Mendelian randomization study reveals a population-specific putative causal effect of type 2 diabetes in risk of cataract

The epidemiological association between type 2 diabetes and cataract has been well established. However, it remains unclear whether the two diseases share a genetic basis, and if so, whether this reflects a putative causal relationship.We used East Asian population-based genome-wide association studies (GWAS) summary statistics of type 2 diabetes (Ncase = 36 614, Ncontrol = 155 150) and cataract (Ncase = 24 622, Ncontrol = 187 831) to comprehensively investigate the shared genetics between the two diseases. We performed: (i) linkage disequilibrium score regression (LDSC) and heritability estimation from summary statistics (ρ-HESS) to estimate the genetic correlation and local genetic correlation pattern between type 2 diabetes and cataract; (ii) multiple Mendelian randomization (MR) analyses to infer the putative causality between type 2 diabetes and cataract; and (iii) summary-data-based Mendelian randomization (SMR) to identify candidate risk genes underling the putative causality. Moreover, to investigate the extent of the population-specific genetic effect size underlying the shared genetics between type 2 diabetes and cataract, we applied the same analytical pipeline to perform a comparative analysis on European population-based GWAS of type 2 diabetes (Ncase = 62 892, Ncontrol = 596 424) and cataract (Ncase = 5045, Ncontrol = 356 096).Using East Asian population-based GWAS summary data, we observed a strong genetic correlation [rg = 0.58, 95% confidence interval (CI) = 0.33, 0.83), P-value = 5.60 × 10-6] between type 2 diabetes and cataract. Both ρ-HESS and multiple MR methods consistently showed a putative causal effect of type 2 diabetes on cataract, with estimated liability-scale MR odds ratios (ORs) at around 1.10 (95% CI = 1.06, 1.17). In contrast, no evidence supports a causal effect of cataract on type 2 diabetes. SMR analysis identified two novel genes MIR4453HG (βSMR = -0.34, 95% CI = -0.46, -0.22, P-value = 6.41 × 10-8) and KCNK17 (βSMR = -0.07, 95% CI = -0.09, -0.05, P-value = 2.49 × 10-10), whose expression levels were likely involved in the putative causality of type 2 diabetes on cataract. On the contrary, our comparative analysis on European population provided universally weak evidence on the genetic correlation and causal relationship between the two diseases.Our results provided robust evidence supporting a putative causal effect of type 2 diabetes on the risk of cataract in East Asians, and revealed potential genetic heterogeneity in the shared genetics underlying type 2 diabetes and cataract between East Asians and Europeans. These findings posed new paths on guiding the prevention and early-stage diagnosis of cataract in type 2 diabetes patients.