An investigation of replicated genetic associations from a genome-wide study of sporadic MND.

We are trying to find genes that make people likely to develop motor neuron disease (MND). This is a wasting disease in which an affected person becomes progressively paralysed over months until they are too weak to breathe.
We know that a few people with MND carry a genetic mutation. For most people with MND we think that certain common genetic variations might increase the risk in certain situations.
MND takes many forms and we do not know if they are really all the same underlying disease or several different conditions that happen to look the same. This makes gene-hunting difficult. Also, even though MND is quite common (about 1 in every 400 people will die from it), life expectancy is very poor and so at any one time there are not many affected people who can help with research.
We have successfully found a genetic signal for MND on chromosome 8 but we now need to pinpoint where the signal is coming from. If we can find out exactly what genetic variation in this area is responsible, we will understand more about MND and this will make it easier to develop a treatment.

Background:
Motor Neuron Disease (MND) is a fatal adult-onset neurological disorder that causes progressive muscle weakness gradually affecting the power of speech, swallowing and limb movement. There is significant disability from the outset and eventually patients are left immobile, unable to communicate or care for themselves. Relentless disease progression engenders feelings of hopelessness so that some people travel abroad seeking euthanasia. The only drug shown to impact on survival, riluzole, has only a modest effect in slowing disease progression and treatment is otherwise largely symptomatic. The mean age of onset is between 50-60 years, cutting short the productive lives of many individuals. Death from respiratory failure usually occurs within 3 years of symptom onset and only 4% of patients survive more than 10 years. Although it is commonly thought of as a rare disease, the lifetime risk is about 1 in 400, with 1 in 380 death certificates carrying this diagnosis in the UK, and since the risk increases with age, it will become more common as the population ages. At present the diagnosis of MND is a death sentence with a miserable disease course, making it one of the most feared illnesses in the developed world.
Previous findings:
In an MRC-funded study, we have performed a genome-wide association study using 300 case and 300 control samples and 2,336 microsatellite markers. The markers were targeted at both gene-dense regions using a method we developed, and at regions previously shown to be of interest in MND. A DNA pooling strategy was followed by individual genotyping of markers of interest. Of the markers analysed, all showed confirmed association in individuals, and one on chromosome 8 showed replicated association in two other populations, from Belgium and the USA.
Objective:
To identify the functional variant(s) associated with sporadic motor neuron disease in the region we have identified on chromosome 8
Methods:
We will analyse the MND-associated region with an informative set of tag-SNPs in UK samples, and fine-map the disease associated locus. We will identify the association peak and identify the strongest positional candidate genes and their functional variants. We will confirm the mapping in Belgian and US populations. This will allow us to examine functional effects of gene variants identified in the laboratory. In parallel with this, we will perform bioinformatics analysis of relevant DNA and protein sequences and expression studies of genotyped brains for secondary evidence (genomic convergence).