Linking Iris Cis-Regulatory Variants to Primary Angle-Closure Glaucoma Via Clinical Imaging and Multiomics

Area of Science:

• Ophthalmology
• Genetics
• Molecular Biology

Background:

• Primary angle-closure glaucoma (PACG) is a complex ocular disease with a significant genetic component.
• Understanding the genetic underpinnings of PACG is crucial for developing effective diagnostic and therapeutic strategies.
• Previous studies have explored genetic associations, but the specific tissues and variants involved remain incompletely understood.

Purpose of the Study:

• To identify pathogenic tissues and critical tissue-specific genetic variants contributing to the development of primary angle-closure glaucoma (PACG).
• To investigate the functional roles of PACG-associated variants in relevant ocular tissues.
• To establish a framework for studying enhancer-modulating variants in ocular diseases.

Main Methods:

• Meta-analyses were conducted to evaluate correlations between PACG susceptibility, axial length (AL), and anterior chamber depth (ACD).
• Propensity score matching was used to identify PACG risk factors independent of ACD and AL in the Handan Eye Study cohort.
• Assay for transposase-accessible chromatin with sequencing (ATAC-seq) and allele-specific self-transcribing active regulatory region sequencing (STARR-seq) were employed to screen PACG genome-wide association study (GWAS) variants for functional roles in chromatin accessibility and enhancer activity.

Main Results:

• Meta-analyses revealed no association between PACG susceptibility loci and ACD or AL.
• Abnormal iris phenotypes were identified as significant independent risk factors for primary angle-closure disease (PACD), irrespective of ACD and AL.
• A substantial enrichment of PACG heritability was observed in open chromatin regions of the human iris.
• Twenty-two of 202 PACG GWAS variants demonstrated enhancer activity within the iris.
• Two iris-specific variants were found to modulate the expression of PLEKHA7 and C10orf53, impacting cytoskeletal organization.

Conclusions:

• The iris is critically important in the pathogenesis of PACG.
• Iris-specific, enhancer-modulating variants identified may contribute to PACG risk.
• The study provides a generalizable framework for investigating ocular diseases through the lens of enhancer-modulating variants.