Testing genetic association with rare variants in admixed populations.

Recent studies suggest that rare variants play an important role in the etiology of many traits. Although a number of methods have been developed for genetic association analysis of rare variants, they all assume a relatively homogeneous population under study. Such an assumption may not be valid for samples collected from admixed populations such as African Americans and Hispanic Americans as there is a great extent of local variation in ancestry in these populations. To ensure valid and more powerful rare variant association tests performed in admixed populations, we have developed a local ancestry-based weighted dosage test, which is able to take into account local ancestry of rare alleles, uncertainties in rare variant imputation when imputed data are included, and the direction of effect that rare variants exert on phenotypic outcome. We used simulated sequence data to show that our proposed test has controlled type I error rates, whereas naïve application of existing rare variants tests and tests that adjust for global ancestry lead to inflated type I error rates. We showed that our test has higher power than tests without proper adjustment of ancestry. We also applied the proposed method to a candidate gene study on low-density lipoprotein cholesterol. Our results suggest that it is important to appropriately control for potential population stratification induced by local ancestry difference in the analysis of rare variants in admixed populations.