Published today in Nature Genetics, the study reveals three new risk genes for ALS and one of these - C21orf2 - increases an individual's risk of developing the dis-ease by 65 per cent. These results could aid the development of personalised treatments for people with ALS by using gene therapy - an approach which involves replacing faulty genes or adding new ones.
One in every 400 people will be diagnosed with amyotrophic lateral sclerosis (ALS) at some point in their lives, yet its causes are largely unknown and effective treatments are therefore lacking.
In ALS, motor neurons in the brain and spinal cord degenerate causing the muscles they control to weaken and waste away. Symptoms normally start in mid-life and eventually affect all movement including swallowing and breathing. Average life expectancy from symptom onset is two to five years.
Variations of the genes we all carry are an important cause of ALS, even though most people do not have an inherited form of the condition. The researchers set out to discover new genes for ALS to find out why the disease develops and how to design new treatments.
Using genetic data from Project MinE, comprising 15,156 ALS patients and 26,224 healthy controls from 15 countries, the researchers combined 'snapshot' genetic information with whole genome sequencing of 1,861 individuals. Whole genome sequencing involves reading every single one of the six billion letters in the human genome. In total 8,697,640 variants across the genome were tested for the risk of developing ALS.
The researchers identified three new risk genes for ALS. One of these, called C21orf2, appeared to be particularly important as a risk factor for ALS. The exact function of C21orf2 is still unknown, but it appears to be part of a system in cells related to their own movement and their internal skeleton. They also found that for any one person, just one or two genes had a substantial effect on whether they developed ALS, which is different from most other conditions in which lots of genes each have a small effect.
Professor Ammar Al-Chalabi from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King's College London, said: 'This tells us that ALS is not the result of a few common gene variations that each contribute a little to the risk. Rather, any one of many rare gene variations contributes a large risk for ALS development. This insight is crucial as it affects the types of treatment strategies that might be effective.'
Professor Jan Veldink from the University Medical Center Utrecht said: 'Most genetics studies in ALS focus on the familial form of the disease. Project MinE is an innovative approach to find genetic causes of all ALS cases. In this study we have found a total of three genomic regions where genetic variation in these regions increases the risk of ALS. One of these regions included a gene named C21orf2. This gene was subsequently shown to harbour rare mutations that directly increase ALS risk. This makes the C21orf2 gene extremely interesting for future studies to shed light on the mechanisms that lead to ALS and possibly future therapeutic strategies.'
Professor Ammar Al-Chalabi added: 'Pinpointing genes which increase the risk of ALS will help us develop new treatments that can stop or improve symptoms of ALS in the future. The more we understand about the genetic basis of ALS, the closer we are to revealing new treatment targets and effective therapies.'
Brian Dickie, Director of Research Development at the Motor Neurone Disease (MND) Association said: 'We are pleased to have been involved since this approach to gene hunting was in its infancy a decade ago. It's so encouraging to see how the collaboration, catalysed by Project MinE, has grown and is now delivering results that will open up new avenues of research across the world.'
The study was funded by the Motor Neurone Disease (MND) Association, Project MinE, the ALS Association and the EU Joint Programme on Neurodegeneration Research through the Medical Research Council (funding of the STRENGTH European consortium).