Evaluating associations of haplotypes with traits

Haplotypes have played a major role in the study of highly-penetrant single-gene disorders, and recent evidence that the human genome has hot-spots and cold-spots for recombination have suggested that haplotype-based methods may play a key role in the study of common complex traits. This report reviews the motivation of using haplotypes for the study of the genetic basis of human traits, ranging from biologic function, to statistical power advantages of haplotypes, to linkage disequilibrium fine-mapping. Recent developments of regression models for haplotype analyses are reviewed, offering a synthesis of current methods, as well as their limitations and areas that require further research. Regression models provide significant advantages, such as the ability to control for non-genetic covariates, the effects of the haplotypes can be modeled, step-wise selection can be used to screen for a subset of markers that explain most of the association, haplotype x environment interactions can be evaluated, and regression diagnostics are well developed. Despite these strengths, the current regression methods tend to lack the sophisticated population genetic perspectives offered by coalescent and other similar approaches. Future work that links regression methods with population genetic models may prove beneficial. Genet. Epidemiol. (C) 2004 Wiley-Liss, Inc.