Association tests using kernel-based measures of multi-locus genotype similarity between individuals

In a genetic association study, it is often desirable to perform an overall test of whether any or all single-nucleotide polymorphisms (SNPs) in a gene are associated with a phenotype. Several such tests exist, but most of them are powerful only under very specific assumptions about the genetic effects of the individual SNPs. In addition, some of the existing tests assume that the direction of the effect of each SNP is known, which is a highly unlikely scenario. Here, we propose a new kernel-based association test of joint association of several SNPs. Our test is non-parametric and robust, and does not make any assumption about the directions of individual SNP effects. It can be used to test multiple correlated SNPs within a gene and can also be used to test independent SNPs or genes in a biological pathway. Our test uses an analysis of variance paradigm to compare variation between cases and controls to the variation within the groups. The variation is measured using kernel functions for each marker, and then a composite statistic is constructed to combine the markers into a single test. We present simulation results comparing our statistic to the U-statistic-based method by Schaid et al. ([2005] Am. J. Hum. Genet. 76:780-793) and another statistic by Wessel and Schork ([2006] Am. J. Hum. Genet. 79:792-806). We consider a variety of different disease models and assumptions about how many SNPs within the gene are actually associated with disease. Our results indicate that our statistic has higher power than other statistics under most realistic conditions.