Large ALS Data Analysis Reveals Common Genetic Cause of Disease

Researchers have found that mutations in the NEK1 gene are the most common genetic causes of amyotrophic lateral sclerosis (ALS), accounting for 3 percent of North American and European ALS patients, both sporadic and familial.

The study, “NEK1 variants confer susceptibility to amyotrophic lateral sclerosis,” published in Nature Genetics, was developed under Project MinE, an international collaborative effort to sequence the genomes of ALS patients, and supported by the ALS Association with funds from the popular ALS Ice Bucket Challenge.

Project MinE was started by two entrepreneurs with ALS, Bernard Muller and Robbert Jan Stuit, as an effort to sequence at least 15,000 DNA samples of ALS patients.

This study involved more than 80 researchers in 11 countries, including Ireland, Italy, Spain, U.K., U.S., the Netherlands, Canada, Belgium, Germany, Turkey, and Australia. It included samples from both familial (hereditary) and sporadic ALS, and was the largest study on familial ALS so far.

“This study was only possible because of the collaboration of all of the scientists involved,” John Landers, PhD, professor of neurology at UMass Medical School, and one of the study’s senior authors, said in a press release.

“It is a prime example of the success that can come from the combined efforts of so many people, all dedicated to finding the causes of ALS. This kind of collaborative study is, more and more, where the field is headed,” Landers said.

The investigators examined the genome of more than 1,000 ALS families and found that a large number of these patients exhibited variants of the NEK1 gene. Variants in this gene again came up as overrepresented in a population of more than 13,000 sporadic ALS cases, compared to control samples.

These variations are predicted to result in a protein whose normal function is impaired. In fact, NEK1 has been associated with several neuronal functions, including the maintenance of the proteins that give neurons their normal shape and that are involved in cellular transport, regulation of the mitochondrial membrane, and DNA repair. Disruption of these functions has already been shown to increase the risk of ALS.

“The discovery of NEK1 highlights the value of big data in ALS research,” said Lucie Bruijn, PhD, MBA, of The ALS Association. “The sophisticated gene analysis that led to this finding was only possible because of the large number of ALS samples available.

“The ALS Ice Bucket Challenge enabled The ALS Association to invest in Project MinE’s work to create large biorepositories of ALS biosamples that are designed to allow exactly this kind of research and to produce exactly this kind of result,” she said.

The researchers now believe that a better understanding of NEK1 involvement in ALS may lead to the development of new therapies for ALS patients.