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Download Thesis This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ The Genetics and Spread of Amyotrophic Lateral Sclerosis Jones, Ashley Richard Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 07. Oct. 2021 THE GENETICS AND SPREAD OF AMYOTROPHIC LATERAL SCLEROSIS Ashley Richard Jones PhD in Clinical Neuroscience - 1 - Abstract Our 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. - 2 - Table of Contents Abstract .......................................................................................................................................... 2 Table of Contents ........................................................................................................................... 3 Table of Figures ............................................................................................................................. 9 Table of Tables ............................................................................................................................ 11 Acknowledgements ...................................................................................................................... 13 Dedication .................................................................................................................................... 15 Chapter 1 Introduction and Literature Review ............................................................................. 17 1.1 Introduction ................................................................................................................... 17 1.2 Literature review of genetic discovery in ALS .............................................................. 19 1.2.1 Genetic Risk Factors ............................................................................................ 19 1.2.2 Genes identified through family-based studies .................................................... 20 1.2.3 Genes causing atypical ALS identified through family based studies .................. 25 1.2.4 Genes identified through candidate gene association studies ............................. 26 1.2.5 Genes identified through genome-wide association studies of unrelated samples 28 1.2.6 Genes identified through other methods .............................................................. 29 1.2.7 Genes modifying Age of Onset ............................................................................ 30 1.2.8 Genes modifying survival ..................................................................................... 32 1.2.9 Genes modifying onset site .................................................................................. 33 1.2.10 Genes modifying sex ............................................................................................ 33 1.2.11 Summary .............................................................................................................. 34 1.3 Literature review of disease spread and gene expression .......................................... 35 1.3.1 Disease spread .................................................................................................... 35 1.3.2 Disease-spread using health states ..................................................................... 38 1.3.3 Gene expression analyses ................................................................................... 39 1.3.4 eQTL analyses ..................................................................................................... 41 1.3.5 Summary .............................................................................................................. 42 Chapter 2 Genetic analyses using genotypes: ATXN2 and PLCD1 ......................................... 43 2.1 Introduction ................................................................................................................... 43 - 3 - 2.1.1 ATXN2 .................................................................................................................. 43 2.1.2 PLCD1 .................................................................................................................. 44 2.2 Methods ........................................................................................................................ 45 2.2.1 Sample population................................................................................................ 45 2.2.2 UK Sample Collection .......................................................................................... 46 2.2.3 UK Genotyping ..................................................................................................... 47 2.2.4 Genotype Statistical Quality Control .................................................................... 47 2.2.5 Phasing and imputation ........................................................................................ 47 2.2.6 Association and haplotype analyses .................................................................... 48 2.3 Results ......................................................................................................................... 49 2.3.1 ATXN2 .................................................................................................................. 49 2.3.2 PLCD1 .................................................................................................................. 50 2.4 Discussion .................................................................................................................... 51 2.4.1 ATXN2 .................................................................................................................. 51 2.4.2 PLCD1 .................................................................................................................. 52 2.4.3 Summary .............................................................................................................. 53 Chapter 3 Residual association at C9ORF72 ........................................................................... 55 3.1 Introduction ................................................................................................................... 55 3.2 Method ......................................................................................................................... 56 3.2.1 Sample collection ................................................................................................
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