An evaluation of statistical approaches to rare variant analysis in genetic association studies.

Power of six tests of rare variant association with a quantitative trait as a function of the percentage of phenotypic variation explained by causal variants in a 50 kb region, assuming the trait mean is determined by the presence or absence of minor alleles at any of the causal variants. Results for two models are presented, both assuming a total MAF of 5% for all causal variants in the region: (a) the maximum MAF of any individual causal variant is 0.5% and (b) the maximum MAF of any individual causal variant is 2%. Power is estimated at a 5% significance level over 10,000 replicates of data. Re-sequencing RVT1: test of phenotype association with the proportion of rare variants, discovered through re-sequencing, at which individuals carry minor alleles. Re-sequencing RVT2: test of phenotype association with the presence/absence of minor alleles in individuals at any rare variant discovered through re-sequencing. GWA <5% RVT1: test of phenotype association with the proportion of low-frequency variants on the GWA chip at which individuals carry minor alleles. GWA <5% RVT2: test of phenotype association with the presence/absence of minor alleles at any low-frequency variant on the GWA chip. GWA single SNP: standard trend test of quantitative trait association with each SNP on the GWA chip, with Bonferroni correction for multiple testing. GWA SNP haplotypes: haplotype trend test of association with the quantitative trait across all SNPs on the GWA chip.