Combined linkage and association analysis in pedigrees

We applied a combined linkage and association model for quantitative traits in pedigrees to identify possible functional polymorphisms and to test for association resulting from population stratification and admixture. Functi onal polymorphisms are identified as variants that are significantly associ ated with a trait (high chi (2) value) and showing no residual evidence of linkage (low lod score). Applying our model to the simulated data in the po pulation isolate (replicate 1) we correctly identified the polymorphism in gene 6 (MG1) that affects Q1. Without modeling association the lod score fo r Q1 was 5.4. At the site of the functional variant (5782 bp) the associati on chi (2) was 88.1 on I df (p < 0.001) and the lod score was 0.003. We est imated a 3.7-unit increase in the average Q1 for each extra copy of the pol ymorphism (95% CI = 2.95-4.41) and there was no evidence of population stra tification or admixture (chi (2) = 0.08 on 2 df). For Q5 and gene 2, modeli ng the sequence variants at I I loci simultaneously identified multiple fun ctional variants. Including the main effect of I I marker genotypes reduced the lod score at gene 2 from 8.7 to 0.9. Again, no evidence of population stratification or admixture was found (all chi (2) < 4.9 on 2 df; p > 0.05) . ((C)) 2001 Wiley-Liss, Inc.