International Study Reveals New Genetic Clues to Age-Related Macular Degeneration

Researchers from the University of Miami Miller School of Medicine’s John P. Hussman Institute for Human Genomics and Bascom Palmer Eye Institute are part of a consortium that has significantly expanded the number of genetic factors known to play a role in age-related macular degeneration (AMD), a leading cause of vision loss among people age 50 and older. Supported by the National Eye Institute, part of the National Institutes of Health, the findings may help improve our understanding of the biological processes that lead to AMD and identify new therapeutic targets for potential drug development.

AMD is a progressive disease that causes the death of the retinal photoreceptors, the light-sensitive cells at the back of the eye. The most severe damage occurs in the macula, a small area of the retina that is needed for sharp, central vision necessary for reading, driving and other daily tasks. There are currently no Food and Drug Administration-approved treatments for the more common form of advanced AMD, called geographic atrophy or “dry” AMD. While therapies for the other advanced form, neovascular or “wet” AMD, can successfully halt the growth of abnormal, leaky blood vessels in the eye, the therapies do not cure the condition, nor do they work for everyone.

Up to this point, researchers had identified 21 regions of the genome — called loci — that influence the risk of AMD. The new research, recently published online in Nature Genetics, raises the number of loci to 34. The Miller School’s Margaret A. Pericak-Vance, Ph.D., the Dr. John T. Macdonald Foundation Professor of Human Genomics and Director of the John P. Hussman Institute for Human Genomics, and William K. Scott, Ph.D., professor and Vice Chair for Education and Training at the Dr. John T. Macdonald Foundation Department of Human Genetics and the John P. Hussman Institute for Human Genomics, and professor of public health sciences, were two of the senior authors on the study.

The International AMD Genomics Consortium, which includes 26 centers worldwide, collected and analyzed the genetic data from 43,566 people of predominantly European ancestry to systematically identify common and rare variations in genetic coding — called variants — associated with AMD. Pericak-Vance is the co-Principal Investigator of the National Eye Institute-funded consortium. Common variants generally have an indirect association with a disease. Rare variants, by contrast, are more likely to alter protein expression or function and therefore have a direct or causal association with a disease. Rare variants were defined as those found in less than 1 percent of the study population.

The study included about 23,000 participants with AMD and 20,000 without it. Researchers analyzed DNA samples from both groups, surveying most of the genome, but also focusing on distinct loci already known or suspected to be associated with AMD. Next, they compared the participants’ DNA to a reference dataset called the 1,000 Genomes project, yielding more than 12 million genetic variants of potential interest. Finally, they went back to the participants’ DNA samples, looking at all 12 million variants, to see if any were found more or less often in people with AMD than those without it.

Other University of Miami investigators include Rebecca Sardell, Ph.D., post-doctoral scholar at the John P. Hussman Institute for Human Genomics, Jaclyn Kovach, M.D., associate professor of clinical ophthalmology at Bascom Palmer Eye Institute, and Stephen Schwartz, M.D., associate professor of ophthalmology and Medical Director at Bascom Palmer Eye Institute at Naples.

“We hope that identifying these variants will lead to treatment and earlier detection of AMD,” said Pericak-Vance. “Our findings bring us closer toward identifying new drug targets for AMD.”

The study findings also bolster associations between AMD and two genes, CFH and TIMP3, which had each previously been linked to AMD. CFH was the very first disease-linked gene to be found through a genome-wide association study. TIMP3 had earlier been linked to Sorsby’s fundus dystrophy, a rare disease that is similar to AMD clinically, but which tends to affect people before the age of 45.

For the first time the researchers also identified a variant specific to the neovascular form of AMD, which may point to reasons why therapy for this form of AMD is effective for some people but not everyone.

“This pivotal paper lays the groundwork for future sight-saving treatments using genetic based therapies for age-related macular degeneration,” said Kovach.

Additionally, 10 of the variants point to genes involved in maintaining the extracellular matrix, the nonliving material among cells that provides structural support and nutrients. Researchers have theorized that abnormalities of the extracellular matrix occur in people with a subtype of AMD that develops without early-stage signs, or that quickly worsens before such signs are detected. If confirmed, a connection between AMD and these extracellular matrix genes may allow for predictive genetic tests and more effective therapies for people with this type of AMD.

The study was funded in part by the NEI Intramural Research Program and by NEI grants: EY023164, EY012118, EY022310, T32-EY023194, P30-EY005722, EY0022005, EY016862, EY022310. The study also was supported by NIH grants from the National Human Genome Research Institute (HG006513, HG007022, 1U01HG006389), the National Institute on Aging (AG019085), and the National Center for Advancing Translational Sciences (UL1TR000427).

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