Identifying single-nucleotide polymorphisms responsible for the linkage signal of rheumatoid arthritis on chromosome 6 by joint modeling of linkage and association

This study evaluated the utility of unrelated controls and flanking markers when performing joint modeling of linkage and association by the LAMP software (version 0.0.6) [Am J Hum Genet 2005, 76:934-949; Am J Hum Genet 2006, 78:778-792]. Analyses were conducted on the simulated rheumatoid arthritis (RA) data in Genetic Analysis Workshop 15 (GAW15), using single-nucleotide polymorphisms (SNPs) on chromosome 6 over the 100 simulated replicates. We found that the LOD score for testing association in the presence of linkage dramatically increased when unrelated controls were added to affected sib pairs (ASPs), and that choosing a sufficient number of flanking markers is critical in order to distinguish between perfect linkage disequilibrium (which leads to the conclusion of a measured SNP explaining a linkage signal) and incomplete linkage disequilibrium (which leads to the conclusion of other undetected causal variants in a linkage region).