New Genetic Research in Macular Degeneration: The International AMD Genomics Consortium

Photograph of a retina with wet age-related macular degeneration

The International Age-Related Macular Degeneration (AMD) Genomics Consortium, which includes 26 centers worldwide, has published new data and information about the role of genes and their contribution to the risk of macular degeneration. Previously, researchers had identified 21 regions of the human genome – called loci – that are associated with an increased risk of AMD.

The new research, published in Nature Genetics, increases the number of loci to 34. Also, for the first time, the researchers have identified a gene variant specific to the neovascular (or wet) form of AMD, which may help in uncovering the reasons why therapy for this form of AMD is effective for some people but not for others.

[Editor’s note: The human genome refers to the complete set of genes contained in the human body. “Loci” is the plural of “locus” or “location” and refers to the regions/locations, scattered throughout the human genome on many different chromosomes, that are associated with an increased risk for AMD.]

About the Research

The study, entitled A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants, was published online on December 21, 2015 and authored by the AMD Genomics Consortium, with Lars G. Fritsche as lead author. The complete list of contributors and their affiliations can be found at the Nature Genetics website. Nature Genetics publishes current genetic research, with an emphasis on the genetic basis for common and complex diseases.

The AMD Genomics Consortium is a network of international investigators, representing 26 centers worldwide, supported by the United States National Eye Institute (NEI), a part of the National Institutes of Health. The current study, which represents the most comprehensive genome-wide analysis to date of genetic variations associated with AMD, was made possible by a number of prior genetic research breakthroughs, including immune system research and AMD risk, the Human Genome Project, and the International HapMap Project.

More about Age-Related Macular Degeneration

NEI image of how someone with macular degeneration sees: overall blurriness with a blind spot in the center
What a person with AMD sees

Age-related macular degeneration (AMD) is gradual, progressive, painless deterioration of the macula, the small sensitive area in the center of the retina that provides clear central vision. The fovea is located in the center of the macula and provides the sharpest detail vision.

Damage to the macula impairs the central (or “detail”) vision that helps with essential everyday activities such as reading, preparing meals, watching television, playing card and board games, and needlework and sewing.

AMD is the leading cause of vision loss for people aged 60 and older in the United States. According to the American Academy of Ophthalmology, 10-15 million individuals have AMD; approximately 10% of people who are affected have the “wet” type of AMD. For more information about vision loss from AMD, see How Does AMD Affect Vision? by Lylas G. Mogk, M.D.

Wet Macular Degeneration (AMD)

In wet, or exudative, macular degeneration (AMD), the choroid (a part of the eye containing blood vessels that nourish the retina) begins to sprout abnormal new blood vessels that develop into a cluster under the macula, called choroidal neovascularization (neo = new; vascular = blood vessels).

The macula is the part of the retina that provides the clearest central vision. Because these new blood vessels are abnormal, they tend to break, bleed, and leak fluid under the macula, causing it to lift up and pull away from its base. This damages the fragile photoreceptor cells, which sense and receive light, resulting in a rapid and severe loss of central vision.

Dry Macular Degeneration

The dry (also called “atrophic”) type of AMD affects approximately 80-90% of individuals with AMD. Its cause is unknown, it tends to progress more slowly than the wet type, and there is not – as of yet – an approved treatment or cure. “Atrophy” refers to the degeneration of cells in a portion of the body; in this case, the cell degeneration occurs in the retina.

In dry age-related macular degeneration, small white or yellowish deposits, called drusen, form on the retina, in the macula, causing it to deteriorate or degenerate over time. These small yellow deposits beneath the retina are a buildup of waste materials, composed of cholesterol, protein, and fats. Typically, when drusen first form, they do not cause vision loss. However, they are a risk factor for progressing to vision loss.

More about the Study

From an International study reveals new genetic clues to age-related macular degeneration, via EurekAlert!:

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.

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 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.

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.”

The Research in Nature Genetics

From the article abstract:

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of more than 12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants distributed across 34 loci.

Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9. Very rare coding variants in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant inSLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

VisionAware will continue to report the results of AMD-related genetic research as they become available. You can read more information about genetic risk factors for AMD at A Nationwide Study Is Investigating Genetic and Other Risk Factors for Macular Degeneration on the VisionAware blog.

Additional Information