Conditional linkage methods--Searching for modifier genes in a large Amish pedigree with known von Willebrand Disease major gene mutation

Von Willebrand Disease (VWD) is the most common bleeding disorder. In addition to known major genes, genetic modifiers, such as ABO blood group, affect quantitative outcome measures for VWD. To study genetic modification of VWD, an 854-member Amish pedigree with established linkage of VWD to a known mutation in the Von Willebrand Factor (VWF) gene on chromosome 12 was utilized. Phenotypic information and genotypic data consisting of VWF mutation status and a genome screen of markers were available for 385 pedigree members. Genetic modifiers of the VWF mutation were investigated using known and new conditional linkage methods that search for modifier genes of a major gene with known mutation.;The MCMC-based program LOKI (Heath, 1997) was used to conduct multipoint linkage analysis of VWD outcome measures while controlling for the known VWF mutation. Adjustment for the mutation did not eliminate the linkage signal on chromosome 12 in the same location as the VWF mutation. Evidence for quantitative trait loci (QTLs) was also found on six other chromosomes.;Smod, a score statistic that detects evidence of a genetic modifier conditional on linkage to a major gene, was developed for sib pair data. To limit the modifier gene main effect, Smod was developed so that variance due to the modifier locus was bounded above by the variance of the interaction between major gene and modifier gene. The performance of Smod was compared to other published score statistics. Power to detect linkage to the modifier locus depended on major gene and modifier gene risk allele frequencies, relative contribution of the major gene main effect to the interaction effect, and the upper bound on the modifier gene main effect.;The Amish pedigree was broken up into sib pair data and analyzed using Smod and other score statistics. Using these statistics, the strongest evidence for QTLs for VWD was also found on chromosome 12 in the region of the VWF mutation. Combined with the LOKI results, further analysis will help determine if intragenic modification is occurring or if linkage disequilibrium between the mutation and analyzed markers is driving results.