Linkage disequilibrium and the search for complex disease genes.

During the past two decades, linkage analysis has been phenomenally successful in localizing Mendelian disease genes. Linkage disequilibrium (LD) analysis, which effectively incorporates the effects of many past generations of recombination, has often been instrumental in the final phases of gene localization (Feder et al. 1996; Hastbacka et al. 1994; Kerem et al. 1989). These successes have fueled hopes that similar approaches will be effective in localizing genes underlying susceptibility to common, complex diseases. With the exception of Mendelian subsets of common diseases (e.g., BRCA1 and BRCA2 for breast cancer, APC for colon cancer, the LDL receptor gene for heart disease), progress on this front has been limited. Typically, a nonparametric linkage analysis, such as a sib-pair analysis, will implicate several genetic regions as targets for further investigation. These regions, often 10–20 Mb in size, remain intractably large for effective positional cloning. It is now hoped that LD approaches, using hundreds of thousands of new polymorphic markers, will overcome this impasse (Risch and Merikangas 1996). The rationale underlying LD mapping of complex disease genes is straightforward and similar to the justification for LD mapping of Mendelian disease genes. With both types of disease genes, the primary advantage of LD analysis remains its ability to use the effects of dozens or hundreds of past generations of recombination to achieve fine-scale gene localization (Jorde 1995). An important difficulty, common to both types of disease genes, is that past historical events (admixture, genetic drift, multiple mutations, and natural selection) can disturb the relationship between LD and inter-locus physical distance. A major difference, of course, is that locus heterogeneity complicates the analysis of complex diseases and may be more extensive for these diseases than for most Mendelian diseases. Furthermore, allelic heterogeneity may be present at each locus. This heterogeneity, the scope of which is largely unknown, will limit the strength of association between a given polymorphism and an observable phenotype. Despite these challenges, LD mapping holds considerable appeal, and there is great demand to resolve the genetics of complex diseases. Consequently, many new techniques have been devised to carry out LD analysis, often with a view toward mapping complex disease loci. The purpose of this review is to summarize these techniques and some of the issues surrounding their application. In particular, the evolutionary factors that can confound or enhance disequilibrium analysis will be discussed, and some thoughts will be offered on the optimal choice of markers and populations for LD analysis.