Sex differences in gene expression patterns are important to highlight, as these differences can be due to genetic regulatory machinery like enhancers, binding sites for transcription factors, or sex steroid hormone receptors that predominantly exist in the non-coding (non-exonic) regions of the genome. Interestingly, these non-coding regions often include disease-associated single nucleotide polymorphisms (SNPs) (e.g., [22, 23]). Differences in the regulatory genome between sexes and the existence of disease-relevant SNPs in regulatory regions support the likely possibility that bi-directional relationships exist between genotype and phenotype that can depend on sex. To add further complexity, these bi-directional relationships can both exaggerate phenotypic variation between sexes, but also minimize differences, as is the case with genetic compensatory mechanisms (e.g., X-inactivation) [24]. Thus, if the statistical associations that capture such relationships are opposite in direction for female compared to male genomes, or substantially stronger for one sex compared to the other, a composite association may mask important relationships. Indeed, this has proven to be the case; a 2015 case/control candidate gene study of age-related macular degeneration (AMD) provided the first evidence of a
