Linkage disequilibrium structure and its impact on the localization of a candidate functional mutation

We have used the unblinded MG1/Q1 Genetic Analysis Workshop 12 simulated da ta as a model system for investigating the use of linkage disequilibrium st ructure and simple genotype-phenotype associations to identify candidate fu nctional mutations within a gene of interest. Analysis of the pattern of pa irwise linkage disequilibrium. indicated three groups of single-nucleotide polymorphisms for which the linkage disequilibrium was high between sites w ithin a group, but lower between sites of different groups. Using linear re gression to predict levels of the trait Q I showed that the known functiona l site, 5782, was usually not the best genetic predictor of Q1, but sites b elonging to the same group as 5782 (i.e., group 2) were always included in the prediction model. In 49 out of the 50 replicates, the functional site w as not the best predictor of the trait. Finally, more detailed analyses dem onstrate that the relationship between the adjusted R 2 for the marker in t he prediction model and its disequilibrium with 5782 was linear with the in tercept at the origin and terminating at the R-2 value for the known functi onal mutation when the disequilibrium is maximal. These data indicate that simple association studies will not identify the functional mutation, but r ather will identify candidate functional mutations that are in very tight l inkage disequilibrium with the functional mutation. (C) 2001 Wiley-Liss, In c.