Given the increasing scale of rare variant association studies, we introduce a method for high-dimensional studies that integrates multiple sources of data as well as allows for multiple region-specific risk indices.Our method builds upon the previous Bayesian risk index by integrating external biological variant-specific covariates to help guide the selection of associated variants and regions. Our extension also incorporates a second level of uncertainty as to which regions are associated with the outcome of interest.Using a set of study-based simulations, we show that our approach leads to an increase in power to detect true associations in comparison to several commonly used alternatives. Additionally, the method provides multi-level inference at the pathway, region and variant levels.To demonstrate the flexibility of the method to incorporate various types of information and the applicability to high-dimensional data, we apply our method to a single region within a candidate gene study of second primary breast cancer and to multiple regions within a candidate pathway study of colon cancer.

作者：Melanie A, Quintana；Fredrick R, Schumacher；Graham, Casey；Jonine L, Bernstein；Li, Li；David V, Conti

来源：Human heredity 2012 年 74卷 3-4期