Science Editor

A multinational team reported results yesterday from the largest genomewide association study to date looking at genetic risk factors underlying multiple sclerosis (MS). The study, which looked at nearly 10,000 individuals with multiple sclerosis and more than 17,000 healthy controls, has confirmed most of the 26 potential risk genes identified to date, and found an additional 29 variants that correlate with risk. The results were published in the Aug. 11, 2011, issue of Nature.

The fact that MS has a genetic component has long been clear, but identification of the specific genes involved has been slow in coming.

After an association with HLA genes was identified in 1972, senior author Alastair Compston, professor of neurology at the University of Cambridge, told reporters at a press conference announcing the findings there was "complete radio silence for 35 years, where nothing else was learned" about the genetic underpinnings of the disease until 2007.

In 2007, two more risk genes were identified; and since then, there have been "a trickle of studies" identifying 26 possible risk genes in all. The study now published in Nature, Compston said, brings that number "from 26 possibles to 57 certainties."

The team estimated that the variants they have identified account for 20 percent of all genetic risk. It's a fuzzy number, since it's unclear just how much of the total risk for developing MS is genetic.

But the study's value does not come from the number of genes, or the percentage of total risk, it has identified.

For one thing, it allows researchers to look directly at patients to better understand the disease. The MS research agenda, Danny Altmann, of the Wellcome Trust, told reporters, has to some extent been driven by mouse models. "A paper like this marks a shift, where we can start to get insights from human patients themselves."

For another, Compston said, the pathways that are implicated by the 57 genes "tell a very coherent story," and it is a story that "puts immunology" – and in particular, T cells – "right at the front end of the disease, unambiguously."

Over time, there are clearly several different things that go awry in multiple sclerosis. The disease is characterized by inflammation, degeneration and a lack of repair processes. One of the major current scientific debates, though, is which of those aspects originally goes wrong.

The current debate is around "which is more important: inflammation or degeneration," Compston said. His team's results strongly favor the idea that "This disease begins with inflammation, and everything else follows."

The findings do not revolutionize the concept of what multiple sclerosis is. "Is this brand new; is this a Eureka moment? The answer to that is no," Compston told reporters, with refreshing honesty.

But, he added, the work is still much more than "just a catalog" of variants that amount to little more than a list of unvalidated drug targets.

Peter Donnelly, of the Wellcome Trust, added that, "a somewhat overused analogy, but not unhelpful," would be to think of the study as providing more pieces of a large and complex jigsaw puzzle. "They don't give you the whole picture from the jigsaw. But there are enough of them that if you look carefully" one can draw out the key role of some of the biology.

One piece of that biology is how MS relates to other autoimmune diseases. More thab a third of the genes identified in the new study are also known to be involved in other autoimmune diseases.

Those relationships, Donnelly told reporters, will be "a pretty exciting story to develop over the years ahead. . . . We're just at the relative early stage . . . in understanding the similarities and the differences between each of those diseases in terms of the genetic part of their risk."

The primary motivation behind the study was not to find new drug targets, but rather to gain a deeper understanding of what's going on in MS that can then drive further research. But the findings do validate the current treatment approaches, which are focused on the immunological component of the disease.

Compston said that over time, MS treatments have become more effective, but can also have more severe side effects. This in turn has led some to argue that targeting the degenerative or repair aspects of the disease offers a better chance at developing more effective and safer treatments.

"What this study does," Compston said, "is to say, 'Yes, this is the right approach . . . press on in this direction.'"