Abstract
Linkage analysis based on identity-by-descent allele-sharing can be used to identify a chromosomal region harboring a quantitative trait locus (QTL), but lacks the resolution required for gene identification. Consequently, linkage disequilibrium (association) analysis is often employed for fine-mapping. Variance-components based combined linkage and association analysis for quantitative traits in sib pairs, in which association is modeled as a mean effect and linkage is modeled in the covariance structure has been extended to general pedigrees (quantitative transmission disequilibrium test, QTDT). The QTDT approach accommodates data not only from parents and siblings, but also from all available relatives. QTDT is also robust to population stratification. However, when population stratification is absent, it is possible to utilize even more information, namely the additional information contained in the founder genotypes. In this paper, we introduce a simple modification of the allelic transmission scoring method used in the QTDT that results in a more powerful test of linkage disequilibrium, but is only applicable in the absence of population stratification. This test, the quantitative trait linkage disequilibrium (QTLD) test, has been incorporated into a new procedure in the statistical genetics computer package SOLAR. We apply this procedure in a linkage/association analysis of an electrophysiological measurement previously shown to be related to alcoholism. We also demonstrate by simulation the increase in power obtained with the QTLD test, relative to the QTDT, when a true association exists between a marker and a QTL.
Highlights
Linkage analysis based on identity-by-descent (IBD) allele-sharing can be used to identify a chromosomal region harboring a quantitative trait locus (QTL), but lacks the resolution required for gene identification
We demonstrate by simulation the increase in power obtained with the quantitative trait linkage disequilibrium (QTLD) test, relative to the QTDT, when a true association exists between a marker and a QTL
We have introduced the QTLD test, a novel approach for detecting association due to linkage disequilibrium in the absence of population stratification
Summary
Linkage analysis based on identity-by-descent (IBD) allele-sharing can be used to identify a chromosomal region harboring a quantitative trait locus (QTL), but lacks the resolution required for gene identification. Fulker et al [1] proposed a variance-components based combined linkage and association analysis for quantitative traits in sib pairs, in which association is modeled as a mean effect and linkage is modeled in the covariance structure. To control for spurious associations due to population stratification and admixture, genotype scores are decomposed into (page number not for citation purposes). Because population structure will affect only the parameter βb, a robust test of association is obtained by comparing a model in which both βb and βw are freely estimated with a model in which βw is fixed at 0. The presence of stratification can be inferred when the estimates of βb and βw differ significantly
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