Li Jiaying, Chen Yun, Wang Wenbin, Zhang Ye, Su Guangsong, Wang Sean K, Zhang Yuanyuan, Yao Yilong, Wu Shen, Lu Wange, Zhang Kunlin, Qiao Chunyan, Li Shuning, Li Hengtong, Cheng Ching-Yu, Liu Yuwen, Wang Ningli
Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China.
Invest Ophthalmol Vis Sci. 2024 Dec 2;65(14):18. doi: 10.1167/iovs.65.14.18.
To elucidate the genetic basis of primary angle-closure glaucoma (PACG) by identifying pathogenic tissue and critical tissue-specific variants.
The correlations among PACG susceptibility, axial length (AL), and anterior chamber depth (ACD) were evaluated using meta-analyses. Propensity score matching was utilized on 2161 participants from the Handan Eye Study to determine the risk factors independent of ACD and AL for PACG. Subsequently, we employed the assay for transposase-accessible chromatin with sequencing (ATAC-seq) and allele-specific self-transcribing active regulatory region sequencing (STARR-seq) to screen 202 PACG genome-wide association study (GWAS) variants for chromatin accessibility and functional roles.
The meta-analysis found that PACG susceptibility loci are not associated with ACD or AL. However, abnormal iris phenotypes emerged as significant independent risk factors for primary angle-closure disease (PACD), unrelated to ACD and AL. Substantial enrichment of PACG heritability was observed in the open chromatin regions of the human iris. Within the iris-relevant cellular context, 22 out of the 202 PACG GWAS variants could influence enhancer activity. Two variants in the iris open chromatin regions were implicated in the modulation of PLEKHA7 and C10orf53 expression. The downregulation of these two genes affects cytoskeletal organization.
Our findings underscore the importance of the iris in the pathogenesis of PACG and identified iris-specific, enhancer-modulating variants that may influence disease risk. Our approach also provides a generalizable framework for studying ocular diseases from the perspective of enhancer-modulating variants.
通过鉴定致病组织和关键的组织特异性变异，阐明原发性闭角型青光眼（PACG）的遗传基础。
使用荟萃分析评估PACG易感性、眼轴长度（AL）和前房深度（ACD）之间的相关性。对来自邯郸眼病研究的2161名参与者采用倾向评分匹配法，以确定独立于ACD和AL的PACG危险因素。随后，我们采用染色质转座酶可及性测序分析（ATAC-seq）和等位基因特异性自转录活性调控区域测序（STARR-seq），筛选202个PACG全基因组关联研究（GWAS）变异的染色质可及性和功能作用。
荟萃分析发现，PACG易感位点与ACD或AL无关。然而，异常虹膜表型是原发性闭角型疾病（PACD）的显著独立危险因素，与ACD和AL无关。在人类虹膜的开放染色质区域观察到PACG遗传力的显著富集。在与虹膜相关的细胞环境中，202个PACG GWAS变异中的22个可能影响增强子活性。虹膜开放染色质区域的两个变异与PLEKHA7和C10orf53表达的调节有关。这两个基因的下调影响细胞骨架组织。
我们的研究结果强调了虹膜在PACG发病机制中的重要性，并鉴定出可能影响疾病风险的虹膜特异性、增强子调节变异。我们的方法还提供了一个从增强子调节变异角度研究眼部疾病的通用框架。
