School of Data and Computer Science, Sun Yat-sen University, Guangzhou, China.
Department of Medical Research Center, Sun Yat-sen Memorial Hospital, and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, China.
Int J Epidemiol. 2022 Jan 6;50(6):2024-2037. doi: 10.1093/ije/dyab175. Epub 2022 Sep 1.
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.
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共享遗传基础，如果是这样，这是否反映了一种假定的因果关系。
我们使用东亚人群为基础的 2 型糖尿病（Ncase=36614，Ncontrol=155150）和白内障（Ncase=24622，Ncontrol=187831）全基因组关联研究（GWAS）汇总统计数据，全面研究这两种疾病之间的共同遗传基础。我们进行了以下分析：（i）使用连锁不平衡评分回归（LDSC）和从汇总统计数据中估计遗传力（ρ-HESS），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性模式；（ii）进行多次孟德尔随机化（MR）分析，推断 2 型糖尿病和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），鉴定潜在因果关系背后的候选风险基因。此外，为了研究 2 型糖尿病和白内障共同遗传基础中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，对欧洲人群为基础的 2 型糖尿病（Ncase=62892，Ncontrol=596424）和白内障（Ncase=5045，Ncontrol=356096）GWAS 汇总数据进行了比较分析。
使用东亚人群为基础的 GWAS 汇总数据，我们观察到 2 型糖尿病和白内障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]。ρ-HESS 和多次 MR 方法均一致表明 2 型糖尿病对白内障有假定的因果效应，估计的易感性尺度 MR 优势比（OR）约为 1.10（95%CI=1.06，1.17）。相反，没有证据支持白内障对 2 型糖尿病有因果效应。SMR 分析鉴定出两个新的基因 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），它们的表达水平可能与 2 型糖尿病对白内障的假定因果关系有关。相比之下，我们对欧洲人群的比较分析提供了普遍较弱的证据，表明这两种疾病之间的遗传相关性和因果关系。
我们的研究结果为东亚人群中 2 型糖尿病对白内障风险的假定因果效应提供了有力的证据，并揭示了 2 型糖尿病和白内障共同遗传基础在东亚和欧洲人群中的潜在遗传异质性。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。
