The contributions of the sex chromosomes to sex-specific genetic architecture of human disease has long been appreciated. For example, an excess of boys express X-chromosome-linked recessive diseases, and skewed patterns of X chromosome inactivation resulting in varied expression of disease phenotypes are seen in female carriers of X-linked mutations20. More generally, dosage differences in X-linked genes between the sexes probably account for some of the sex-specific genetic architecture of common diseases and phenotypes. In turn, the Y chromosome in males harbors relatively few genes, most of which are expressed exclusively in the testes and others that are typically thought of as ‘housekeeping’ genes (of the latter, most have X chromosome homologues that escape X inactivation)21. Thus, it is perhaps unlikely that Y-linked genes per se directly affect disease risk, other than constituting major contributors to genetic causes of male infertility22. However, Y-linked genes may interact with autosomal genes to differentially affect disease risk in males and females.
