A large deletion spanning multiple enhancers near PITX2 increases primary open-angle glaucoma risk

Area of Science:

• Genomics
• Ophthalmology
• Genetic Epidemiology

Background:

• Genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) and indels linked to primary open-angle glaucoma (POAG) risk.
• However, these common variants typically have small effect sizes, contributing minimally to individual disease risk.
• The increasing availability of whole-genome sequencing data allows for the investigation of structural variants (SVs) and complex genomic features in disease etiology.

Purpose of the Study:

• To investigate the association between structural variants within known glaucoma loci and the risk of developing primary open-angle glaucoma (POAG).
• To assess the utility of whole-genome sequencing data in identifying SVs that may be missed by conventional genotyping methods.
• To explore the role of SVs in the genetic architecture of POAG.

Main Methods:

• A cross-sectional study design was employed using data from the All of Us Research Program.
• POAG case and control cohorts were established based on age criteria and ICD diagnosis codes.
• Logistic regression analyses, adjusted for age, sex, and ancestry principal components, were used to test for associations between SVs and POAG risk within 500 kilobases of 309 known glaucoma risk loci.

Main Results:

• The analysis included 516 POAG cases and 18,716 controls of European ancestry.
• A significant association was found for an 8,732 base pair deletion upstream of the PITX2 gene (chr4:110680827-110689558).
• This deletion was associated with a 7.3-fold increased odds of POAG (p=2.4×10^-5) and was present in 1.6% of cases versus 0.25% of controls. Functional annotation indicated enhancer elements overlapping the deletion, suggesting regulatory disruption.

Conclusions:

• Whole genome sequencing effectively identifies rare structural variants with substantial effect sizes, improving POAG risk stratification beyond conventional SNP/indel analyses.
• The identified deletion in the PITX2 locus expands the known spectrum of structural variation associated with glaucoma, linking it to adult-onset disease.
• Disruption of regulatory elements by SVs, such as the PITX2 deletion, may influence the age of onset and clinical severity of POAG.