Recent advances in whole genome genotyping technologies, the availability of large, well-defined population-based disease cohorts, and a better understanding of common human sequence variation, coupled with the development of appropriate quality control and analysis pipelines, have led to the identification of many novel common genetic determinants of complex traits [The Wellcome Trust Case Control Consortium, 2007; Zeggini et al., 2008; Barrett et al., 2008; Raychaudhuri et al., 2008; Cooper et al., 2008; Willer et al., 2009; Aulchenko et al., 2009; Prokopenko et al., 2009]. Nevertheless, despite these successes, much of the genetic component of these traits remains unaccounted for. Although there may be many undiscovered common polymorphisms associated with complex traits, it seems unlikely that the “common-disease common-variant” hypothesis is all encompassing. One unexplored paradigm which may contribute to this unexplained genetic component is a model of multiple rare causal variants, defined here to have a minor allele frequency (MAF) of less than 1%, each of modest effect, but residing within the same functional unit, for example, a gene. Joint analysis of rare variants within a gene, searching for accumulations
