Genetic Epidemiology 21(Suppl1): (2001) Combined Linkage and Association Analysis in Pedigrees Kimberly D. Siegmund, Hita Vora, and W. James Gauderman Department of Preventive Medicine, University of Southern California, Los Angeles, California 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. Functional polymorphisms are identified as variants that are significantly associated with a trait (high x 2 value) and showing no residual evidence of linkage (low lod score). Applying our model to the simulated data in the population isolate (replicate I) we correctly identified the polymorphism in gene 6 (MGI) that affects Ql. Without modeling association the lod score for Ql was 5.4. At the site of the functional variant (5782 bp) the association X 2 was 88.1 on 1 df(p < 0.001) and the lod score was 0.003. We estimated a 3.7-unit increase in the average Q1 for each extra copy of the polymorphism (95% CI = 2.95-4.41) and there was no evidence of population stratification or admixture (X 2 = 0.08 on 2 df). For Q5 and gene 2, modeling the sequence variants at 11 loci simultaneously identified multiple functional variants. Including the main effect of 11 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 x 2 < 4.9 on 2 df; p > 0.05). 0 200 I Wiley-Liss, Inc. Key words: admixture, mixed-effects model, population stratification variance-components model INTRODUCTION Recently, several authors have extended the traditional variance components models for quantitative trait linkage analysis to include association tests for marker alleles [Fulker et al., 1999; Abecasis et al., 2000a,b; Sham et al., 2000]. Modeling marker alleles as fixed covariate effects, the model can be used to test for effects due to linkage, association, or both simultaneously. A special coding for the marker alleles allows one to Address reprint requests to Dr. Kimberly D. Siegmund, Department of Preventive Medicine, 1540 Alcazar Street CHP 220, Los Angeles, CA 90089 USA. 2001 Wiley-Liss, Inc.