People often talk about HD in black and white terms: You either have the gene or you don’t. If you do, people say that your ‘repeat length’—the number of extra CAG segments in your HD gene—determines how early or late you will get signs and symptoms of the disease.
But HD is not really that simple. Two people with identical repeat lengths may wind up with very different HD experiences, and one might start to be affected years or even decades later than the other. That difference means that something else—other human genes and environmental factors (like lifestyle, diet, environment, etc.)—must be partly determining the ‘age of onset’. And the fact that identical twins with HD tend to become sick at almost exactly the same age implies that genes are playing a big role.
To understand this better, an international team of researchers is analyzing how the other genes in our DNA influence the course of HD, speeding it up or slowing it down and changing the age of onset. “Our study is aimed at finding those genetic factors that make onset even earlier or later than you’d expect based on the length of the CAG repeat,” says Jim Gusella, PhD, director of the Center of Human Genetic Research at Massachusetts General Hospital in Boston, USA. Gusella was part of the consortium that identified the HD gene in 1993 and is now central in this new era of research.
Why Other Genes Matter
Your CAG repeat length—the number of extra repeated segments in the HD gene—is related to when you first have symptoms, but it only accounts for about half of the variability in the age of onset of HD. So if one person is first diagnosed with HD-related movement problems at age 48, and another first gets symptoms at 63, only about half of that 15-year difference can be chalked up to the differences between their CAG lengths. The other half of the difference must be due to other genes and factors such as sleep, diet, exercise, stress levels, and so forth, that are currently being investigated.
If the international team that Gusella is part of can identify genes that postpone symptoms of HD, that will mean two things. For one, it shows that changing the course of HD is possible. Second, identifying genes that delay the onset of symptoms could open up new areas of human biology that could possibly be altered to postpone HD, perhaps for a long time. “You may be able to design a drug that does that same thing, but has a much bigger effect,” Gusella says.
It’s no simple matter to identify the genes that are most important because many different genes probably have small positive and negative influences on the age of onset. Just by chance, any one person likely has a few that postpone symptoms and a few that hasten symptoms. “You have to scan all the variations in an individual, and compare them in a large number of individuals to find the regions that correlate well,” says Gusella. Since 2008, the researchers have analyzed millions of small variations in 4,000 people with the HD gene—including volunteers from REGISTRY, the study that preceded Enroll-HD in Europe—to look for patterns in genetic variation in people who have an early or late age of onset. They’re casting a wide net, looking across the whole genome.
With this data they’ve zeroed in on 46 regions of the human genome that have variations that seem to be connected to the age of onset. Other groups are also trying to understand how these regions might affect the health of people with the HD gene. The next phase of research will narrow it down further. “We’re in the process of hunting down the exact genes,” says Seung Kwak, PhD of CHDI. They’re now analyzing samples from at least another 4,000 people, and intend to include more in the future—including samples from Enroll-HD participants.
The payoff for this project is potentially huge: knowing what already affects the way HD unfolds, in real life and in living human beings. Rather than rely on tests in mice or other animals, this approach learns from the experiment that nature has already conducted, says Kwak. “There’s nothing better than knowing what actually slows the disease in people,” agrees Gusella.
For more about the study, read the story published in July at HDBuzz.
This story was originally published in the Spring 2015 issue of Enroll!