A COMPARISON OF UNIVARIATE AND MULTIVARIATE TESTS FOR GENETIC-LINKAGE

A variety of robust and model-dependent genetic linkage methods were a pplied to log transformed lipid levels from a large pedigree in which the LDL receptor defect has been shown to segregate by molecular biolo gic techniques. Application of the Haseman-Elston and a variance-compo nents based test for linkage identified LDL and cholesterol as cosegre gating with the marker C3, which is genetically linked to the LDL rece ptor defect. Consideration of lipid fractions as a multivariate respon se identified (0.723 x cholesterol) - (0.551 x triglycerides) as most strongly supporting evidence for linkage with C3. Subsequent segregati on and linkage analyses provided support for an autosomal dominant maj or gene influencing either LDL or the function of cholesterol and trig lycerides. Genetic linkage to LDL was only mildly supported, with a ma ximum lod score of 0.51 at a recombination fraction of theta = 0.33. G enetic linkage of the linear function to C3 was more strongly supporte d, with a maximum lod score of 1.69 at theta = 0.09. Bivariate analysi s of clinical affection (with either type IIa or type IIb hyperlipidem ia) and quantitative measures (LDL or the linear function) generally l ed to decreased lod scores, indicating, in this pedigree, loss of info rmation when using clinical affection. (C) 1993 Wiley-Liss, Inc.