Five Gene Variations Hike Risk of Macular Degeneration

Just five common genetic variations spread over three genes may explain half of the genetic risk for the leading cause of vision loss in older people, a new multidisciplinary study shows. Depending on a person’s genotype, the risk of advanced age-related macular degeneration (AMD) could be lower than 1 in 100 or higher than 1 in 2.

The dramatic findings provide a powerful tool to predict an individual’s chances of advanced AMD, especially for those at very high or very low risk. Experts predict an emerging epidemic of blindness in countries where people live long enough to develop the late-onset eye disease.

Photo by Graham Ramsay

The unambiguous genetic risk profile developed for age-related macular degeneration by (clockwise from front) Johanna Seddon, Mark Daly, Julian Maller, and Sarah George and their co-authors may be more or less favorable depending on diet, smoking, and weight.

The study also shows how common genetic variations can make a lot of people more—or less—susceptible to disease. In the next few months, results are expected from similarly sizeable analyses of multiple sclerosis, type 2 diabetes, metabolic syndrome, bipolar disorder, autism, premature heart attacks, and rheumatoid arthritis.

“We have to be careful, because not all the people who have a risk genotype will end up with the disease,” said Johanna Seddon, director of the epidemiology unit at the Massachusetts Eye and Ear Infirmary and the principal investigator of the study, which appears in the Aug. 27 online edition of Nature Genetics. “However, once you begin grouping together the four to five different genotypes and have a high-risk variant on all five, you have an extremely high risk of AMD,” said Seddon, also an HMS associate professor of ophthalmology.

Equally encouraging is the precedent these AMD analyses may set for other studies of their kind. “We can take away more general lessons with respect to complex, late-onset disease,” said Mark Daly, HMS assistant professor of medicine at Massachusetts General Hospital and a corresponding author of the study. “There are instances when the idea of scanning the genome for high-frequency but low-penetrance genetic effects makes sense and will actually teach us a substantial amount of disease etiology.”

The Epidemiology of AMD
In about one third of people older than 75, age-related macular degeneration affects a small, thin area of the retina at the back of the eye. The macula transmits the crucial center third of our field of vision and lets us see details, such as the letters in these words, as well as color and fine movement.

To ophthalmologists peering in through enlarged pupils, the most obvious and benign feature of AMD is the lipid, protein, and cellular debris, known as drusen, deposited between two layers of different cell types. Sometimes drusen can evolve into forms of AMD that cause severe vision loss, either from patches of atrophy or cell death (the advanced “dry” form of the disease) or from abnormal capillaries growing under and into the retina (the “wet” form). Such advanced AMD affects six to eight percent of people older than 75 and is the leading cause of blindness. In 2003, people over 75 in the United States numbered 18 million. In 2025, this group is expected to expand to 27 million, with a corresponding jump in AMD.

In the last 20 years, Seddon has identified plenty of epidemiological evidence implicating both lifestyle factors and genes in the risk of onset or progression of AMD. Cigarettes and excess weight, for example, increase the risk of advanced AMD. On the other hand, she found, lutein and zeaxanthin, carotenoids in dark green leafy vegetables, seem to reduce the risk, as do omega-3 fats, found mostly in fish. In fact, the National Eye Institute is launching a randomized clinical trial of lutein and fish oil supplements to see just how effective they are in preventing progression of the disease. But these lifestyle choices are just part of the story. In her twin study of elderly U.S. World War II veterans last year, Seddon discovered that genetics contributes a whopping 46 to 71 percent to the severity of AMD.

Image courtesy of Johanna Seddon

Steps toward disease. Five common genetic variations spread over three genes may explain about half of the genetic risk for AMD. This graph illustrates the 36 different possible risk genotypes from (on the bottom left axis) variations in a coding and a non-coding region of the CFH gene on chromosome 1 and (on the bottom right) variations in the complement component 2 (C2)/ complement factor B (BF) gene region on chromosome 6, and the LOC387715 gene region on chromosome 10. People with the genotype combination represented by the skyscraper in back have 250 times the risk of people with the flatland genotype combination in front.

The two lines of research—lifestyle and genetics—came together in another study by Seddon published this summer, showing that even a well-validated disease gene is not destiny. A higher body mass index or smoking noticeably bumped up the chances of advanced AMD in people with a high-risk gene.

The Next Big Thing
Meanwhile, Daly and his colleagues had been developing a more powerful statistical approach to studying complex human diseases based on the emerging notion that scientists would inevitably find many common gene variations behind many common disorders. This is in contrast to the rare single-gene mutations that drove much of genetic research for so long. But it has been hard to conduct studies on enough people to detect multiple genes having more subtle effects on disease and impossible to genotype enough of people’s genomes to discover the relatively few guilty genes.

Six years ago, Daly discovered a fundamental feature of the human genome and, with colleagues, showed that it could provide a new express lane to screening the whole genome (see Focus, June 7, 2002). Now, this blocklike inheritance pattern of the human genome and the most common variations of the resulting human haplotypes have been mapped and cataloged by the International HapMap Consortium (see Focus, Nov. 11, 2005).

Even with the big accomplishments of the human genome project and the HapMap project, scientists have considered the next step the most difficult—applying the new tools and techniques to the diseases that have resisted genetic analysis for 20 years or more. “This will be an extremely interesting year,” said co-author David Altshuler, a leader of the HapMap Consortium, director of medical and population genetics at the Broad Institute of Harvard and MIT, and HMS associate professor of medicine at MGH. “For the first time, it’s practical to systematically ask the question, How do common genetic variants distribute between people who do and don’t have the disease?”

With its multiple lines of supporting evidence, the AMD genetics story provides a strong endorsement for the common-genes approach. For the latest study, Seddon teamed up with Daly and Altshuler to apply the HapMap tools to a composite of Seddon’s well-characterized AMD study populations. In their paper, they analyzed 1,536 common single nucleotide polymorphisms covering candidate genes in 2,172 unrelated individuals of European descent older than 60. Clinical examinations confirmed that about 1,200 had a form of advanced AMD and about 900 people were free of all signs of the eye disease.

The HMS researchers verified and calculated the relative contributions from four alleles of three genes. The analyses validated common AMD risk variants reported last year by independent research groups. The HMS collaborators also found a novel variant in a noncoding region of the CFH gene. That variant was independently discovered and reported by another group in the same issue of Nature Genetics.

Interestingly, the genes do not appear to interact. Instead, they contribute a cumulative risk. And they seem to increase the risk for both wet and dry types of AMD equally.

In the short run, such information can help select candidates for clinical trials of new therapies. In the long run, the greatest value is to expose the underlying disease mechanisms—such as a problem in the complement immune system—and develop interventions that better prevent or treat AMD. In the clinic, Seddon said, it would be important to advise people with a risk genotype about modifiable lifestyle factors that can reduce their risk of AMD.

—Carol Cruzan Morton

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