Search for gene search for sporadic amyotrophic lateral sclerosis

May 17 2006

Though it's the more common form of the disease, sporadic Amyotrophic Lateral Sclerosis (ALS), which affects roughly 90 percent of those living with the fatal neurodegenerative illness, has been the one less studied, simply because, unlike familial ALS, no genes have turned up.

This week, however Bryan Traynor, M.D. and John Hardy, Ph.D., scientist-grantees with the Packard Center for ALS Research at Johns Hopkins, are beginning the first in-depth screening for genes that underlie the "spontaneous" illness, which, like all ALS, destroys the motor neurons that enable movement, including breathing.

Hardy and Traynor are researchers in the National Institute on Aging's Laboratory of Neurogenetics in Bethesda, Maryland. Traynor also is a faculty member with the Johns Hopkins School of Medicine.

"In the forest of exciting research that's going on in ALS," says Packard Director, Jeffrey Rothstein, "this is a tall tree. We've been waiting some time for this one."

If all goes well, Traynor says, the work will clarify the role of genes - or lack of it - in sporadic ALS. "That role," he adds, "has long been uncertain. We don't know, for example, if sALS is triggered by a handful of interacting genes or genes plus environment or environment alone. The study aims to clarify that."

The results could strongly shape the search for a cure.

Supported by The Packard Center, the ALS Association and the National Institute for Neurological Disease and Stroke, the investigation stands out for several reasons: it's large enough for trustworthy results, involving close to 1,200 ALS patients and healthy controls. It brings in international scope: half of the study focuses on Italian populations. But most important, its razor-sharp technology - a high-throughput variety that uses robotics and just-available gene finder chips - mines each patient's DNA for information with a speed and accuracy not possible even a year ago. The research should be completed and data interpreted, the scientists say, early next year.

As a plus for ALS researchers worldwide, the raw DNA-based data from the study will quickly be made available online. Scientists expanding the study can add their data, improving accuracy of future research.

Why hasn't such a study gone on before? "Simply put, the technology wasn't available," Traynor explains. The research - known scientifically as a high-resolution genome-wide association study - relies upon spotting unusual patterns in patients' DNA (they're associated with having the disease) that healthy controls don't have or have far less frequently.

The patterns are sets of small variations in the order of the several billion bases that make up human DNA. Everyone has variations, known as single nucleotide polymorphisms, or SNPs (snips). Snips are useful because they can serve as signposts for the real quarry - disease-related genes. They're something like having a few different-colored beads on an otherwise-white necklace. If, say, the red bead always shows up in ALS patients, that's meaningful.

Fortunately, the Human Genome Project identified large numbers of SNPs. And last year, the completed HapMap project helped scientists pick out which are most revealing, i.e. those more likely to be near a gene-bearing stretch of DNA.

In the ALS study, the research team will search the genomes of 276 American sporadic ALS patients, testing them and a like number of controls for some 400,000 SNPs - a fair guarantee that no stretch of DNA will go unnoticed. As a check, the study includes DNA from 276 Italian patients and controls from a DNA bio-bank in Turin, Italy.

Under the logic that the signposts in patients' DNA associate physically near a sporadic ALS-related gene or genes, the study should make finding those genes far easier. "My gut feeling," Traynor says, "is that we'll find several tied to the disease."

"But even if get no associations, that's still a powerful result," he says. "That would suggest sporadic ALS isn't gene-based, that we should focus instead on the environment." If that's the case, the team is well situated. Not only is Italian collaborator Adriano Chio a noted investigator on environmental risk factors of ALS - he recently discovered that Italian soccer players had higher odds of having the illness - but the group also has an ongoing collaboration with a European consortium of ALS registries (EURALS), which actively surveys the populations of Italy, the UK and Ireland (25 million citizens) for ALS cases. To date, EURALS has collected health and lifestyle information on 900 patients and 1,700 controls.

Traynor, a genetic epidemiologist, is part of a project that's already combing registry data for risk factors.

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