Identifying susceptibility genes using linkage and linkage disequilibrium analysis in large pedigrees

Linkage and linkage disequilibrium tests are powerful tools for mapping com plex disease genes. We investigated two approaches to identifying markers a ssociated with disease. One method applied linkage analysis and then linkag e disequilibrium tests to markers within linked regions. The other method l ooked for linkage disequilibrium with disease using all markers. Additional ly, we investigated using Simes' test to combine p-values from linkage dise quilibrium tests for nearby markers. We applied both approaches to all repl icates of the Genetic Analysis Workshop 12 problem 2 isolated population da ta set. We reported results from the 25(th) replicate as if it were a real problem and assessed the power of our methods using all replicates. Using a ll replicates, we found that testing all markers for linkage disequilibrium with disease was more powerful than identifying markers that were in linka ge with disease and then testing markers within those regions for linkage d isequilibrium with the implementations that we chose. Using Simes' test to combine p-values for linkage disequilibrium tests on correlated markers see med to be of marginal value. ((C)) 2001 Wiley-Liss, Inc.