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Genomic meta-analysis across patient DNA of European ancestry uncovers three additional genetic loci behind glaucoma

Research conducted by an international consortium of ophthalmic genetic specialists has reported the identification of a further three loci believed to contribute to the pathology of primary open angle glaucoma. In a significant publication in the journal Nature Genetics, the researchers reported the results of a meta-analysis on the genome-wide association study results of eight independent analyses from the United States (3,853 cases and 33,480 controls), Australia (1,252 cases and 2,592 controls), Europe (875 cases and 4,107 controls) and Singapore (1,037 cases and 2,543 controls). The meta-analysis of the top single nucleotide polymorphisms identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 1011) encoding a mitochondrial protein; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 1010); and rs2745572[A] upstream of the FOXC1 gene (OR = 1.17, P = 1.76 × 1010).


The study, funded by the US National Eye Institute (NEI), a division of the National Institutes of Health (NIH), suggests that the total number of genes behind the most common form of glaucoma now totals 15. The three newly identified regions include polymorphisms around ATXN2, TXNRD2 and FOXC1. SNPs in the ATXN2 region are located in genomic sequences enriched for enhancers in lymphoid cells, especially in an SP1 transcription factor binding site and in an ESR2 (estrogen receptor 2) binding site. 22 SNPs in the TXNRD2 region appear to be significantly enriched for enhancers and DNase I hypersensitivity sites. According to the researchers, the reported regions had not been previously associated with POAG or with glaucoma-related quantitative traits, optic nerve parameters or IOP.


Of the genomic regions identified each had previously been associated with neurobiology. ATXN2 has been associated with spino-cerebellar ataxia 2 with optic atrophy, while a particular region of the same gene has been associated with retinal venular caliber in individuals of European descent. TXNRD2 encodes the mitochondrial protein thioredoxin reductase 2 which is understood to reduce the levels of reactive oxygen species generated by oxidative phosphorylation in the mitochondria, previously proposed as a cause of retinal ganglion cell dysfunction. Finally, FOXC1 is a member of the forkhead family of transcription factors, previously identified as a cause of anterior segment dysgenesis and early-onset glaucoma with dominant inheritance. In conclusion the authors claim that, “these genes suggest new pathways that may contribute to glaucoma development, including abnormal ocular development (FOXC1), neurodegeneration (ATXN2) and mitochondrial dysfunction secondary to accumulating reactive oxygen species (TXNRD2). Targeting these pathways could lead to effective and potentially preventative glaucoma therapies.”