Efficient Software for Multi-marker, Region-Based Analysis of GWAS Data.

Genome-wide association studies (GWAS) have associated many single variants with complex disease, yet the better part of heritable complex disease risk remains unexplained. Analytical tools designed to work under specific population genetic models are needed. Rare variants are increasingly shown to be important in human complex disease, but most existing GWAS data do not cover rare variants. Explicit population genetic models predict that genes contributing to complex traits and experiencing recurrent, unconditionally deleterious, mutation will harbor multiple rare, causative mutations of subtle effect. It is difficult to identify genes harboring rare variants of large effect that contribute to complex disease risk via the single marker association tests typically used in GWAS. Gene/region-based association tests may have the power detect associations by combining information from multiple markers, but have yielded limited success in practice. This is partially because many methods have not been widely applied. Here, we empirically demonstrate the utility of a procedure based on the rank truncated product (RTP) method, filtered to reduce the effects of linkage disequilibrium. We apply the procedure to the Wellcome Trust Case Control Consortium (WTCCC) data set, and uncover previously unidentified associations, some of which have been replicated in much larger studies. We show that, in the absence of significant rare variant coverage, RTP based methods still have the power to detect associated genes. We recommend that RTP-based methods be applied to all existing GWAS data to maximize the usefulness of those data. For this, we provide efficient software implementing our procedure.