Sex-different phenotypic correlations: Due to genes or environment?

Abstract

Differences in physical features and disease prevalence between men and women are examples of sexual dimorphisms. However, sex differences can manifest not only in trait means but also in how strongly risk factors are linked to diseases (e. g. BMI to cardiovascular disease), a question heavily under-researched. To fill this gap, we set out to identify sex differences in phenotype correlations (rP) and decompose them into genetic (rG) and environmental (rE) contributions. Our analysis revealed 250 trait pairs with significant sex-different phenotypic correlations in the UK Biobank. Overall, we observed a predominance of environmental contributions to sex-different effects: 182 trait pairs (73%) exhibited exclusively sex-different rE, while 68 (27%) showed sex differences in both rE and rG, and no trait pair was affected solely by sex-specific rG. For example, we detected sex-different environmental correlation between C-reactive protein and BMI (rE(men) = 0.07 vs rE(women) = 0.25), but no sex-difference in genetic correlation. On the contrary, glycated haemoglobin and LDL cholesterol showed genetic correlation only in women (rG(women) = 0.17; 95% CI = [0.1, 0.23]), but environmental correlation only in men (rE(men) = -0.18; 95% CI = [-0.19, -0.16]). Some of the observed sex differences - including those involving testosterone, SHBG, urate, waist-hip ratio, and triglycerides - may reflect underlying sex-specific genetic architectures, as evidenced by low between-sex genetic correlations. In conclusion, environmental factors are the predominant contributors to sex differences in phenotypic correlations between complex traits, with modest detectable contributions from sex-specific genetic architectures. Recognising these patterns can inform the development of more effective, sex-informed interventions.