Abstract
Admixture is an important evolutionary force that can and should be used in efforts to apply genomic data and technology to the study of complex disease genetics. Admixture linkage disequilibrium (ALD) is created by the process of admixture and, in recently admixed populations, extends for substantial distances (of the order of 10 to 20 cM). The amount of ALD generated depends on the level of admixture, ancestry information content of markers and the admixture dynamics of the population, and thus influences admixture mapping (AM). The authors discuss different models of admixture and how these can have an impact on the success of AM studies. Selection of markers is important, since markers informative for parental population ancestry are required and these are uncommon. Rarely does the process of admixture result in a population that is uniform for individual admixture levels, but instead there is substantial population stratification. This stratification can be understood as variation in individual admixtures and can be both a source of statistical power for ancestry-phenotype correlation studies as well as a confounder in causing false-positives in gene association studies. Methods to detect and control for stratification in case/control and AM studies are reviewed, along with recent studies showing individual ancestry-phenotype correlations. Using skin pigmentation as a model phenotype, implications of AM in complex disease gene mapping studies are discussed. Finally, the article discusses some limitations of this approach that should be considered when designing an effective AM study.
Highlights
Genetic analysis of phenotypes and diseases has traditionally followed two approaches: family-based linkage analysis and population-based association studies
Linkage disequilibrium (LD)-based association studies have been successful in both fine scale mapping[5,6] and initial disease gene mapping in homogeneous populations that have undergone recent bottlenecks
Since the amount of admixture linkage disequilibrium (ALD) created is proportional to the level of admixture in a population, it is important briefly to review studies on admixture levels across populations
Summary
Genetic analysis of phenotypes and diseases has traditionally followed two approaches: family-based linkage analysis and population-based association studies. While in linkage analysis it is the co-segregation of alleles in families that is measured, population-based studies use non-random associations between phenotypes and alleles in populations to identify causative genes. Linkage disequilibrium (LD) is an important aspect of genetic association studies and is generated in a population through mutation, selection, drift, non-random mating and admixture.[1] Allelic associations due to LD are significant and are correlated with physical distance within small genomic regions but decay over time due to recombination.[2,3,4] LD-based association studies have been successful in both fine scale mapping[5,6] and initial disease gene mapping in homogeneous populations that have undergone recent bottlenecks (eg Hirschsprung disease in Mennonites,[7] Bardet– Beidle syndrome in Bedouins[8]). False-positive associations due to population stratification are important confounders in LD-based association studies
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