Removing the sampling restrictions from family-based tests of association for a quantitative-trait locus

One strategy for localization of a quantitative-trait locus (QTL) is to tes t whether the distribution of a quantitative trait depends on the number of copies of a specific genetic-marker allele that an individual possesses. T his approach tests for association between alleles at the marker and the QT L, and it assumes that association is a consequence of the marker being phy sically close to the QTL. However, problems can occur when data are not fro m a homogeneous population, since associations can arise irrespective of a genetic marker being in physical proximity to the QTL-that is, no informati on is gained regarding localization. Methods to address this problem have r ecently been proposed. These proposed methods use family data for indirect stratification of a population, thereby removing the effect of associations that are due to unknown population substructure. They are, however, restri cted in terms of the number of children per family that can be used in the analysis. Here we introduce tests that can be used on family data with pare nt and child genotypes, with child genotypes only, or with a combination of these types of families, without size restrictions. Furthermore, equations that allow one to determine the sample size needed to achieve desired powe r are derived. By means of simulation, we demonstrate that the existing tes ts have an elevated false-positive rate when the size restrictions are not followed and that a good deal of information is lost as a result of adheren ce to the size restrictions. Finally, we introduce permutation procedures t hat are recommended for small samples but that can also be used for extensi ons of the tests to multiallelic markers and to the simultaneous use of mor e than one marker.