Set-based genetic association and interaction tests for survival outcomes based on weighted V statistics

With advancements in high-throughout technologies, studies have been conducted to investigate the role of massive genetic variants in human diseases. While set-based tests have been developed for binary and continuous disease outcomes, there are few computationally efficient set-based tests available for time-to-event outcomes. To facilitate the genetic association and interaction analyses of time-to-event outcomes, We develop a suite of multivariant tests based on weighted V statistics with or without considering potential genetic heterogeneity. In addition to the computation efficiency and nice asymptotic properties, all the new tests can deal with left truncation and competing risks in the survival data, and adjust for covariates. Simulation studies show that the new tests run faster, are more accurate in small samples, and account for confounding effect better than the existing multivariant survival tests. When the genetic effect is heterogeneous across individuals/subpopulations, the association test considering genetic heterogeneity is more powerful than the existing tests that do not account for genetic heterogeneity. Using the new methods, we perform a genome-wide association analysis of the genotype and age-to-Alzheimer's data from the Rush Memory and Aging Project and the Religious Orders Study. The analysis identifies two genes, APOE and APOC1, associated with age to Alzheimer's disease onset.