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. Functional polymorphisms are identified as variants that are significantly associated 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 population isolate (replicate 1) we correctly identified the polymorphism in gene 6 (MG1) that affects Q1. Without modeling association the lod score for Q1 was 5.4. At the site of the functional variant (5782 bp) the association chi 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 (chi 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 chi 2 < 4.9 on 2 df; p > 0.05).
Siegmund
K D
KD
Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA.
Vora
H
H
Gauderman
W J
WJ
D000328:Adult; D002648:Child; D002874:Chromosome Mapping / Q000706:statistics & numerical data*; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008126:Lod Score; D008297:Male; D008957:Models, Genetic; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics