Most forms of MND are likely to be caused by many small contributory risk factors, including subtle genetic, lifestyle, and environmental influences. In combination, they may ‘tip the balance’ towards someone developing the disease. For the majority of people with MND, genetics plays a subtle role in the development of the disease. However, for 5-10% of people who have the inherited forms of MND (that is, it runs in their family), their genetic makeup is more significant.
Exposure to environmental factors that might contribute to the development of MND has been extensively studied over the years. These studies have identified possible links with prior exposure to mechanical and/or electrical trauma, military service, high levels of exercise, agricultural chemicals, and variety of heavy metals. The evidence obtained in these studies has often been circumstantial or conflicting and there are no clear conclusions. With such limited information it is not possible to provide advice or guidance to reduce the risk of developing MND.
Up to 10% of people with MND have a family history of the disease. This is caused by a mistake in the genes, which is passed down from one generation to the next. A number of the genes responsible for inherited MND have already been identified but it is important to find out why these genetic mistakes occur. This will provide clues to how motor neurones are damaged in MND and may help our understanding of all types of the disease, including MND where there is no known family history (known as sporadic MND).*It is important to know that having one of the genes associated with MND does not necessarily mean the person will go on to develop the disease, although it may increase the likelihood.*
Thanks to the development of a technique called Whole Genome Sequencing (WGS), researchers have been able to read the complete DNA of a person, the genome. A slightly less expensive version of WGS is Whole Exome Sequencing (WES), allowing us to focus just on the genes where the vast majority of changes linked to MND is likely to be found (these correspond to around 5% of the genome). WES ‘sorts out’ all of the protein-coding genes in a genome, called the exome. The aim of WES is to identify genetic variants that alter these proteins. Three new genes have already been discovered to be associated with MND using this technique.
Although it is important to discover genes associated with causing the disease, it is also crucial to identify genes that might affect survival. A number of common gene variants associated with MND survival have been identified through genome-wide association studies (these identify ‘hot spots’ in the genome but they don’t identify the genes responsible for a disease), and other methods such as structural variants.
Structural variation is a difference in the way an organism’s chromosome is built. For example, some parts may have been removed (deletion) or foreign sequences inserted (insertion). The variation is not enough to cause a chromosome abnormality but is enough to make it a likely contribution to disease susceptibility. Genome-wide studies have shown that deletion is the most common variation observed in MND cases.
The following presentations will discuss WES and genome-wide mapping at the Symposium. Find their abstracts using the codes below in Abstracts online:
- C66: Characterisation of a novel ALS-associated candidate gene identified from whole exome sequencing
- C68: Integrating copy number analysis with structural variation detection in whole genome sequenced ALS UK cohort
More abstracts relating to genetics can be found in session 8A.
Epidemiology is the branch of medicine that looks at the potential causes of MND by studying genetic, clinical and lifestyle information from groups of people affected by the disease. It then tries to identify associations between a range of environmental risks, such as exercise, diet and smoking, and aspects of MND such as age at onset, survival, and look for interactions between different risk factors. No one consistent environmental risk has yet been identified. It is thought that a pre-existing genetic flaw, combined with a number of environmental and lifestyle factors, eventually ‘tips the balance’ towards developing the disease. According to researchers, the onset of MND is a six-step process, with genetics and environment both playing a part. More recent thinking is that in familial MND, while environmental factors still play a role, this process is likely to be shortened to fewer steps.
Many dietary features have been studied to establish if these have a role in the onset or progression of MND. Despite much research looking at vitamins, proteins, amino acids and other nutrients, no clear beneficial or adverse effects have yet been identified. Comparing newly diagnosed patients with healthy controls, recent research suggests that a slight risk reduction is seen for decaffeinated coffee, tea, whole bread, raw vegetables and citrus fruits. Eating red meat, pork and processed meat, sodium and zinc was associated with an increased risk. These findings would suggest that some foods and nutrients (including specific vitamins and minerals) are risk factors while others may have a protective effect. Further research that explicitly looks at some nutrients matched with specific genetic tests needs to be carried out before a more definitive answer can be found. This will be discussed at the Symposium.
From all the environmental risks that have been studied, smoking is the only one that is considered a likely risk factor. Although not conclusive, there does seem to be consistent evidence pointing to the association between the number of years exposed to cigarette smoke and MND. It has been seen that for current smokers the odds of developing MND are higher than for people who have never smoked. This association appears to be primarily related to smoking duration rather than smoking intensity. Furthermore, there was a clear inverse relation found between cessation of smoking and risk of MND – that is, the longer the time since a person had given up smoking, the less likely it was that they would develop the disease. This may help form ideas for further research and improve understanding of what causes the disease.
The following presentations will discuss epidemiology at the Symposium. Find their abstracts using the codes below in Abstracts online:
- C56: Presymptomatic lifestyle classified according to C9orf72 genotype
- C57: Genetic mutations shorten the multistep process in ALS
- C58: ALS and food intake in Italy
- C59: The effects of duration and intensity of cigarette smoking on the risk of ALS
More abstracts relating to epidemiology can be found in session 7B.