A versatile gene-based test for genome-wide association studies

Abstract

We have derived a versatile gene-based test for genome-wide association studies (GWAS). Our approach, called VEGAS (versatile gene-based association study), is applicable to all GWAS designs, including family-based GWAS, meta-analyses of GWAS on the basis of summary data, and DNA-pooling-based GWAS, where existing approaches based on permutation are not possible, as well as singleton data, where they are. The test incorporates information from a full set of markers (or a defined subset) within a gene and accounts for linkage disequilibrium between markers by using simulations from the multivariate normal distribution. We show that for an association study using singletons, our approach produces results equivalent to those obtained via permutation in a fraction of the computation time. We demonstrate proof-of-principle by using the gene-based test to replicate several genes known to be associated on the basis of results from a family-based GWAS for height in 11,536 individuals and a DNA-pooling-based GWAS for melanoma in approximately 1300 cases and controls. Our method has the potential to identify novel associated genes; provide a basis for selecting SNPs for replication; and be directly used in network (pathway) approaches that require per-gene association test statistics. We have implemented the approach in both an easy-to-use web interface, which only requires the uploading of markers with their association p-values, and a separate downloadable application.

Figure 1

Comparison of the −log₁₀(p value)s from the PLINK Set-Based Test and VEGAS on a GWAS of Height in 3,611 Individuals The PLINK set-based test was performed on 413 genes on chromosome 22 with 10⁴ permutations (circles) and on seven genes on other chromosomes; these were selected on the basis of having the smallest p values from the VEGAS analysis, at 10⁶ to 10⁷ permutations (triangles). The p values from VEGAS were obtained by running 10³ to 10⁷ multivariate normal simulations per gene. The straight diagonal line indicates a 1:1 relationship.

Figure 2

Comparison of the −log₁₀(p value)s from Permutations and VEGAS When Only the Single Best SNP from Each Gene Is Considered Results are based on a GWAS of height in 3611 individuals. Permutations were performed on 413 genes on chromosome 22 with 10³ permutations and on seven additional genes with 10⁵–10⁶ permutations. The p values from VEGAS were obtained from 10³–10⁶ multivariate normal simulations per gene. The straight diagonal line indicates a 1:1 relationship.