Sex differences in disease genetics

AbstractThere is long-standing evidence for gene-by-sex interactions in disease risk, which can now be tested in genome-wide association studies with participant numbers in the hundreds of thousands. Contemporary methods start with a separate test for each sex, but simulations suggest a more powerful approach should be to use sex as an interaction term in a single test. The traits currently with the most compelling evidence for sex-dependent genetic effects are for adiposity (predictive of cardiac disease), type II diabetes, asthma and inflammatory bowel disease. Sexually dimorphic gene expression varies dynamically, by age, tissue type, and chromosome, so sex dependent genetic effects are expected for a wide range of diseases.Key conceptsCompelling findings of sex-dependent genetic effects on disease have been made in adiposity-related anthropometric traits, type II diabetes, and inflammatory bowel disease. Other disorders remain to be more fully investigated, regardless of what sexual differences they exhibit in prevalence and presentation.Current evidence indicates that sex difference in gene expression is not required for a SNP to have a sex-dependent effect. However, sex differences in gene expression vary dynamically, by organ and age, so generalisations may be inaccurate without comprehensive data.Sex-dependent risk alleles are predicted to be of greater effect size than conventional ones, because natural selection acts only against the sex which has the disease. There is evidence for this from a high-powered GWAS of adiposity-related traits.Many of the large GWAS meta-analyses look for sex-dependent genetic effects by testing male and female groups separately. However, this may be under-powered compared to a whole-sample, gene-by-sex interaction test.GlossaryGenome-wide association study (GWAS). Method for identifying molecular genetic variation that controls heritable traits, in a population sample. Involves assessing the correlation between allele frequencies and phenotype value, at millions of markers of common genetic variation across the genome.Sexual dimorphism. A difference between males and females in a population for the value of a particular trait. May include anything from anatomical measurements to expression level of a gene.Sex-dependent genetic effect. A disease risk allele is termed sex-specific when it increases risk in one sex only but has no effect on the disease in the other sex. The term sex-biased is used for an allele causes a significant increase in risk of disease in both sexes, but for which the magnitude of the risk increase is significantly different between males and females. There are also reports where an allele that increases risk of a disease in one sex reduces risk of the same disease in the other sex but none have been replicated, and there is no biochemical reason why this could be true. It effectively constitutes a sexually antagonistic effect, but should be distinguished from intra-locus sexual conflict which explicitly requires than an allele have opposing effects on the evolutionary fitness of males and females (Bonduriansky and Chenoweth 2009). All of the above relationships constitute a form of sex-dependent genetic effect.