The advent of genome-wide association (GWA) studies has led to the discovery of hundreds of thousands of genotype-phenotype associations with robust statistical significance (42, 66). For example, as of October 2012 the Catalog of Published Genome-Wide Association Studies, hosted by the National Human Genome Research Institute (http://www.genome.gov/gwastudies/) (29), listed more than 7,500 associations between single-nucleotide polymorphisms (SNPs) and complex traits with P<10−5 coming from more than 1,400 GWA publications. These studies survey most of the genome by examining available samples for phenotype associations against up to 3,000,000 polymorphisms. Performance of GWA studies was largely facilitated by technological advances in high-throughput genotyping technologies providing accurate and reproducible genotyping (81) in combination with the progressive drop in genotyping costs. Additionally, the results of the International HapMap Consortium and the 1000 Genomes Project provided further useful insights about human genetic variation by systematically cataloguing common and low-frequency variation, and by characterizing linkage disequilibrium patterns in the human genome (1, 33-35); this information is now used routinely in GWA studies.
