Sex-specific genetic architecture of human disease

Key Points 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. It is increasingly clear that genetic factors contribute to the different manifestation of human diseases between males and females. Genotype-by-sex interactions on disease risk might be common in humans; ignoring such effects in searches for disease-associated genes may result in important loci being missed. Sexual dimorphism in anatomical, physiological and behavioural traits are characteristics of many vertebrate species. In humans, sexual dimorphism is also observed in the prevalence, course and severity of many common diseases, including cardiovascular diseases, autoimmune diseases and asthma. Although sex differences in the endocrine and immune systems probably contribute to these observations, recent studies suggest that sex-specific genetic architecture also influences human phenotypes, including reproductive, physiological and disease traits. It is likely that an underlying mechanism is differential gene regulation in males and females, particularly in sex steroid-responsive genes. Genetic studies that ignore sex-specific effects in their design and interpretation could fail to identify a significant proportion of the genes that co