February 18, 2019Ophthalmology
Age-related macular degeneration (AMD) is a disease that blurs the sharp, central vision you need for straight-ahead activities such as reading, sewing, and driving. AMD affects the macula, the part of the eye that allows you to see fine detail. AMD causes no pain. In some people, AMD advances so slowly that vision loss does not occur for a long time. In others, the disease progresses faster and may lead to a loss of vision in one or both eyes. As AMD progresses, a blurred area near the center of vision is a common symptom. Over time, the blurred area may grow larger or you may develop blank spots in your central vision. Objects also may not appear to be as bright as they used to be. AMD by itself does not lead to complete blindness, with no ability to see.
AMD is a complex disease influenced by a yet-to-be-understood mix of genetic and behavioral factors. Smoking, for example, increases the risk of developing the disease, while eating leafy greens and fish reduces it. More research is needed to understand how these environmental factors interact with genes to contribute to the development of the disease and its severity.
According to an article published in Nature Genetics (11 February 2019), has identified genes associated with AMD. These findings provide a more expanded and in-depth picture of the genetic contributions to AMD, and how they present new pathways for treatment development.
Previously, a study that compared populations of people with and without AMD, identified 34 small genomic regions -called loci-and 52 genetic variants within these loci that were significantly associated with AMD. However, according to the authors, as with other common and complex diseases, most of the variants turned out not to be present in protein-coding regions of the genome. The authors then explored whether the variants might regulate AMD-relevant genes, possibly at promoters, which are sequences within DNA that turn genes on, or enhancers, which increase the activity of promoters. If the variants did indeed regulate gene expression, a key question remained: what were the genes that the variants were regulating?
In order to address this issue, the authors studied 453 retinas, the eye tissue affected by AMD, from deceased human donors with and without AMD. The analysis involved sequencing each retina's ribonucleic acid (RNA), the messenger molecule that carries instructions from DNA for making proteins. A total of 13,662 protein-coding and 1,462 non-protein coding RNA sequences were identified. To search for the genetic variants regulating gene expression in the retina, the study team used expression quantitative trait loci (eQTL) analysis. Computational methods allowed the researchers to detect patterns between the genes expressed in the retina and a pool of more than 9 million previously identified genetic variants. Specifically, they looked for variants with a high probability of being responsible for variations in gene expression among people with and without AMD. The analysis pointed to target disease genes at six of the 34 AMD loci identified in the earlier research. In addition, integration of this data with earlier AMD studies identified three additional target AMD genes, which had never before been shown to play a role in AMD. This analysis also suggested as many as 20 additional candidate genes providing insights into the genes and pathways involved in pathobiology of AMD. Among the most plausible target genes were B3GLCT and BLOC1S1, which could affect AMD-related cell functions such as signaling; the breakdown and disposal of unwanted proteins; and the stability of the extracellular matrix, the cell's infrastructure for distribution.
Crucial to the study was the authors development of a database of retinal gene expression. Called EyeGEx the database provides a resource for vision researchers, not only for studies of AMD, but for research into the genetic causes of other diseases such as diabetic retinopathy and glaucoma.