Phenotype and aetiology of ALS investigated using genetic, environmental, and clinical data analysis

Abstract

The work presented in this thesis uses large-scale data collection and analysis techniques to understand the factors modifying ALS risk and phenotype. I test the hypotheses that overall incidence of amyotrophic lateral sclerosis (ALS) in the UK is similar to previously reported values, smoking is a modifier of disease risk in ALS and SOD1 mutations are modifiers of ALS phenotype.

Amyotrophic lateral sclerosis is a neurodegenerative disease characterised by death or loss of function of upper and or lower motor neurons leading to paralysis. There is currently no cure for ALS, and symptoms are relentlessly progressive with most people dying within 2-3 years of diagnosis, generally of respiratory failure.

ALS has a variable phenotype, with age of onset and progression differing between people. Additionally, although genetic modelling shows that up to 40% of variance in liability could be attributable to environmental factors, these have yet to be established.

Disease risk and phenotype modifiers can only be understood by analysing detailed genetic, environmental and clinical information on large numbers of people, using multiple methodologies.

In this thesis I report an updated incidence estimate for the UK based on data from the newly established MND Register for England, Wales and Northern Ireland. I also present work on whether people in the UK who smoke are at risk increased of ALS by using a novel to ALS methodology to quantify smoking intensity, and follow up with a Mendelian Randomisation study to provide corroboration with our findings. Finally, I present a global study of clinical phenotype in people with ALS who have tested positive for mutations in the SOD1 gene.

We find that ALS incidence in the UK is similar to previously reported values. Smoking is unlikely to be a risk factor for ALS, and that people with SOD1 ALS have a distinct phenotype from those with sporadic ALS.

Date of Award	1 Dec 2021
Original language	English
Awarding Institution	King's College London
Supervisor	Ammar Al-Chalabi (Supervisor)