NIH Group Finds No Clear DNA Clues to ALS

No significant differences were found in a recent study of 276 people with sporadic (nonfamilial) amyotrophic lateral sclerosis (ALS) and 271 without the disease, says a report issued in February by a large group of U.S., British and Italian researchers.

Jennifer Schymick at the Neurogenetics Laboratory of the National Institutes of Health (NIH) in Bethesda, Md., and colleagues, who published their findings in the April issue of Lancet Neurology, initially identified 34 DNA differences in their ALS-affected versus unaffected blood samples, all of which came from white, non-Hispanic U.S. residents with no family history of ALS. The study was funded by the NIH, the Packard Center at Johns Hopkins University in Baltimore and private organizations.

Among the identified differences were several in genes associated with the cytoskeleton, which is the scaffolding of cells, and genes that influence transport of compounds inside nerve fibers.

The investigators feared, however, that they might have identified “false positives,” meaning differences that appeared to be significant between the two groups actually weren’t. They therefore applied an extremely conservative mathematical procedure to their data analysis, after which none of the differences reached significance.

The MDA-supported Translational Genomics Research Institute (TGen) in Phoenix announced in November at an international ALS meeting in Yokohama, Japan, that it had identified significant genetic differences in the DNA of ALS-affected compared to unaffected study participants. (See “Genome-Wide Search Hits Pay Dirt,” ALS Newsmagazine, January 2007.) This group expects to publish a paper in the near future.

That study, which compared the genomes (all genes) of 1,200 people with and 2,000 people without sporadic ALS, identified some 50 genetic differences in the two groups. Several are related to so-called adhesion proteins, which form molecular glue that holds cells in place.

“I think the two studies can’t be directly compared at this point,” said Sharon Hesterlee, MDA vice president of Translational Research. “The TGen study, which has not yet been published, used somewhat different statistical methods and larger sample sizes. Ultimately, both studies will probably need to be confirmed independently before hard and fast conclusions can be drawn.”