New insights into MND: 5 more genetic variants found

New insights into MND: 5 more genetic variants found

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A recent study has assessed the extent to which genetics plays a role in the development of MND, in both familial and non-familial (sporadic) forms of the disease.

This research has arisen as a result of an international collaboration of several research institutes, many of whom have been supported by the MND Association. The world-class institutes involved in the study included the Sheffield Institute of Translational Neuroscience (SITraN), the Euan Macdonald Centre for MND research in Edinburgh and the UMC Utrecht Brain Centre in the Netherlands. Collaborations between specialist research institutes, such as those mentioned above, play a huge role in helping to drive MND research forward through sharing their expertise and resources.

Studies so far have found several different genetic changes that are associated with the development of MND, but these changes are only able to explain the genetic connection to the disease in a small number of people living with MND – not all people with the genetic changes go onto develop MND. This study aimed to find out if there are novel changes within DNA that could increase susceptibility to developing the disease. This could have a huge impact on the development of new gene therapies which target these specific genetic changes and potentially provide more opportunities for clinical trial involvement in the future.

What did they do?

This study is the largest Genome-wide Association Study (GWAS) to be conducted into MND so far. This massive study would not be possible without the generous donation of DNA samples from people living with MND across the world, which included samples from the MND Association UK MND Collections biobank and genetic data collected by the Project MinE gene-hunting consortium.

GWAS involve researchers analysing the ‘blueprints’ of a group of people to obtain information about their genetic make-up (DNA) in relation to a certain disease or characteristic. They help researchers to see how DNA might vary between individuals in the group, due to changes in genes, and the effects that these changes may have on the disease or trait being studied.

The team of researchers analysed the genes of an incredibly large number of people; over 29,000 people with MND and over 122,000 individuals without MND. The huge sample size being analysed in this study provides a very good picture of the different gene changes that may be related to the risk of developing the disease. The individuals without MND acted as control samples to allow comparisons to be made between any genetic changes seen in those with MND and those without.

The study team categorised any genetic changes seen into one of three groups:

  1. Rare variants – changes in genes that aren’t seen very often
  2. Repeat expansions – changes in a gene that mean that a small section of the genetic sequence is repeated many times
  3. Regulatory effects – changes in one gene that cause the action of another gene to be disrupted.

MND is referred to as a ‘multifactorial’ disease meaning there is no single cause, but a combination of genetic and environmental factors increases the risk of developing the disease. As well as looking for new genetic changes that may contribute to the development of MND, the researchers used the data to help them study some of the environmental or lifestyle risk factors that may increase the risk of developing MND.

What did they find?

This study confirmed links between 10 previously known gene variants associated with MND development, including changes in the SOD1 and C9orf72 genes. The researchers were also able to identify a novel variant in the NEK1 gene. This gene had been previously associated with MND via a rare variant, which was not found in many people with the disease, but here they found a more common variant in the NEK1 gene.

This GWAS also revealed 5 new gene variants that are associated with an increased risk of developing MND. These changes were found to occur in the HLA gene, SLC9A8/SPATA2 gene, ERGIC1 gene, COG3 gene and PTPRN2 gene.

Interestingly, some of these genetic changes have also been found to be associated with other neurodegenerative diseases. The 15 different gene variants identified in this study were cross analysed with gene variants already associated with the development of Alzheimer’s disease (AD), Parkinson’s disease (PD), progressive supranuclear palsy (PSP) and Frontotemporal Dementia (FTD). Cross analysis showed that there are genetic correlations between MND and these other neurodegenerative diseases, with a high probability of shared genetic risks with Alzheimer’s and Parkinson’s.

The lifestyle risk factor portion of this study investigated any possible links between environmental factors and MND development. There were 22 total risk factors that were assessed in this study, including Body Mass Index (BMI), smoking, alcohol consumption, physical activity and cholesterol.  Results showed that cholesterol levels had a stronger link to the development of MND than any of the other environmental factors assessed, and the study concluded that higher cholesterol levels may have a causative role in MND. However, a previous study that has looked into the link between cholesterol and risk of developing MND has suggested that high cholesterol levels may reduce the risk. Due to conflicting findings, more research is needed into whether high cholesterol levels do play a role in MND and how they may lead to developing the disease. The biological pathways linked to this may serve as potential targets for therapeutics if it can be confirmed that high cholesterol levels are involved in MND.

What does this mean?

MND research is becoming increasingly focused on the role that genes play in the development of the disease and how gene therapies may provide more personalised treatment options for people with MND in the future. Several gene therapies for MND are currently being researched, with many of these targeting the 10 gene changes that had previously been found and were confirmed in this study. While this study has made a very important discovery in terms of MND and genetics, further research will be needed to assess exactly how these 5 new gene changes may result in damage to the motor neurons so that gene therapies specific to these variants can be designed and trialled.

Gene discoveries can help researchers determine what biological pathways and systems are involved in causing MND. As we learn more, better treatments can be designed and if needed, target them at specific groups of people. Understanding how people with MND could be better sub-grouped will also help trial outcomes.

The study here found a relationship between high total cholesterol and a risk of developing MND, but this does not necessarily affect disease progression. Before any advice on treatment or preventative strategies can be given, further studies will be required to help determine if and how high cholesterol plays a role.

This study also prompts further collaboration across the field of neurodegenerative diseases as gene therapies for other conditions may be of use in MND research as well. Bringing the international network of researchers and patients together will accelerate our understanding of MND and the search for a cure.


Paper published on medRxiv (15 March 2021): Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology


The MND Association’s vision is a world free from MND. Realising this vision means investing more in research, further developing partnerships with the research community, funding bodies and industry, while ensuring that advances in understanding and treating MND are communicated as quickly and effectively as possible. Our Research Development team, composed of 11 members, work hard to achieve this. Principally, the Research Information team within this are involved in communication activities including this MND Research blog.