTS OF SINGLE-LOCUS APPROXIMATIONS ON ESTIMATES OF THE REQUIRED SAMPLE-SIZE

We investigated the power of the affected sibpair method for detecting a disease locus when the disease is inherited through two bi-allelic loci. The power was computed for all possible values of the gene frequ encies and penetrances that lead to a given population prevalence and a given sibling relative risk. A method to generate rapidly all possib le models that give a specific population prevalence and relative risk is provided. We applied it to the case of a two-locus disease with a prevalence of 10% and a low sibling relative risk of 1.5. For this par ticular example, regardless of the true underlying model, a sample siz e (N approximate to 450 for alpha = 0.05, N approximate to 1,500 for a lpha = 0.0001) may be determined such that one would expect enough pow er (0.80) to detect at least one of the two disease genes. In addition to the general case, we examined a special class of models in which t he marginal penetrances at each locus are either recessive or dominant . In this instance: the gene frequencies were excellent predictors of the power afforded by a particular sample size. These methods have bee n implemented in a C program called SIBPOWER which is freely available from the first author. With this program, investigators can perform t heir own power calculations for any two-locus model of their choice th us avoiding the need to use single-locus approximations that may gross ly underestimate the necessary sample size. (C) 1997 Wiley-Liss, Inc.