“Amplification Is the Primary Mode of Gene-By-Sex Interaction in Complex Human Traits”, 2022-05-08 ():
Sexual dimorphism is observed in many complex traits and diseases and is suspected to be in part due to widespread gene-by-sex interactions (GxSex). To date, empirical evidence for GxSex in GWAS data has been elusive. We hypothesized that GxSex may be pervasive but largely missed by current approaches if it acts primarily through sex differences in the magnitude of many genetic effects (“amplification”), regulated by a shared cue such as a sex hormone, rather than differences in the identity of causal variants or the direction of their effect.
To test this hypothesis, we inferred the genetic covariance structure between males and females across 27 physiological traits in the UK Biobank. We found amplification to be a pervasive mode of GxSex across traits. As one example, we estimate that 38% of variants have a greater effect on urate levels in females than males. For some traits, notably those related to body mass, testosterone levels are associated with the magnitude of genetic effects in both males and females, but the association is opposite in sign between the sexes.
Finally, we developed a novel test of sexually-antagonistic viability selection linking GxSex signals to allele frequency divergence between adult males and females. Using independent allele frequency data, we find marginally-significant evidence for contemporary sexually-antagonistic selection on genetic variation associated with testosterone.
In summary, our results suggest that the systematic amplification of genetic effects is a common mode of GxSex that may contribute to sexual dimorphism and fuel its evolution.