PT  - JOURNAL ARTICLE
AU  - Haoyang Zhang
AU  - Xuehao Xiu
AU  - Angli Xue
AU  - Yuedong Yang
AU  - Yuanhao Yang
AU  - Huiying Zhao
TI  - The putative causal effect of type 2 diabetes in risk of cataract: a Mendelian randomization study in East Asian
AID  - 10.1101/2021.02.08.430342
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.02.08.430342
4099  - http://biorxiv.org/content/early/2021/02/10/2021.02.08.430342.short
4100  - http://biorxiv.org/content/early/2021/02/10/2021.02.08.430342.full
AB  - 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 (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 (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 (rg=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 (βSMR=−0.34, p-value=6.41×10−8) and KCNK17 (βSMR=−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 MessagesWe 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 practiceCompeting Interest StatementThe authors have declared no competing interest.