Advancing research in neurodegenerative disease: genome analysis in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is an incurable, terminal neurodegenerative disease characterised by rapid-onset loss of upper and lower motor neurones resulting in progressive paralysis and death from respiratory failure, typically within 3-5 years of symptom onset. ALS is an exemplar disease for the general process of neurodegeneration, as it exhibits most of the features observed across neurodegenerative diseases.

The most common known genetic cause of ALS is a massive hexanucleotide repeat expansion in the gene C9orf72, which causes around 10% of all cases of the disease. Very large-scale genetic studies have attempted to identify novel ALS genes in remaining unexplained cases, but these have been limited in their success as they have principally assessed the contribution of common genetic variation, whereas it is now widely accepted that most of the uncharacterised genetic determinants of ALS risk are very rare.

Recently, a large international genome sequencing initiative called Project MinE was launched with the aim of identifying these rare genetic causes of ALS. The project will ultimately sequence the entire genomes of 15,000 ALS patients and 7,500 healthy control subjects, with the Irish ALS Research Group contributing 1,050 individuals which are funded by both philanthropic donations and other research project grants. The data generated by the project will be analysed together by the Project MinE Consortium, as well as being distributed to the individual research groups that contribute samples and funding to the project for local-level analyses within individual cohorts.

The Institutional Strategic Support Fund will provide support for the necessary storage infrastructure to facilitate these analyses, which will traverse over 100 terabytes of raw data and generate the same again during analyses. This infrastructure will serve as a management platform for these large datasets as well as a test platform before scaling up to national supercomputing infrastructure provided by the Irish Centre for High-end Computing (ICHEC). The research carried out in this project will create a new paradigm for research into the genomics of neurodegenerative disease and will lead to the development of more effective therapies.