to identify reward-related activation of the ventral striatum even though none of the loci had significant main effects. Similarly, Grucza et al. (2010) identified interactions among over 300 candidate genes as well as age of onset of smoking to identify epistatic interactions that have been missed due to prior emphasis of main effects. These sorts of studies might be an important next step for GWAS studies. It should be possible to explore epistatic relationships using animal models where four homozygous groups that are isogenic except at the putatively interacting alleles could be used to directly test these relationships and explore their molecular origins. Finally, as attention is increasingly focused on the study of rare alleles, animal models will be an invaluable tool to validate the importance of these genes for human psychiatric disorders (e.g., Bevilacqua et al. 2010), including substance abuse disorders, because they provide an easy means of generating large cohorts of mice with the desired genotypes.
