Linkage analysis: Power estimation and comparison of methods.

Abstract

Many genetic traits have complex modes of inheritance; they may exhibit incomplete or age-dependent penetrance or fail to show any clear Mendelian inheritance pattern. As primary linkage maps for the human genome near completion, it is becoming increasingly possible to map these traits. Prior to undertaking a linkage study, it is important to consider whether the available pedigrees are likely to provide sufficient information for the lod score method to demonstrate linkage if it exists. In addition, it is important to consider which of the competing methods of linkage analysis will be most efficient in attempting to map the genes for the complex trait. A computer simulation method to estimate the power of a proposed study to detect linkage for a complex genetic trait, given a hypothesized genetic model for that trait, is described. The method simulates genotypes consistent with observed trait phenotypes in such a way that the probability of detecting linkage can be estimated by statistics of the maximum lod score distribution. The method uses terms available when calculating the pedigree likelihood, and is applicable to any trait determined by one or a few genetic loci. The efficiencies of the lod score, affected-pedigree-member (APM), and sib-pair methods of linkage analysis are also compared for several trait models, pedigree types, and data subsamples. The average linkage information for the lod score method was consistently greater than that for the APM and sib-pair methods when the trait model was correctly specified; it was generally less than that for the Mean sib-pair test when the trait model was misspecified. The average per person information for the lod score method was generally less than that for the APM method and the Mean test.