Abstract

Identifying and characterizing the genetic variants that affect human traits is one of the central objectives of human genetics. Ultimately, this aim will be achieved by examining the relationship between interesting traits and the whole genome sequences of many individuals. Whole genome re-sequencing of thousands of individuals is not yet feasible, but advances in laboratory methods (for example, to enable the genotyping of thousands of individuals at hundreds of thousands of SNP sites) and in statistical methodology (for example, to enable accurate correction for population stratification and genotype imputation) have resulted in substantial progress in our understanding of complex disease biology. Here, we discuss practical study designs for the first generation of whole genome sequencing studies. These will enable the examination of 1,000s of individuals at >10 million of polymorphic sites. These studies will be enabled by continuing advances in laboratory technology and statistical methods and should further refine our understanding of complex disease genetics. I illustrate the possibilities both with simulation and with data from the 1000 Genomes Project and other ongoing projects.