AbstractOur knowledge of the genetic contribution to Amyotrophic Lateral Sclerosis (ALS) is rapidly growing, and there is increasing research into how ALS spreads through the motor system and beyond. This thesis examines how genetic and non-genetic factors in ALS influence its spread.
The genetic methods employed were PCR, genotyping, AFLP, DNA sequencing and gene expression. The methods to examine spread were H&E staining, clinical history, age of onset (AOO), survival and health utility. Statistical procedures applied included regression analyses of genetic and non-genetic factors, maximum likelihood estimation of genetic-phenotype variance and health utility, RNA-sequence analyses, and differential gene expression analysis.
I found (A) that variation in the ATXN2 gene contributes to ALS, as does variation in C9ORF72 after correcting for the known C9ORF72 pathological hexanucleotide repeat (HREM). (B) On comparing regions of the spinal cord, patterns of differential gene expression between ALS cases and controls appeared consistent with spread and pathology. Functional annotation clustering revealed these genes were mostly involved in blood vessel and angiogenin-like function, glycoprotein-based activity, and leukocyte activity. (C) A significant proportion of survival variance in ALS could be explained by genetic variance. There were SNPs that predicted survival and AOO, one showing epistasis with the C9ORF72 HREM. (D) When modelling ALS progression using staging and a clinical trial dataset, the time and duration of each stage was statistically predictable. Staging also predicted health utility and other functional and psycho- metrics.
The spread and pathology in ALS spinal cord regions affected gene expression profiles, which is likely a consequence of genetic susceptibility in that region. Indicators of spread, AOO and survival, could be predicted using genotypes. Disease progression was predictable as measured by clinical staging and health metrics. In summary, ALS spread seems to occur at a fixed rate in an individual and is influenced by genetics.
|Date of Award||2014|
|Supervisor||Ammar Al-Chalabi (Supervisor) & John Powell (Supervisor)|