The putative causal effect of type 2 diabetes in risk of cataract: a Mendelian randomization study in East Asian

BackgroundThe 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 causal relationship. MethodsWe utilized 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 1. linkage disequilibrium score regression (LDSC) and heritability estimation from summary statistics ({rho}-HESS) to estimate the genetic correlation and local genetic correlation between type 2 diabetes and cataract; 2. multiple Mendelian randomization (MR) analyses to infer the putative causality between type 2 diabetes and cataract; and 3. Summary-data-based Mendelian randomization (SMR) to identify candidate risk genes underling the causality. ResultsWe observed a strong genetic correlation (rg=0.58; p-value=5.60x10-6) between type 2 diabetes and cataract. Both {rho}-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% confidence interval [CI] ranging from 1.06 to 1.17). In contrast, no evidence supports a causal effect of cataract on type 2 diabetes. SMR analysis identified two novel genes MIR4453HG ({beta}SMR=-0.34, p-value=6.41x10-8) and KCNK17 ({beta}SMR=-0.07, p-value=2.49x10-10), whose expression levels were likely involved in the putative causality of type 2 diabetes on cataract. ConclusionsOur results provided robust evidence supporting a causal effect of type 2 diabetes on the risk of cataract in East Asians, and posed new paths on guiding prevention and early-stage diagnosis of cataract in type 2 diabetes patients. Key MessagesO_LIWe utilized genome-wide association studies of type 2 diabetes and cataract in a large Japanese population-based cohort and find a strong genetic overlap underlying the two diseases. C_LIO_LIWe performed multiple Mendelian randomization models and consistently disclosed a putative causal effect of type 2 diabetes on the development of cataract. C_LIO_LIWe revealed two candidate genes MIR4453HG and KCNK17 whose expression levelss are likely relevant to the causality between type 2 diabetes and cataract. C_LIO_LIOur study provided theoretical fundament at the genetic level for improving early diagnosis, prevention and treatment of cataract in type 2 diabetes patients in clinical practice C_LI