Sex-specific genetic architecture of human disease

Nearly all human diseases are sexually dimorphic with respect to prevalence, age of onset, severity or disease course. Sex-specific differences in physiology, behaviour or anatomy might contribute to some of the differences in disease risk, but genetics also plays a part.Gene expression patterns differ between males and females of all species examined, not only for genes on the sex chromosomes, but also for genes on the autosomes.Genes with sex-biased gene expression evolve rapidly at the protein-coding level, whereas differences in gene regulation are often highly conserved.Differences in gene expression between the sexes probably contribute to sexual dimorphism in disease risk and course.Studies of disease-associated quantitative traits in humans suggest that many have a sex-specific genetic architecture, with estimates of heritability differing between males and females.Genotype-by-sex interactions are common in model organisms, indicating that genotype-specific effects differ between males and females. Recent examples of genotype-by-sex interactions on disease risk suggest that such effects might be common in humans as well.Genetic linkage and association studies that do not consider sex-specific genotype effects could miss a significant proportion of genes contributing to risk for complex diseases.