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

Background 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 causal relationship. Methods We utilized East Asian population-based genome-wide association studies (GWAS) summary statistics of type 2 diabetes ( N case =36,614, N control =155,150) and cataract ( N case =24,622, N control =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 (ρ-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. Results We observed a strong genetic correlation ( r g =0.58; 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% 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 ( β SMR =−0.34, p-value=6.41×10 −8 ) and KCNK17 ( β SMR =−0.07, p-value=2.49×10 −10 ), whose expression levels were likely involved in the putative causality of type 2 diabetes on cataract. Conclusions Our 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 Messages We 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. We performed multiple Mendelian randomization models and consistently disclosed a putative causal effect of type 2 diabetes on the development of cataract. We revealed two candidate genes MIR4453HG and KCNK17 whose expression levelss are likely relevant to the causality between type 2 diabetes and cataract. Our 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