New research identifies genetic region influencing age of ALS onset

The International Consortium on Amyotrophic Lateral Sclerosis Genetics (ALSGEN), which is funded in part by the Robert Packard Center for ALS Research, has identified eight new genetic regions of interest associated with ALS and six regions associated with age of ALS onset. Identifying these genetic contributions is important, scientists say, because it may help bring about better understanding and treatment of ALS.

"This is an interesting genetic discovery with broad implications for all ALS patients. The researchers identified a genetic locus that may predict how disease progresses in all forms of ALS. We now need to identify the gene(s) in this area of the genome that affects the age of ALS onset. That information will be critical in the identification of critical factors that we can modify pharamcologically to slow ALS," said Piera Pasinelli, Science Director for the Robert Packard Center for ALS Research at Johns Hopkins, and a neuroscientist at Thomas Jefferson University in Philadelphia.

ALS, also known as Lou Gehrig's Disease, is a neurodegenerative disease that affects motor neurons, which control muscle movement. As the disease progresses, people lose their ability to walk, talk, breathe, and swallow.  Currently, there is no cure, and people generally survive only 2 to 5 years after diagnosis.

Over the past decade, scientists have made significant progress identifying some of the genes linked to familial ALS, which is the inherited form of the disorder. Approximately 90 percent of ALS sufferers have the sporadic form of the disease, and researchers have struggled to identify genetic factors that influence who develops the disease and when. ALSGEN began to tackle this problem by combining data from previous ALS genetic studies to increase the chances that smaller genetic risk factors would be identified.

Using DNA from 4,243 ALS patients and 5,112 controls gathered from 13 different cohorts from across the United States and Europe, ALSGEN researchers scoured their genomes for areas that were associated with the development of sporadic ALS and the age at which the disease first developed. The researchers identified eight regions across the genome that were associated with the development of ALS, but the strongest association was in a region of chromosome 1 (1p34.1) that affected age of onset. ALS sufferers who carried a particular genetic marker in this area were, on average, 2.5 years younger when symptoms of ALS began to appear (56.5 years in those carrying the marker, compared to 59 years in those without).

Researchers hope to use future studies to zoom in on the specific genes influencing ALS onset, and determine the cellular pathways through which they operate. As the current study did not specifically measure disease progression, ALSGEN scientists say that they would like to see whether people who develop ALS earlier have a faster disease progression and how long they survive. The scientists also want to identify any environmental factors that influence age of onset.

"Unravelling the genetics of Lou Gehrig's  disease is essential to our understanding of how the disease works and ultimately provides targets for the development of treatments designed to slow progression. The current research represents an important first-step in understanding the sporadic form of the disease, and sets the stage for larger follow-up studies in the future," said Packard scientist Bryan Traynor, a Investigator and Chief of the Neuromuscular Diseases Research Unit at the National Institutes of Health.

Financial support for this work came from the Robert Packard Center for ALS Research at Johns Hopkins University, theALS Association, Microsoft Research, and the Intramural Research Program of the NIA and NINDS. Analysis and computing resources were provided by the Wake Forest School of Medicine Center for Public Health Genomics.