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

Abstract

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 putative causal relationship.

Methods: 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).

Results: 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.

Conclusions: 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.

Keywords: Mendelian randomization; Type 2 diabetes; cataract.