How to model a complex trait. 2. Analysis with two disease loci.
Complex traits are often governed by more than one trait locus. The first step towards an adequate model for such diseases is a linkage analysis with two trait loci. Such an analysis can be expected to have higher power to detect linkage than a standard single-trait-locus linkage analysis. However, it is crucial to accurately specify the parameters of the two-locus model. Here, we recapitulate the general two-locus model with and without genomic imprinting. We relate heterogeneity, multiplicative, and additive two-locus models to biological or pathophysiological mechanisms, and give the corresponding averaged ("best-fitting") single-trait-locus models for each of the two loci. Furthermore, we derive the two-locus penetrances from the averaged single-locus models, under the assumption of one of the three model classes mentioned above. Using these formulae, if the best-fitting single-locus models are available, investigators may perform a two-trait-locus linkage analysis under a realistic model. This procedure will maximize the power to detect linkage for traits which are governed by two or more loci, and lead to more accurate estimates of the disease-locus positions.
Strauch
Konstantin
K
Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Sigmund-Freud-Strasse 25, DE-53105 Bonn, Germany. strauch@uni-bonn.de
Fimmers
Rolf
R
Baur
Max P
MP
Wienker
Thomas F
TF
D003198:Computer Simulation; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D006801:Humans; D008126:Lod Score; D008957:Models, Genetic; D015233:Models, Statistical; D040641:Quantitative Trait Loci