Methods for high-density admixture mapping of disease genes

Area of Science:

• Population Genetics
• Genomic Research
• Statistical Genetics

Background:

• Admixture mapping (MALD) is proposed for localizing disease variants differing in frequency between populations.
• Recent gene flow in admixed populations (e.g., African Americans) creates linkage disequilibrium extending over large genomic regions.
• Advancement requires computational methods for inferring ancestral origin and characterizing admixture linkage disequilibrium.

Purpose of the Study:

• To develop and validate statistical methods for estimating ancestral origin along the genome using linked marker genotypes.
• To empirically characterize the extent of admixture linkage disequilibrium in admixed populations.
• To provide power calculations for admixture mapping studies under various disease models and population mixture scenarios.

Main Methods:

• Developed statistical methods to infer ancestral origin at specific genomic loci based on composite marker genotypes.
• Applied the developed methods to estimate ancestral origin and measure admixture linkage disequilibrium in African American populations.
• Performed power calculations for admixture mapping studies considering disease risk, sample size, and ancestry proportions.

Main Results:

• The developed approach accurately estimates ancestral origins along the genome.
• Strong admixture linkage disequilibrium was shown to extend, on average, for 17 centimorgans (cM) in African Americans.
• Admixture mapping studies maintain high power across a wide range of mixture proportions (10%-90%).

Conclusions:

• The developed statistical methods are effective for inferring ancestral origins in admixed populations.
• Admixture mapping is a powerful approach for disease gene discovery, with significant linkage disequilibrium extending over large genomic regions.
• Studying approximately 2500 markers in 2500 patients can provide substantial power to detect common disease-associated loci.