Abstract
PURPOSE: To elucidate the genetic basis of primary angle-closure glaucoma (PACG) by identifying pathogenic tissue and critical tissue-specific variants. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.