Genetics in medicine : official journal of the American College of Medical Genetics · 2026
Individuals heterozygous for LTBP2 loss-of-function variants have an increased risk of adult-onset primary open-angle glaucoma.
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Garcia Mauricio, Luo Yuyang, Lama Jyoti, Young Terri L, Rossin Elizabeth, Pasquale Louis R, Hysi Pirro G, Khawaja Anthony P, Mackey David A, Craig Jamie E, Souzeau Emmanuelle, Aboobakar Inas F, Segrè Ayellet V, Wiggs Janey L, UK Biobank Eye, Vision Consortium, International Glaucoma Genetics Consortium (IGGC)
Аннотация
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.
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.