To date, studies of genotype–sex interactions have interrogated genetic associations that have different effects in males and females on physiological or disease traits. These studies have had varying success, as discussed above15. Even among the more prominent examples discussed in this review, it has not yet been possible to relate the associated polymorphisms to sex-specific differences in the regulation of gene expression. Moreover, a large number of studies of diseases or QTLs in families have reported sex–specific linkages. However, as mentioned above, few have demonstrated that differences in lod scores between males and females are significant or tested directly for interactions. On the other hand, animal model studies suggest that genotype–sex interactions are widespread and that many important genes will be missed if such interactions are ignored. In that context, we favor testing for genotype–sex interactions in association studies, particularly for sexually dimorphic phenotypes, although appropriate significance testing is required to avoid type I errors. For example, it is striking that no pharmacogenetic study to date has looked for genotype–sex interactions on drug response, although sex-specific responses to drugs are well known86-88, or that genotype– sex interactions on development has not been explored.
