Abstract Many complex human diseases exhibit sex or age differences in gene expression. However, the presence and the extent of genotype-specific variations in gene regulation are largely unknown. Here, we report results of a comprehensive analysis of expression regulation of genetic variation related to 11 672 complex disease-associated SNPs as a function of sex and age in whole-blood-derived RNA from 5254 individuals. At false discovery rate <0.05, we identified 14 sex- and 10 age-interacting expression quantitative trait loci (eQTLs). We show that these eQTLs are also associated with many sex- or age-associated traits. These findings provide important context regarding the regulation of phenotypes by genotype–environment interaction.