Genome-Wide Association Study of Retinopathy in Individuals without Diabetes

BackgroundMild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes. MethodsA working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. ResultsNo SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, −1.3±0.23 (beta ± standard error), p = 6.6×10−9. Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r2 ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension. ConclusionsThis GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

背景：在无糖尿病或高血压的人群中可观察到轻度视网膜病变（微动脉瘤或点状出血），此类病变可能提示其他器官存在微血管疾病。我们针对无糖尿病人群的轻度视网膜病变开展了全基因组关联研究（Genome-Wide Association Study, GWAS）。
方法：工作组就队列内GWAS的表型标准化、协变量选择及分析方案达成共识。我们对来自6个队列共19411名高加索人群的GWAS结果进行了逆方差加权固定效应荟萃分析。本研究的首要分析纳入无糖尿病个体，次要分析则按高血压患病情况进行分层。我们还单独分析了既往被证实与糖尿病和高血压（视网膜病变的两大最常见病因）相关的单核苷酸多态性（Single Nucleotide Polymorphism, SNPs）的结果。
结果：在首要分析以及合并高血压参与者的次要分析中，未发现达到全基因组显著性水平的SNPs。在针对无高血压参与者的分析中，7号染色体上组蛋白脱乙酰酶9基因（Histone Deacetylase 9, HDAC9）内的SNP rs12155400与视网膜病变相关，β值±标准误为−1.3±0.23，P值为6.6×10⁻⁹。研究证据提示该结果为假阳性发现。该位点的次要等位基因频率较低（约2%），填充质量中等（r²≈0.7），且HDAC9基因内未发现其他与该结局相关的常见变异。其他GWAS中被证实与糖尿病、高血压相关的SNPs，在无糖尿病人群或合并/未合并高血压的亚组中，均未发现与视网膜病变存在关联。
结论：本项针对无糖尿病人群视网膜病变的GWAS未发现显著的遗传关联证据。未来需开展进一步研究以鉴定与该类病变相关的基因，从而助力阐明微血管疾病的全新通路及决定因素。