February 20 , 2007
EARLY NEWS FROM FIRST LARGE SEARCH FOR SPORADIC ALS GENES
Packard Center researcher, support, helps key study.
The largest-scale search for genes that underlie sporadic amyotrophic lateral sclerosis (sALS), the most common form of the disease, has crossed its first hurdle with the successful compiling of genetic information on more than 550 patients and controls.
The data from this first phase have revealed 34 gene changes that may possibly be linked to the risk of having sALS. Following phases will verify that, as well as add new data from larger populations.
“This is the first major step in finding how genetics may influence the form of ALS that affects most patients,” says Jeffrey Rothstein, Packard Center director. “It’s an important starting point, not only for understanding sALS but also for providing specific enough tools to find therapies.”
Researchers in the study, supported by The Packard Center for ALS Research at Johns Hopkins, the National Institute of Neurological Disorders and Stroke (NINDS) and the ALS Association published their initial results online this week in the journal, Lancet Neurology.
In keeping with their desire for worldwide collaboration in the next phases of this gene search, the scientists have made study data freely available through the Coriell Cell Repositories web site. (The Repository is a largely NIH-sponsored bank of patient DNA and cell cultures.)
Packard Center grantee Bryan Traynor and John Hardy, both with the NIH, led an American team of researchers in this first phase of the million-dollar project. Data from an equally-large Italian arm of the study will be added later. “If all goes well,” Traynor says, “the work will clarify the role of genes that’s 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.”
In the study, DNA was collected from patients and healthy controls and successfully scanned in signpost regions called single nucleotide polymorphisms, or SNPs. The idea was to find if specific, distinctively patterned SNPs appear more frequently in those with the disease than those without it.
The 34 distinctive SNPs that came out of the study so far “represent only the tip of the iceberg,” says Traynor. “Thousands of others that are less significantly associated with ALS may ultimately turn out to be just as important.”
Critical to the work—known as a high resolution, genome-wide association study—is its technology. It’s a high-throughput approach (that is, it treats many samples simultaneously) that uses robotics and just-available gene finder chips to mine each patient’s DNA for information with a speed and accuracy not possible 12 months ago.
This first phase, which began last spring, was completed in record time, reflecting the highly collaborative nature of the involved scientists and clinicians. The NINDS, for example, contributed the American samples in the study from among those that ALS clinicians at multiple medical centers nationwide sent to the Coriell repositories.
In the decade since discovering the cause of some inherited forms of ALS—namely, a mutation producing a flawed version of the enzyme superoxide dismutase (SOD1)—a handful of other ALS-related mutations have been brought to light.
The genetic underpinnings of sporadic ALS, however, are far less certain. Sporadic ALS, affecting 90 percent of ALS patients, apparently arises spontaneously without family history. Even though the disease is clinically indistinguishable from the ALS that runs in families, different genes may be responsible for each. Something is held in common, however, in the way that they both kill motor neurons. An added benefit to the new work, then, is that gene changes identified sALS can help understand the heritable forms.
