An alternative approach for discovering genotype–sex interactions, in particular in the context of gene regulation, is to directly study gene expression as a quantitative phenotype, and identify genetic variation that is associated with expression levels differently in males and females. Because thousands of gene expression phenotypes can be measured simultaneously, it is likely that genotype–sex interaction effects on gene expression will be easier to detect than studies of physiological and disease traits, and that all types of interactions will be present (e.g., Figure 2). With the availability of many data sets with both dense SNP typing and measurements of global gene expression in the same individuals89-92, it should be possible to directly assess sex-specific genotype effects on heritable variation in mRNA abundance using eqtl mapping approaches90,93. Moreover, because the ultimate goal of eQTL mapping is to identify regulatory variation that results in physiological or disease phenotypes94, this approach can be extended to study the sex-specific architecture of these phenotypes (Figure 5). Traits or diseases with sex-specific genetic architecture, such as those shown in Figures 3 and 4, would be excellent candidates for these studies.
