In order to evaluate the relative merits of different analytical approaches to identify rare variant associations with a quantitative trait, we have performed simulations using simple models of population genetics to generate high-density haplotype data in a 50-kb genomic region used to represent a functional unit of interest. We considered a range of models for association of the trait with multiple causal variants in the same region, under two different assumptions: (i) the mean trait value is determined by the presence or absence of a minor allele at any causal variant; and (ii) the mean trait value determined by the proportion of causal variants at which a minor allele is present. Trait association models were then parame-terised in terms of: (i) the maximum MAF of any individual causal variant; (ii) the total MAF of all causal variants; and (iii) their joint contribution to the phenotypic variance. Full details of the simulation process are described in the Appendix.
