NEW YORK (GenomeWeb) – Through a meta-analysis drawing on a number of genome-wide association studies, an international team of researchers homed in on loci in three genes associated with primary open-angle glaucoma susceptibility.
Glaucoma is the global leading cause of blindness, and primary open-angle glaucoma, the most common form of the disease, is marked by retinal ganglion cell apoptosis and progressive optic nerve damage.
In the first stage of their meta-analysis, researchers led by Massachusetts Eye and Ear Infirmary's Janey Wiggs drew on nearly 4,000 cases and about 33,500 controls from the US to search for SNPs linked to primary open-angle glaucoma. In the second stage, they examined whether the most significant of theseSNPs were also significant in sets of Australian, European, and Singaporean Chinese studies. As they reported in Nature Genetics today, their meta-analysis revealed three loci — in TXNRD2, in ATXN2, and upstream of FOXC1 — linked to primary open-angle glaucoma.
"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)," Wiggs and her colleagues wrote in their paper. "Targeting these pathways could lead to effective and potentially preventative glaucoma therapies."
For their discovery stage, she and her colleagues performed a meta-analysis using summary data from eight independent datasets, encompassing a combined 3,853 cases and 33,480 controls of European ancestry from the US. All the cases, the researchers noted, had vision loss consistent with glaucoma without a secondary cause.
For each of the eight datasets, site-specific quality control, principal components analysis, and imputation were performed with the 1000 Genome Project reference panel. The researchers also conducted a sensitivity analysis to ensure that the results weren't skewed by any one dataset.
In this stage, one SNP, located some 50 kilobase pairs away from FOXC1, reached genome-wide significance and some 873 others, including some in regions that hadn't before been linked to POAD, reached a p-value of less than 1x10-5.
Wiggs and her colleagues then conducted a replication study on the most significant SNPs they identified, drawing on 1,155 cases and 1,992 controls of European ancestry from Australia, and performed a meta-analysis using both the US- and the Australian-based cohort. From this meta-analysis, they found that SNPs 50 kilobase pairs away from FOXC1, within intron 14 of ATXN2, and within intron 11 of TXNRD2 reached genome-wide significance.
They further examined these regions in a second Australian dataset as well as within three European datasets and one Singaporean Chinese dataset. All three of these top SNPs reached genome-wide significance in the additional cohorts, the researchers reported, with the exception of the ATXN2 SNP, which was too rare within the Singaporean Chinese population for the researchers to evaluate it in that dataset.
The researchers also noted that they confirmed SNPs in regions previously linked to intraocular pressure or to primary open-angle glaucoma itself, including TMC01, CDKN2B-AS1, and SIX6. They also identified a locus on chromosome 12q that's associated with normal-tension glaucoma, a subtype of the condition.
FOXC1, Wiggs and her colleagues noted, is a member of the forkhead transcription factor family. While FOXC1 hasn't previously been linked to primary open-angle glaucoma, they added that a previous study drawing on some of the same datasets implicated loci in GMDS, which is located 3' to FOXC1. However, the researchers noted that these signals, which are about 400 kilobase pairs apart, are independent.
In addition, they noted that neither the ATXN2 nor the TXNRD2 regions have been associated with primary open-angle glaucoma before.
However, a CAG repeat within ATXN2 can lead to spinocerebellar ataxia 2 with optic atrophy and an intermediate-length expansion may contribute to amyotrophic lateral sclerosis development. The ATXN2-SH2B3 region, the researchers added, has also been linked with retinal venular caliber in people of European ancestry. ATXN2 mRNA, the researchers said, is expressed in the cornea, retina, optic nerve, and other parts of a healthy eye.
TXNRD2, meanwhile, encodes thioredoxin reductase 2, which is a mitochondrial protein that's important for lowering the levels of reactive oxygen species that oxidative phosphorylation and other mitochondrial processes generate. It, too, is expressed in normal human eye tissue, the researchers said.
This suggests that the reduction of reactive oxygen species by TXNRD2 could prevent mitochondrial dysfunction and the retinal ganglion cell apoptosis that occurs in glaucoma, they added.
"This is the first direct report to show the association of a gene linking oxidative damage to glaucoma," said Neeraj Agarwal, a program director at the National Eye Institute, which funded the study, in a statement.