Sex differences in the risk of cataract associated with type 2 diabetes: a Mendelian randomization study

Type 2 diabetes (T2D) is a recognized risk factor for developing cataract. However, it is unclear if the shared genetic variance and potential genetic causal relationship between T2D and cataract are different for males and females. We evaluated sex-specific genetic correlation (rg) and putative genetic causality between the two diseases by using linkage disequilibrium score regression (LDSC) and six Mendelian randomization (MR) approaches after leveraging large-scale population-based genome-wide association studies (GWAS) summary of T2D and cataract. Application of LDSC found a significant genetic correlation between T2D and cataract in East Asian males (rg=0.68, 95% confident interval [CI]=0.17 to 1, p-value=8.60x10-3) but a non-significant genetic correlation in East Asian females (rg=0.25, CI= -0.02 to 0.52, p-value=8.38x10-2). MR analyses indicated a consistently stronger (paired t-test |t|=5.87, p-value=2.04x10-3) causal effect of T2D on cataract in East Asian males (liability OR=1.20 to 1.41, p-value=5.86x10-27 to 6.60x10-6) than in females (liability OR=1.12 to 1.21, p-value=2.02x10-14 to 1.82x10-2). In Europeans, the LDSC analysis suggested a close significant genetic correlation between the two diseases in males (rg=0.20, 95% confident interval [CI]=0.08 to 0.32, p-value=7.00x10-4) and females (rg=0.17, CI= 0.05 to 0.29, p-value=4.90x10-3); but the MR analyses provided weak evidences on a causal relationship between the two diseases in both sexes. These results presented the first evidence on sex difference of the casual relationship between cataract and T2D in East Asians, and supported a potential genetic heterogeneity of the shared genetics underlying T2D and cataract between East Asians and Europeans in both sexes.