Scientists have zeroed in on genes associated with age-related macular degeneration (AMD), a leading cause of vision loss and blindness among people age 65 and older. These findings provide a more expanded and in-depth picture of the genetic contributions to AMD, and they present new pathways for treatment development. The study was published in Nature Genetics.
Previously, researchers had compared populations of people with and without AMD and identified 34 small genomic regions--called loci--and 52 genetic variants within these loci that were significantly associated with AMD. "However, as with other common and complex diseases, most of the variants turned out not to be present in protein-coding regions of the genome, leaving us to wonder how they were having a biological effect on AMD," said the lead investigator.
The researchers 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?
The team 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, they 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.
"So far most studies in AMD have focused on analyses of genetic variants in DNA. This study for the first time leverages transcriptional (RNA) data to expand on the genetic architecture of AMD," said another author.
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 teams 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.
Future studies will aim to explain the function of the target AMD genes to determine how they relate to AMD pathobiology and to look for targets for new treatment strategies.
https://www.nei.nih.gov/content/nih-researchers-home-genes-linked-age-related-macular-degeneration
https://www.nature.com/articles/s41588-019-0351-9
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