Combined linkage and association mapping of quantitative trait loci by multiple markers

Using multiple diallelic markers, variance component models are proposed for high-resolution combined linkage and association mapping of quantitative trait loci (QTL) based on nuclear families. The objective is to build a model that may fully use marker information for fine association mapping of QTL in the presence of prior linkage. The measures of linkage disequilibrium and the genetic effects are incorporated in the mean coefficients and are decomposed into orthogonal additive and dominance effects. The linkage information is modeled in variance-covariance matrices. Hence, the proposed methods model both association and linkage in a unified model. On the basis of marker information, a multipoint interval mapping method is provided to estimate the proportion of allele sharing identical by descent (IBD) and the probability of sharing two alleles IBD at a putative QTL for a sib-pair. To test the association between the trait locus and the markers, both likelihood-ratio tests and F-tests can be constructed on the basis of the proposed models. In addition, analytical formulas of noncentrality parameter approximations of the F-test statistics are provided. Type I error rates of the proposed test statistics are calculated to show their robustness. After comparing with the association between-family and association within-family (AbAw) approach by Abecasis and Fulker et al., it is found that the method proposed in this article is more powerful and advantageous based on simulation study and power calculation. By power and sample size comparison, it is shown that models that use more markers may have higher power than models that use fewer markers. The multiple-marker analysis can be more advantageous and has higher power in fine mapping QTL. As an application, the Genetic Analysis Workshop 12 German asthma data are analyzed using the proposed methods.