Three studies point to same risk gene for age-related macular degeneration

NIH-funded research helps unravel the biology of AMD

News Brief

Three studies reported in Nature Genetics have converged on the same gene as a rare, but powerful risk factor for age-related macular degeneration (AMD), a common cause of vision loss in older people.

AMD involves damage to the macula, a part of the eye’s retina that is needed for sharp central vision. The causes of the disease are complex, with aging, genetics, diet, and lifestyle factors such as smoking all playing a role. Together, these factors are superimposed in ways that aren’t fully understood.

The new research, which was funded in part by the National Institutes of Health, solidifies a link between AMD and genes encoding the complement system, a set of proteins that plays a central part in immune responses and inflammation. In particular, the findings bring a gene called C3 into the spotlight.

“Genetic studies to date have shown that the complement system plays an important role in AMD. These new studies enhance our understanding of disease mechanisms, and offer further insights into the development of therapeutic agents that may prevent AMD development and progression,” said Grace Shen, Ph.D., director of the retinal diseases program at NIH’s National Eye Institute (NEI), which helped fund the studies.

The complement system is a large group of proteins that work together to trigger inflammatory and immune responses that defend our bodies against infection. It also supports function of the retina by cleaning up old or damaged cells. The system consists of nine complement component proteins, called C1, C2, C3, and so on up to C9. When activated, these proteins can essentially punch holes into bacteria and destroy them. Complement factors H and I (CFH and CFI) are proteins that inhibit the complement system and keep it from attacking the body’s own cells.

The CFH gene was the first gene linked to AMD in 2005. Since then, the disease has been connected to individual differences—or variants—found in 19 regions of the human genome (our entire set of genes). Most of these are common variants, which are small blips in the genetic code that are found in more than one of every 100 people. Nearly all of the common gene variants linked to AMD produce small increases, by about 30 percent on average, in the risk of developing the disease.

The new studies looked for an association between AMD and rare gene variants—those found in less than one per every 100 people. The reason: to provide more specific clues to the underlying biology of the disease.

“Compared to common variants, rare variants are more likely have a larger impact on gene function and on the risk of disease,” said Anand Swaroop, Ph.D., chief of the Neurobiology, Neurodegeneration & Repair Laboratory at NEI.

Another motivation was to round out current knowledge of AMD’s heritability—which is the influence of genetics, as opposed to the environment, on disease risk. “The common gene variants that have been linked to AMD only explain about half its heritability. Rare variants can help fill in that gap and may point to new therapies,” said Johanna M. Seddon, M.D., Sc.M., a professor of ophthalmology and director of the Ophthalmic Epidemiology and Genetics Service at Tufts Medical Center in Boston.

Drs. Swaroop and Seddon were part of independent efforts to identify rare variants linked with AMD. Scientists at deCode Genetics in Reykjavik, Iceland led a third such effort. Each team used an approach called targeted sequencing, looking for variants within the code (or sequence) of select genes, rather than scanning the entire human genome as in past studies. Altogether, the studies examined DNA samples from more than 7,000 people with AMD and an even larger number of people without known AMD.

All three studies identified a single rare variant in the C3 gene that increases the risk of AMD by about 3-fold (or 200 percent). This variant affects a part of the C3 protein that enables it to respond to inhibition by CFH. Two of the studies, but not the Icelandic study, also confirmed a link between AMD and a strong, rare variant in the CFH gene, first identified by Dr. Seddon. In the current research, her group also found a link with rare variants in the CFI and C9 genes.

The research suggests that drugs designed to suppress the complement system, and particularly C3, could be useful against AMD. Such drugs would be a breakthrough for people with the most common form of late-stage AMD, called dry AMD or geographic atrophy. There are currently no effective treatments for this type of AMD.

Dr. Swaroop’s collaborators were Gonçalo Abecasis, D.Phil, at the University of Michigan in Ann Arbor, and Elaine Mardis, Ph.D., at Washington University in St. Louis. Dr. Seddon collaborated with Soumya Raychaudhuri, M.D., Ph.D., at Harvard Medical School and Brigham and Women’s Hospital, and Mark Daly, Ph.D., at the Broad Institute, both in Boston. DeCode co-founder and chief executive officer Kari Stefansson, M.D., led the third study.

This research was funded in part by the NEI intramural research program, and NEI grants EY022005, EY016862, EY009859, EY014448, and EY011309. Funding was also provided by NIH’s Human Genome Research Institute.


Zhan X, Larson DE, Wang C, et al. “Identification of a rare coding variant in complement 3 associated with age-related macular degeneration.” Nature Genetics, September 2013. DOI: 10.1038/ng.2758.

Seddon JM et al. “Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration.” Nature Genetics, September 2013. DOI: 10.1038/ng.2741.

Helgason H et al. “A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration.” Nature Genetics, September 2013. DOI: 10.1038/ng.2740.