Sex differences in genetic correlation between ischaemic heart disease and depression found in 1.14 million European ancestry individualsGenetic links between heart disease and depression are twice as strong in women

Background and Aims Comorbidity between ischaemic heart disease (IHD) and depression (DEP) is prevalent and more pronounced in woman than in men. The biological basis of these sex differences, however, remains unclear. We aimed to assess the contribution of genetic and biological risk factors to sex differences in IHD-DEP comorbidity. Methods We analysed sex-stratified genome-wide association study summary statistics from 1.14 million individuals of European ancestry across multiple large-scale cohorts and international consortia. Global and local genetic correlations (rg), pleiotropic loci, and IHD-DEP shared genes were identified using LDSC, MiXeR, LAVA, conjunctional FDR, and FLAMES. We conducted conditional analyses using genetic and phenotypic data for 331 putative risk factors. Results The rg between IHD and DEP was twice as high in females (rg =.43) compared to males (rg =.21), explaining a greater proportion of comorbidity in females (21% vs 13%). Pleiotropy analyses identified sex-specific genomic regions and genes contributing to IHD-DEP comorbidity. Genetic conditional analysis indicated that behavioural traits (alcohol use, insomnia, social deprivation) contributed more to male IHD-DEP comorbidity, whereas asthma and female-specific health traits contributed more to female IHD-DEP comorbidity. Phenotypic mediation largely reflected the same pattern. Conclusions Higher IHD-DEP comorbidity in females compared to males is partly attributable to greater shared genetic liability. Distinct genes and differing contributions of behavioural, metabolic, immunological, and reproductive factors further shape these sex differences. These results support sex-aware risk stratification-targeting alcohol, sleep, and loneliness in males and endocrine status and asthma control in females.