Genome-wide linkage and candidate gene association studies (reviewed by Agrawal and Bierut, 2012; Enoch, 2013; Rietschel and Treutlein, 2013) have been largely unsuccessful in identifying replicable risk loci for AD, with the exception of studies of the alcohol metabolizing enzyme genes, which showed strong association in populations of Asian, European, and African ancestry (Thomasson et al., 1991; Chen et al., 1999; Edenberg, 2007, Bierut et al. 2012). We will not review those studies in detail here, however, as the focus is on genome-wide studies. Both linkage and candidate gene methods have major limitations. Linkage studies necessitate the recruitment of family-based samples with several affected individuals and typically identify regions containing multiple genes. Candidate gene studies are biased in that a specific gene of interest must be specified a priori, limiting the conclusions that can be drawn from the findings. The genome-wide association study (GWAS) approach was proposed to identify loci associated with complex traits without a dependence on prior hypotheses, and became feasible due to the completion of the Human Genome Project in 2001 and subsequent rapid advancements in genotyping
