The power to detect linkage disequilibrium with quantitative traits in selected samples

Results from power studies for linkage detection have led to many ongoing a nd planned collections of phenotypically extreme nuclear families. Given th e great expense of collecting these families and the imminent availability of a dense diallelic marker map, the families are likely to be used in alle lic-association as well as linkage studies. However, optimal selection stra tegies for linkage may not be equally powerful for association. We examine the power to detect linkage disequilibrium for quantitative traits after ph enotypic selection. The results encompass six selection strategies that are in widespread use, including single selection (two designs), affected sib pairs, concordant and discordant pairs, and the extreme-concordant and -dis cordant design. Selection of sibships on the basis of one extreme proband w ith high or low trait scores provides as much power as discordant sib pairs but requires the screening and phenotyping of substantially fewer initial families from which to select. Analysis of the role of allele frequencies w ithin each selection design indicates that common trait alleles generally o ffer the most power, but similarities between the marker- and trait-allele frequencies are much more important than the trait-locus frequency alone. S ome of the most widespread selection designs, such as single selection, yie ld power gains only when both the marker and quantitative trait loci (QTL) are relatively rare in the population. In contrast, discordant pairs and th e extreme-proband design provide power for the broadest range of QTL-marker -allele frequency differences. Overall, proband selection from either tail provides the best balance of power, robustness, and simplicity of ascertain ment for family-based association analysis.