Sex-specific genetic architecture of human disease

Abstract

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.