New Genetic Clues Revealed in Search for Cause of Age-Related Macular Degeneration
December, 21, 2015 - 11:35 AM
An international study of about 43,000 people 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
(NEI), 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.
AMD is caused by a combination of genetic, environmental and
lifestyle risk factors. For example, smoking increases the risk of AMD,
while eating leafy greens and fish, such as salmon, halibut, and tuna,
may reduce the risk. Up to this point, researchers had identified 21
regions of the genome—called loci—that influence the risk of AMD. The
new research, published in Nature Genetics, brings the number up to 34 loci.
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. 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. The researchers analyzed DNA samples from both groups,
surveying most of the genome, but also focusing in on distinct loci
already known or suspected to be associated with AMD. Next, they
compared the participants’ DNA to a reference dataset called the 1000
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.
“The investigation is akin to looking at a Google map of the United
States and attempting to pinpoint several leaders and satellite
operations in a crime syndicate,” said a co-leader of the study, Anand
Swaroop, Ph.D., chief of NEI’s Neurobiology-Neurodegeneration and
Repair Laboratory. “It’s possible to find the key players by zooming in
and seeing specific regions in rich detail, but first you have to know
where to look. Pooling the genetic information from such a large
population is what allowed us to look across the genome for possible
culprits in AMD, even very small, very rare ones.”
The researchers have now discovered a total of 52 genetic variants
that are associated with AMD. These variants are located among 34 loci,
16 of which had not been previously associated with AMD.
“If you think of these loci as points on our Google map in our search
for the crime syndicate members, or the genetic causes of AMD, in some
cases they are as big as a zip code, but in other cases they pinpoint an
area as narrowly defined as a few houses within a neighborhood
subdivision,” Dr. Swaroop said.
“These variants provide a foundation for genetic studies of AMD going
forward,” said one of the senior authors, Jonathan L. Haines, Ph.D., of
Case Western Reserve University in Cleveland. “The next step is to
investigate what the variants are doing to the genes and how they affect
gene function. Do they turn them on or off? Do they interact with other
genes spurring a series of events along a pathway that leads to 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 that
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.
Additionally, 10 of the variants point to genes involved in
maintaining the extracellular matrix, the nonliving material amongst
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.
“Even with the pooling of genetic information from such a large
population, the variants identified by the international consortium
still cannot account for all of the heritability of AMD,” said Grace L.
Shen, Ph.D., a group leader and director of the retinal diseases program
at NEI. “We are, however, on track for discovering important variant
genes that may play a role in AMD heritability.”
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