liability threshold, with the number of cases matching those in the original phenotype data. Causal loci were randomly selected from LD-pruned SNPs excluded from the initial two-stage, genome-wide scoring analysis, which have not been filtered for MAF and thus include rare variants (Fig. S1), with 100 replicates drawn for each disease model. The heritability of the disease phenotypes was set at a conservative 0.65, the median of estimates reported for AD in a pair of published studies (Heath et al. 1997; Knopik et al. 2004). Effect sizes were fixed for each model, making the variance accounted for by a causal locus proportional to the total number of loci in a given disease model and its respective minor allele frequency. With the program PLINK and the R statistical package (R Development Core Team 2011), genome-wide association tests, followed by the aforementioned two-stage, scoring routines, delineated according to MAF class, were conducted on the simulated disease phenotypes and the corresponding COGA or SAGE genotype data.
