In addition to finding many genes that could contribute to the ALS, the researchers believe the study has settled a few important questions about the disease.

Theres a long-standing debate about where ALS originates in the cell, said Johnathan Cooper-Knock, a Stanford visiting scholar and lecturer at the University of Sheffield in the United Kingdom. This new technique has surfaced genetic evidence that really pins down the axon of motor neurons as the place of disease origin. (The axon of the neuron is a long cord that helps transmit electrical signals from one neuron to another.)

A paper describing the study was published Jan. 18 in Neuron. Snyder, the Stanford W. Ascherman, MD, FACS, Professor of Genetics, is the senior author. Zhang and Cooper-Knock are co-lead authors.

Typically, ALS researchers investigate one gene at a time, performing in-depth analyses to tease out if and how that gene might contribute to the onset of the disease. The Stanford teams approach was to cast a net far and wide for genes that may play a role in ALS. Zhang trained the algorithm to sift through millions of data points from studies known as genome-wide associated screens, which contain anonymized genetic information from thousands of patients with and without ALS. The strategy was to look for genetic mutations that often occur in people who have ALS.

The team narrowed the search further: Sorting through ALS patients data, the algorithm looked for mutations only in genes that support motor neuron function. Searching only in motor neurons allowed our approach to discover more risk genes compared with previous methods, Zhang said. The analysis spit out 690 candidate genes, some that were already known to be implicated in ALS.

We can use this information to learn more about how and why motor neurons fail in ALS, Cooper-Knock said. As an example, he added, Many of the genes we uncovered pointed to the disease originating in the axon of the cell, rather than the cell body.

Previously it was not clear if axon defects were an effect of the disease, but our results indicate these defects are likely causative, added Snyder.

One gene, which repeatedly showed up in the data analysis, caught the researchers attention: KANK1, which is involved in functions at the very end of the axon. Through a series of experiments using stem cells and gene editing, the team showed that mutations in this gene lead to loss of a protein called TDP-43 from the nucleus of motor neurons, a hallmark of ALS.

If you were to look in the brains of 100 people with ALS and analyze the motor neurons, youd see this loss of TDP in something like 98, Cooper-Knock said. Its almost the definition of ALS. If this phenomenon isnt occurring, you probably dont have ALS.

The finding is an exciting discovery, but its too early to consider KANK1 a drug target. Zhang said. More research will be needed to determine if reversing the effects of a mutated KANK1 gene can help treat the disease.

The team also plans to do some experimental work on other hits from their dataset to determine whether any of the other hundreds of genes identified in the analysis could lead to ALS pathology.

Other Stanford co-authors of the study are life science researchers Minyi Shi, PhD, and Annika Weimer, PhD.

Researchers from the University of Sheffield; UC San Francisco; the Montreal Neurological Institute; Lund University; the Weizmann Institute of Science; and the University Medical Center in Utrecht, the Netherlands, contributed to this study.

This study was funded by the European Research Council, Health~Holland, the ALS Foundation Netherlands, the National Lottery of Belgium, the KU Leuven Opening the Future Fund, the Kingsland Fellowship, the My Name5 DoddieFoundation, the Wellcome Trust and the National Institute for Health Research.

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Discovery of hundreds of genes potentially associated with ALS may steer scientists toward treatments - Stanford Medical Center Report