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.

中文翻译：

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孟德尔随机化研究揭示了 2 型糖尿病与白内障风险之间特定人群的假定因果关系

背景 2 型糖尿病和白内障之间的流行病学关联已得到充分证实。然而，目前尚不清楚这两种疾病是否具有共同的遗传基础，如果是的话，这是否反映了假定的因果关系。方法 采用东亚人群全基因组关联研究（GWAS）汇总统计 2 型糖尿病（Ncase = 36 614，Ncontrol = 155 150）和白内障（Ncase = 24 622，Ncontrol = 187 831），全面调查这两种疾病有共同的遗传基因。我们进行了：（i）连锁不平衡评分回归（LDSC）和汇总统计遗传力估计（ρ-HESS），以估计 2 型糖尿病和白内障之间的遗传相关性和局部遗传相关模式；(ii) 多重孟德尔随机化 (MR) 分析，以推断 2 型糖尿病与白内障之间的假定因果关系；(iii) 基于汇总数据的孟德尔随机化 (SMR)，以确定假定因果关系下的候选风险基因。此外，为了调查 2 型糖尿病和白内障之间共享遗传学基础的人群特异性遗传效应大小的程度，我们应用相同的分析流程对基于欧洲人群的 2 型糖尿病 GWAS 进行比较分析（Ncase = 62 892，Ncontrol = 596 424）和白内障（Ncase = 5045，Ncontrol = 356 096）。结果 使用基于东亚人群的 GWAS 摘要数据，我们观察到 2 型糖尿病和 2 型糖尿病之间存在很强的遗传相关性 [rg = 0.58，95% 置信区间 (CI) = 0.33, 0.83)，P 值 = 5.60 × 10–6]白内障。ρ-HESS 和多种 MR 方法一致显示 2 型糖尿病对白内障的假定因果影响，估计责任量表 MR 比值比 (OR) 约为 1.10 (95% CI = 1.06, 1.17)。相比之下，没有证据支持白内障与 2 型糖尿病之间存在因果关系。SMR分析确定了两个新基因MIR4453HG (βSMR = -0.34, 95% CI = -0.46, -0.22, P值= 6.41 × 10–8)和KCNK17 (βSMR = -0.07, 95% CI = -0.09, -0.05 ，P值= 2.49×10-10），其表达水平可能与2型糖尿病与白内障的假定因果关系有关。相反，我们对欧洲人群的比较分析为这两种疾病之间的遗传相关性和因果关系提供了普遍较弱的证据。结论 我们的结果提供了强有力的证据，支持 2 型糖尿病与东亚人白内障风险之间的假定因果关系，并揭示了东亚人和欧洲人之间 2 型糖尿病和白内障的共同遗传潜在的遗传异质性。这些发现为指导2型糖尿病患者白内障的预防和早期诊断提供了新的途径。