Sex-specific effects of depression on the incidence and risk factors for coronary heart disease: insights from multi-omics approaches.

AIMS: Depression and coronary heart disease (CHD) exhibit notable sex disparities; however, the sex-specific effect of depression on the development of CHD remains unexplored. We explored these effects using multi-omics approaches. METHODS AND RESULTS: In the UK Biobank cohort, we conducted sex-stratified survival analyses and multi-omics investigations, including sex-specific two-sample and one-sample Mendelian randomisation (MR) analyses, reproductive factor assessments, Life's Essential 8 factor evaluations, and plasma proteomics analysis. Depression was associated with a higher risk of CHD in females (adjusted hazard ratio [aHR]: 1.30; 95% confidence interval [CI]: 1.24-1.37) than in males (aHR: 1.14; 95% CI: 1.09-1.19; P-interaction < 0.001), compared with individuals without depression. Sex-specific two-sample and one-sample MR analyses showed that genetically predicted depression in females was causally related to CHD, but no causal effect was observed in males. Some key reproductive factors in females with depression were associated with a high risk of CHD. Among the Life's Essential 8 factors, poor control of nicotine exposure, blood pressure, body mass index, and blood glucose had an additional effect on CHD risk in females with depression compared with that in males (all P-interaction < 0.05). Analysis of the UKB-PPP cohort revealed 26 proteins with sex-specific associations, predominantly significant in females. CONCLUSIONS: Our findings highlight significant sex differences in the effect of depression on CHD risk, which could inform sex-specific preventive strategies for reducing the cardiovascular burden in individuals with depression.