Currently, most studies of rare variants utilise data from commercially available GWA chips, which are far from ideal since they are designed for capturing common human genetic variation. However, the availability of data more appropriate for rare variant association analysis is just around the corner, with whole genome re-sequencing efforts, such as the 1,000 Genomes project (http://www.1000 genomes.org) soon reaching completion. Furthermore, large-scale deep re-sequencing technologies are becoming increasingly efficient and cost effective, and thus may soon be realistic for rare variant discovery in specific genes in large disease or population-based cohorts. We have developed a novel test of association with rare variants discovered through such re-sequencing efforts, based on the accumulation of minor alleles within the same functional unit, for example a gene-coding region extended up and downstream to incorporate additional functional elements and the regulatory region. We have then undertaken a simulation study to focus on two distinct, but timely, scenarios with the aim of addressing specific, as yet unanswered, methodological questions in each. First, when deep re-sequencing data are available to discover rare variants, do methods based
