Researchers from Project MinE have identified 15 genetic risk profiles for Amyotrophic Lateral Sclerosis (ALS). This leads to important new insights regarding ALS. This study was published in the leading professional magazine Nature Genetics.
This is the largest genetic study in ALS so far and was initiated by Project MinE, a large initiative to track down the genetic basis of ALS, which is coordinated by prof. Jan Veldink. In total, the DNA of almost 30.000 patients and over 120.000 control subjects was investigated. This study was an international collaboration, with researchers from all over the world participating.
15 genetic risk profiles
It has been known for some time that genetics play a significant part in the origin of ALS. Roughly 1 to 10 people with this disease have multiple family members that are affected by ALS as well. Also, with sporadic ALS (when ALS doesn’t run in the family), genetic mutations still can play an important role, especially in designing new treatments for ALS. So far, Project MinE led to the discovery of multiple genes that are related to the development of ALS. Also, researchers were able to confirm the results shown by earlier studies and it seems that the genes that have been marked as rare causes for familial ALS also play a part in sporadic ALS. This helps the development of future gene-based therapies.
Wouter van Rheenen, researcher at UMC Utrecht and first author of the study:
“In our research we find that many of the genetic risk factors are shared with other neurodegenerative diseases like for example Alzheimer’s disease, Parkinson’s, and Frontotemporal dementia. This shows that these different diseases may have similarities regarding the underlying processes. However, with ALS the genetic factors are mostly reflected in one cell type in the central nervous system: the glutamatergic nerve cells.”
These nerve cells use glutamate to communicate with other cells. The specific involvement of this subtype of nerve cells wasn’t observed in other neurodegenerative diseases. Inflammation reactions, as for example shown in Alzheimer’s disease and Multiple Sclerosis, didn’t seem to play a part in getting ALS or not. This helps guide novel therapy developments.
High cholesterol and clearing proteins
“To better understand how these newly discovered 15 genetic risk factors increase the chance of getting ALS, we have looked at the data and to which biological process they are involved. This led to interesting new insights. This is how we discovered that many of these factors play a part in ‘autophagy’ in the cell”,
as Wouter mentions. Autophagia is the process where broken parts of the cell, for example wrongly produced proteins, are cleared. “Besides, we also find cues that a high cholesterol increases the chance of getting ALS. Earlier studies have shown that a high cholesterol may hinder autophagy. So possibly these two processes have something to do with each other. However, more research is needed to know how this process works. It is too early to state that cholesterol is a way to prevent or slow down ALS, it can even have adverse events, so we do not advise to actively lower blood cholesterol as a result of this study.
These new results are an important step in the search for novel treatments for ALS. However, researchers emphasize that if someone is carrier of (one of) the genetic factors, this definitely will not always lead to ALS. Therefore, there is no need to undergo genetic testing because of these results. These results mainly provide new clues to start developing new treatment strategies.
- The publication of this scientific article is ‘open access’. Click here to download it for free.
- Click here to read the elaborate English summary of the magazine Nature Genetics.
van Rheenen, W., van der Spek, R.A.A., Bakker, M.K. et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet 53, 1636–1648 (2021). https://doi.org/10.1038/s41588-021-00973-1