Research Highlight February 03, 2016

Genome-wide association analysis implicates new genes, disease pathways in primary open-angle glaucoma

Primary open-angle glaucoma is the leading cause of permanent blindness worldwide. It also a complicated disease, both in the clinic and in the laboratory, where scientists are working to identify its root causes. Previous genome-wide association studies found interesting genetic associations with the disease, but none with a strong signal. A large team of researchers, led by Janey Wiggs of Harvard Medical School and including JAX Assistant Professor Gareth Howell, Ph.D., broadened the search to include many patient studies in a meta-analysis, incorporating nearly 4,000 cases and more than 33,000 controls.

The investigation, published in Nature Genetics, identified three additional genetic regions associated with glaucoma susceptibility, providing new disease pathways to investigate and potential therapeutic targets. Two of the genetic regions, ATXN2 and TXNRD2, had not previously been associated with any glaucoma-related quantitative trait. Howell and lab member Keating Pepper used immunolabeling to confirm that both genes are expressed in normal mouse retinal ganglion cells and in the optic nerve head. Other team members found expression in normal human ocular tissues as well.

ATXN2 had previously been associated with other forms of neurodegeneration. TXNRD2 is known to encode thioredoxin reductase 2, a mitochondrial protein that reduces the levels of damaging reactive oxygen species, and it is the first mitochondrial protein to be associated with glaucoma risk. The third gene identified, FOXC1, is a transcription factor involved with ocular development that earlier studies had implicated in early-onset forms of glaucoma, but it had not been previously associated with adult-onset forms. All three pathways—ocular development, neurodegeneration and mitochondrial function—offer opportunities for potentially preventative glaucoma therapies.

Cooke Bailey et al, 2016. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nature Genetics 48: 189-94. doi:10.1038/ng.3482