title: A powerful approach to test an optimally weighted combination of rare variants in admixed populations.
abstract: Population stratification has long been recognized as an issue in genetic association studies because unrecognized population stratification can lead to both false-positive and false-negative findings and can obscure true association signals if not appropriately corrected. This issue can be even worse in rare variant association analyses because rare variants often demonstrate stronger and potentially different patterns of stratification than common variants. To correct for population stratification in genetic association studies, we proposed a novel method to Test the effect of an Optimally Weighted combination of variants in Admixed populations (TOWA) in which the analytically derived optimal weights can be calculated from existing phenotype and genotype data. TOWA up weights rare variants and those variants that have strong associations with the phenotype. Additionally, it can adjust for the direction of the association, and allows for local ancestry difference among study subjects. Extensive simulations show that the type I error rate of TOWA is under control in the presence of population stratification and it is more powerful than existing methods. We have also applied TOWA to a real sequencing data. Our simulation studies as well as real data analysis results indicate that TOWA is a useful tool for rare variant association analyses in admixed populations.
authors.affiliation: Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, United States of America.
authors.forename: Xuexia
authors.initials: X
authors.lastname: Wang
authors.forename: Shuanglin
authors.initials: S
authors.lastname: Zhang
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Mingyao
authors.initials: M
authors.lastname: Li
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Sha
mesh_terms: D000465:Algorithms; D016022:Case-Control Studies; D003198:Computer Simulation; D056726:Genetic Association Studies / Q000379:methods*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005828:Genetics, Population; D005838:Genotype; D006400:Hematocrit; D006801:Humans; D008957:Models, Genetic; D010641:Phenotype; D044382:Population Groups / Q000235:genetics*
keywords: admixed population; genetic association study; population stratification; rare variants