August 30, 2006

New variants of CFH gene show stronger association with AMD

Non-coding DNA may be the cause of multi-gene disease

ANN ARBOR, MI - Following reports a year ago on a gene variant strongly linked to age-related macular degeneration (AMD), a team of University of Michigan scientists has identified 20 variants of the same gene that show an even stronger association with the disease. In the September issue of Nature Genetics, the U-M team also reports that the non-coding DNA around the gene may be the primary source of the trouble.

A team led by Michigan researchers Gonçalo Abecasis, Ph.D., and Anand Swaroop, Ph.D., looked at 84 genetic differences in and around the Complement Factor H (CFH) gene in 726 patients with AMD and in 268 unaffected people. The study included 235 pairs of relatives, including siblings, and parent-child pairs.

Age-related macular degeneration is the leading cause of blindness in Caucasians, affecting about 20 percent of those over age 80, and is known to be hereditary. The disease involves a loss of central vision that makes reading, driving and recognizing faces increasingly difficult.

“The Complement Factor H gene is an extremely important gene,” says Swaroop, the Harold F. Falls Collegiate Professor of Ophthalmology and Visual Sciences, who authored several reports on AMD genes and identified the region around CFH as a major site of disease. “We simply needed a closer look at what is actually happening around that gene.  Perhaps these new variants cause disease by regulating levels of activity or expression of the gene, or perhaps they affect other genes,” he says.

None of the 84 genetic variants studied seemed to account for macular degeneration by itself. Instead, the variants seemed to make multiple, distinct contributions. The researchers found that variants appeared to be organized into one of four common combinations, called haplotypes. Two of the haplotypes were found to increase disease susceptibility and two decreased it (perhaps providing protection from disease). There was also an array of relatively rare haplotypes that didn’t fit neatly into one of the four groups and which were also associated with increased susceptibility.

What the researchers infer from this pattern is that there are multiple changes of DNA in the region of the CFH gene that can lead to disease susceptibility and that, because they are non-coding regions of the DNA, may be involved in some sort of regulatory function.

“There’s probably more than one way to get to macular degeneration,” says Abecasis, associate professor of biostatistics in the U-M School of Public Health. He observes that AMD is a multifactorial disease, meaning it is caused by multiple genes that may interact in many unknown combinations to cause the disease.

Multigenic disorders are the next great frontier of medical genetics, but they’re difficult to study and often the genetics vary from one affected individual to the next. For example, not everyone with a CFH gene defect will develop AMD. Age-related macular degeneration is one of the few multigenic disorders for which a set of susceptibility genes has been identified.

“Single-gene disorders almost always involve a broken protein,” Abecasis says. “We wondered if we would find the same thing in a multigenic disease.”  Abecasis says that the latest research has changed the way we and others are thinking. “It comes out to be a much more complicated picture genetically,” he observes. “Macular degeneration has become the model system for studying multigenic diseases.”

The complexity of these genetic factors has implications for therapeutics, observes Swaroop.  Excitement over the discovery of CFH has led some to begin talking about therapeutic approaches for AMD, but it is still a little early, he says. “Within the next year, we should have a much better idea of how CFH and several other AMD genes together cause the disease.”

The study was supported by grants from National Institutes of Health, The Foundation Fighting Blindness, and the Sramek Foundation.


Citation:  CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration

Advance online publication:

# # #

Written by Betsy Nisbet

Last Modified: Monday, 28-Mar-2016 13:28:06 EDT