Two methods, linkage analysis and linkage disequilibrium (LD) mapping or association study, are usually utilised for mapping quantitative trait loci (QTL). Linkage mapping is appropriate for low resolution mapping to localise trait loci to broad chromosome regions within a few cM (510 cM), and is based on family data. Linkage disequilibrium mapping, on the other hand, is useful in high resolution or fine mapping, and is based on both population and family data. Using only one marker, one may carry out single-point linkage analysis and linkage disequilibrium mapping. Using two or more markers, it is possible to flank the QTL by multipoint analysis. The development and thus availability of dense marker maps, such as single nucleotide polymorphisms (SNP) in human genome, presents a tremendous opportunity for multipoint fine mapping. In this article, we propose a regression approach of mapping QTL by linkage disequilibrium mapping based on population data. Assuming that two marker loci flank one quantitative trait locus, a two-point linear regression is proposed to analyse population data. We derive analytical formulas of parameter estimations, and non-centrality parameters of appropriate tests of genetic effects and linkage disequilibrium coefficients. The merit of the method is shown by the power calculation and comparison. The two-point regression model can capture much more linkage and linkage disequilibrium information than that derived when only one marker is used. For a complex disease with heritability h 2 50.15, a study with sample size of 250 can provide high power for QTL detection under moderate linkage disequilibria. European Journal of Human Genetics (2002Genetics ( ) 10, 607 -615. doi:10.1038 Keywords: high resolution mapping; linkage mapping; linkage disequilibrium mapping; QTL
IntroductionMuch research has been done on linkage mapping of qualitative or quantitative trait loci (QTL). Schork investigated multipoint identity-by-descent analysis of human quantitative traits. 1 Fulker and Cardon worked out a sib-pair approach of a two-point interval mapping for QTL. 2 Researchers have been extending the available methods toward several directions: (1) Fulker et al. 3 extended the method of Fulker and Cardon 2 for usage in multipoint interval mapping; (2) Almasy and Blangero worked on multipoint mapping for general pedigrees; 4 (3) Liang et al. proposed a unified sampling method for both qualitative and quantitative traits; 5 (4) Pratt et al. used an exact multipoint algorithm to analyse family data by variance component models. 6 The focus of the above studies was on linkage mapping, which is based on family data. Linkage analysis is appropriate for low resolution genetic mapping to localise trait loci to broad chromosome regions within a few cM (510 cM).Linkage disequilibrium (LD) mapping or association study, on the other hand, is based on both family and population data, and is useful in high resolution of genetic mapping, ie, fine disease gene mapping. The reason for the These exciting developments a...