Composite statistics for QTL mapping with moderately discordant sibling pairs

Extreme discordant sibling-pair (EDSP) designs have been shown in theory to be very powerful for mapping quantitative-trait loci (QTLs) in humans. How ever, their practical applicability has been somewhat limited by the need t o phenotype very large populations to find enough pairs that are extremely discordant. In this paper, we demonstrate that there is also substantial po wer in pairs that are only moderately discordant, and that designs using mo derately discordant pairs can yield a more practical balance between phenot yping and genotyping efforts. The power we demonstrate for moderately disco rdant pairs stems from a new statistical result. Statistical analysis in di scordant-pair studies is generally done by testing for reduced identity by descent (IBD) sharing in the pairs. By contrast, the most commonly-used sta tistical methods for more standard QTL mapping are Haseman-Elston regressio n and variance-components analysis. Both of these use statistics that are f unctions of the trait values given IBD information for the pedigree. We sho w that IBD sharing statistics and "trait value given IBD" statistics contri bute complementary rather than redundant information, and thus that statist ics of the two types can be combined to form more powerful tests of linkage . We propose a simple composite statistic, and test it with simulation stud ies. The simulation results show that our composite statistic increases pow er only minimally for extremely discordant pairs. However, it boosts the po wer of moderately discordant pairs substantially and makes them a very prac tical alternative. Our composite statistic is straightforward to calculate with existing software; we give a practical example of its use by applying it to a Genetic Analysis Workshop (GAW) data set.