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Large-Scale Gene Study Identifies Clues about Sporadic ALS


For release: Tuesday, April 3, 2007

Researchers at the National Institutes of Health (NIH) have completed the first large-scale study of the role of common genetic variation in sporadic amyotrophic lateral sclerosis (ALS), which occurs in people without any family history of the disease.  The results provide interesting hints about the causes of the disorder and can serve as a starting point for future studies.

"The work shows there is no single gene out there which causes most of sporadic ALS, but we now have many leads to follow," says Bryan Traynor, M.D., of the National Institute of Mental Health (NIMH) at NIH and The Johns Hopkins University School of Medicine, who led the study in collaboration with researchers at the NIH's National Institute on Aging (NIA) and other institutions.  The work was also funded in part by the National Institute of Neurological Disorders and Stroke (NINDS).  The results appear in the April 2007 issue of Lancet Neurology.[1]

ALS, also called Lou Gehrig's disease, is a devastating neurological disease which causes progressive muscle wasting and paralysis.  The disease kills about 10,000 Americans a year.  About five percent of people with ALS have known genetic mutations, but the cause of the majority of cases is unknown.  Many researchers believe that sporadic ALS results from a combination of genetic vulnerability and exposure to environmental factors that may trigger the disease.

"Sporadic ALS looks much like familial ALS, so we had hoped the genes would be the same," says Dr. Traynor.  "However, this is not the case.  The five familial genes identified so far don't seem to cause much or any of the sporadic ALS we see."

The researchers studied blood samples of 276 people with sporadic ALS and 271 people with no neurological disease.   They looked at 555,352 gene variations called single-nucleotide polymorphisms, or SNPs, in the blood samples and found 34 SNPs that might be linked to an increased risk of ALS.  Each SNP represents a variation of one DNA base, or letter, in a gene.  These variations are found throughout the human genome.  Some SNPs affect gene function, but many others do not.

The blood samples used in this study were obtained from the NINDS Human Genetics Resource Center at the Coriell Institute (http://ccr.coriell.org/ninds), a publicly funded "bank" or repository for human cells, DNA samples, clinical data, and other information that aims to accelerate research on the genetics of nervous system disorders.  The samples were collected by the ALS Research Group, a group of investigators who helped create a large ALS DNA, cell line, and data bank to serve as a public resource to the scientific community. 

The samples and data from the new study are now freely available from the NINDS repository and can serve as valuable resources for future studies.

“The collections in the NINDS repository are on the cutting edge of genetics, because the public sharing of biological samples and data is simple and broad.  It allows every contribution made by a patient to yield the maximum knowledge possible, while protecting privacy in a standardized, reliable fashion,” says Katrina Gwinn, M.D., of the NINDS. 

The study was made possible by a new technology called "SNP chips."  These chips are glass slides with 12 million microscopic beads that react with specific sequences of DNA or RNA.  "With these chips, we can measure 555,000 SNPs in 3 days, whereas with the old technology, it would take something like 30 years," Dr. Traynor explains. 

Several of the SNPs identified in this study were associated with genes that affect the cytoskeleton, or network of filaments that gives cells their structure and helps them respond to signals.  Another of the SNPs is near a gene that affects neurons' ability to form connections.  Since axons from motor neurons are often several feet long and very thin, it makes sense that cytoskeleton proteins have to be working correctly for the motor neurons to function, Dr. Traynor notes.  However, the associations between these genes and sporadic ALS need to be confirmed by other studies, he adds.

"If you roll dice 555,352 times you are bound to get lucky by chance alone on some of those throws. The next step is to go back and figure out which of these "hits" are real and which are false," says Dr. Traynor.

While the 34 gene variations identified in this study appeared to be the most promising leads for future research, thousands of other gene variations might turn out to be important after further analysis, the researchers note.

The researchers are now planning to replicate the study using samples from the European population.  Combining the data from the two studies will improve the odds of detecting gene variations that are important in ALS.  The ultimate goal of these studies is to find an effective treatment for the disease.  "The better we can understand what causes the neurons to die, the better we can understand how to fix it," says Dr. Traynor. 

The NIMH, the NIA, and the NINDS are components of the National Institutes of Health (NIH) within the Department of Health and Human Services.  The NIH — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research. It investigates the causes, treatments, and cures for both common and rare diseases.  For more information about NIH and its programs, visit http://www.nih.gov.

-By Natalie Frazin

[1]Schymick JC, Scholz SW, Fung H-C, Britton A, Arepalli S, Gibbs JR, Lombardi F, Matarin M, Kasperaviciute D, Hernandez DG, Crews C, Bruijn L, Rothstein J, Mora G, Restagno G, Chio A, Singleton A, Hardy J, Traynor BJ.  "Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls."  Lancet Neurology, April 2007, Vol. 6, No. 4, pp. 322-328.

Last Modified April 3, 2007