Individuals heterozygous for LTBP2 loss-of-function variants have an increased risk of adult-onset primary open-angle glaucoma.

Abstract

Purpose: Glaucoma, a leading cause of irreversible blindness, can affect individuals across the lifespan, with childhood glaucoma typically exhibiting Mendelian inheritance and adult-onset disease inherited as complex traits. While large-scale genome-wide association studies suggest several childhood glaucoma genes may also contribute to adult-onset disease, the impact of heterozygosity for deleterious variants in recessive childhood glaucoma genes on the risk of adult-onset primary open-angle glaucoma has not been assessed.

Methods: Using exome sequence data for >450,000 participants in the UK Biobank, we investigated the association of heterozygosity for loss-of-function variants with adult-onset glaucoma for three genes (LTBP2 (HGNC:6715), CYP1B1 (23228), and CPAMD8 (HGNC:28543) known to cause autosomal recessive childhood glaucoma.

Results: Gene burden testing demonstrated a significant increase in adult-onset glaucoma risk for individuals with heterozygous loss-of-function (LoF) LTBP2 variants (OR of 4.14, 95% CI 2.73 - 6.28, p = 4.0 × 10^-13). This association was replicated by gene burden testing in the All of Us cohort. Glaucoma participants with LTBP2 LoF variants were diagnosed 8 years earlier than participants without LoF LTBP2 variants. The LoF variants with heterozygous effects are localized in key protein domains, and single-nucleus expression of LTBP2 supports a pathogenic role for extracellular matrix dysfunction in the trabecular meshwork and Schlemm's canal. No significant associations were detected for CYP1B1 or CPAMD8.

Conclusion: These findings suggest that LTBP2, a gene known to contribute to autosomal recessive childhood glaucoma, also confers an increased risk of developing adult-onset disease in a heterozygous LoF state.