Accumulating evidence suggests that nearly all human diseases have sex-specific differences in prevalence, age of onset, and/or severity. Classic examples include the predominance of men with cardiovascular disease throughout adult life but a higher rate of occurrence in post-menopausal women compared to men6
, the higher prevalence of asthma among boys in childhood and higher occurrence of new cases among girls around and following puberty7
, and the increased prevalence of autoimmune diseases in women throughout life but particularly for diseases that onset during or immediately following the reproductive years8
(). In addition to those diseases highlighted in , significant sex differences have been described for many common birth defects, neurological and psychiatric disorders, as well as for some common cancers. For example, in infancy or childhood, neural tube defects, congenital dislocation of the hip, and scoliosis are more common among girls whereas autism, stuttering, and pyloric stenosis
are more common among boys9
. In adulthood, major depression and Alzheimer disease are more common in women10,11
whereas schizophrenia, Parkinson disease, and colorectal cancer are more common in men12-14
Sex-specific prevalence rates, age of onset, and sex ratios for common sex-skewed diseases
It should be noted that differences in prevalence rates or age of onset do not necessarily imply that genetic variation leads to different effects in males and females15
, as many of these differences could be due to hormonal profiles, particularly with regard to sex steroids (), or to behaviors that differ between the sexes (e.g., exposure to cigarette smoke)16
. For example, the consistent associations between increased risk for disease among females during and following puberty (asthma), during the reproductive years (autoimmune disease), or post-menopausal (cardiovascular disease) have implicated sex hormones as important mediators of disease pathogenesis and contributors to sex differences in prevalence rates and progression.
Importantly, differences in the immune systems of males and females have been observed as early as in the first few years of life, suggesting a developmental component to sex-specific differences in disease risk17
. Such differences could result in sex-specific thresholds of susceptibility to immune-mediated diseases throughout life. Interestingly, immune responses may be modulated by sex hormones18,19
. In fact, the transient rise in sex steroid levels (‘minipuberty’) that occurs in early infancy1
(), could pattern immune cells differently in boys and girls. Thus, both the immune and endocrine systems likely contribute to sexual dimorphism in the epidemiology of many common diseases. However, recent evidence suggests that some of the differences between males and females may also be due to differences in genetic architecture. The review henceforth will focus on such sex-specific genetic effects.