The relative importance of common vs. rare variants in the etiology of complex diseases remains a subject of some debate. Common genetic variants are likely to contribute to the control of complex diseases, although their individual effects on risk may be quite modest, and furthermore multiple genes are likely to be involved. Rare genetic variants are also likely to contribute to risk, and while their individual effect may be larger, their rarity in the population makes it difficult to identify and confirm their effects in case-control designs. Identification of very rare genetic variants is not practical using genetic association analysis because of the extremely large sample sizes needed; however, the sample sizes proposed in this project will enable us to identify relatively rare alleles (e.g., allele frequency as low as 0.05) associated with moderately increased disease risk. A major limitation of GWA analysis in a single phase is the unacceptable number of false positive SNPs that will be identified simply due to the extremely large number of statistical tests conducted. The multi-phase study design proposed will specifically to limit false
