The commonest muscle disease that occurs in patients over the age of 45 years is a muscle wasting disease called inclusion body myositis (IBM). Patients typically develop progressive muscle wasting and weakness that progresses and causes marked disability and ultimately death from immobility over the course of around 10 years. There are no effective treatment for patients with IBM. The precise cause of this muscle disease is not known. However, on muscle biopsies from patients there seems to be a combination of some mild inflammation in the muscle and also an accumulation of abnormal proteins, similar to the accumulated proteins that are seen in the brains of patients with neurodegenerative diseases such as Alzheimer's, fronto-temporal dementia and motor neurone disease. Previous research has indicated that there may be genetic factors that predispose people to getting IBM but the previous studies have been quite small and not conclusive. In this research we have brought together experts in IBM from all over the world including Europe, USA and Australia to generate increased awareness of IBM, define diagnostic criteria, collect clinical information and DNA. Over the last three years we have been able to collect the largest group ever of IBM patients and DNA samples - approximately 950 cases and this number will be over 1000 once this study begins. The patient DNA and muscle tissue has been carefully stored for this work. This very large collection of DNA has put us in a very good position to undertake much more detailed genetic studies than have ever been done before to try and work out what the genetic risks factors and genes are that predispose people to this devastating disease. We plan to use the latest next generation sequencing techniques to unravel all the coding variants (those that alter proteins) that are present in 200 IBM patients DNA samples in comparison with 200 patients that are controls with normal muscles. We will analyze the DNA that we have already extracted from patients muscle tissue as this is the best diagnostic group. We will replicate the variants found in a further 700 IBM cases and over 2200 other controls. We are highly experienced in next generation sequencing technology and this has been strengthened by the recent award of a Wellcome Trust equipment grant to purchase the latest next generation sequencer. Recently we have used these techniques to identify the genetic causes of other neuromuscular disorders. In comparison with other disorders like Alzheimer's disease, where proteins are aggregated in the brain as opposed to the muscle as in IBM, the greatest advancement have been made with the identification of disease genes and genetic risk factors. If we can work out what the key genes are and how these disease causing pathways function, we will pave the way for new therapies and treatments to help patients.