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Investigating the Genetic Influence on the Pathological Burden of Multiple Sclerosis / KELSEY ALLEN

Swansea University Author: KELSEY ALLEN

Abstract

Introduction: Permanent disability in multiple sclerosis (MS) is primarily driven by neuronal and axonal loss. While genome-wide association (GWAS) studies have begun identifying genetic variants associated with the clinical course of MS, the variants underpinning pathological severity have not been...

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Published: Swansea, Wales, UK 2025
Institution: Swansea University
Degree level: Master of Research
Degree name: MSc by Research
Supervisor: Howell, O. and Angelini, R.
URI: https://cronfa.swan.ac.uk/Record/cronfa70449
first_indexed 2025-09-22T11:33:48Z
last_indexed 2025-10-02T06:38:59Z
id cronfa70449
recordtype RisThesis
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spelling 2025-10-01T15:49:34.6423647 v2 70449 2025-09-22 Investigating the Genetic Influence on the Pathological Burden of Multiple Sclerosis c49c1106547e0db27312ab4309aa4e48 KELSEY ALLEN KELSEY ALLEN true false 2025-09-22 Introduction: Permanent disability in multiple sclerosis (MS) is primarily driven by neuronal and axonal loss. While genome-wide association (GWAS) studies have begun identifying genetic variants associated with the clinical course of MS, the variants underpinning pathological severity have not been described. Understanding these novel variants and their influence on the clinical course of MS can be used to further develop our knowledge of this heterogenous disease.Aims: To uncover genetic variants and describe the expression of mapped genes that associate with the pathological severity of MS.Methods: Using data from an integrated GWAS expression quantitative trait loci COLOCation (eQTL COLOC) analysis of progressive MS (n = 310), we investigated the association between gene variant status and neuron density, extent of demyelination and retrospectively determined clinical milestones. In situ hybridisation (ISH) revealed gene expression and localisation in a subset of MS and controls (n = 20).Results: Previously described variant rs7289446 (SEZ6L) was not associated with quantitative measures of neuron density, demyelination or clinical outcomes. A 2nd variant mapping to DYSF:CYP26B1 (rs7564433), which represents the first GWAS validated mapped gene (rs10191329), was associated with higher neuron density, lower demyelination, slower disease progression and an older age at death in heterozygote allele carriers (p < 0.05). Independent single nucleotide polymorphisms (SNPs), mapping to PCSK5 and COMMD10, genes not previously linked to MS, were associated with increased neuron density in the thalamus, pons (p < 0.05; PCSK5) and frontal cortex (p <0.05; COMMD10), specifically among heterozygous carriers. The average age of onset was 4.6 yrs lower in COMMD10 major allele carriers compared to heterozygotes.COMMD10 and PCSK5 neuronal and glial expression was elevated in normal MS grey matter (GM) compared to control and lesion GM.Summary: We describe gene variants that associate with neuron density and show the altered expression of mapped genes in MS. Our findings provide insights into biological mechanisms underlying MS severity, offering potential opportunities for targeted therapies and personalised MS care. E-Thesis Swansea, Wales, UK Multiple sclerosis, neuropathology, disease severity, digital pathology 1 9 2025 2025-09-01 A selection of content is redacted or is partially redacted from this thesis to protect sensitive and personal information. COLLEGE NANME COLLEGE CODE Swansea University Howell, O. and Angelini, R. Master of Research MSc by Research 2025-10-01T15:49:34.6423647 2025-09-22T12:26:31.7091771 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science KELSEY ALLEN 1 70449__35158__5cc5a7d340844140a5b5f1ef6312a0b0.pdf 2024_Allen_K.final.70449.pdf 2025-09-22T12:36:02.3322740 Output 3095423 application/pdf E-Thesis – open access true Copyright: The author, Kelsey Allen, 2024 true eng
title Investigating the Genetic Influence on the Pathological Burden of Multiple Sclerosis
spellingShingle Investigating the Genetic Influence on the Pathological Burden of Multiple Sclerosis
KELSEY ALLEN
title_short Investigating the Genetic Influence on the Pathological Burden of Multiple Sclerosis
title_full Investigating the Genetic Influence on the Pathological Burden of Multiple Sclerosis
title_fullStr Investigating the Genetic Influence on the Pathological Burden of Multiple Sclerosis
title_full_unstemmed Investigating the Genetic Influence on the Pathological Burden of Multiple Sclerosis
title_sort Investigating the Genetic Influence on the Pathological Burden of Multiple Sclerosis
author_id_str_mv c49c1106547e0db27312ab4309aa4e48
author_id_fullname_str_mv c49c1106547e0db27312ab4309aa4e48_***_KELSEY ALLEN
author KELSEY ALLEN
author2 KELSEY ALLEN
format E-Thesis
publishDate 2025
institution Swansea University
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
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description Introduction: Permanent disability in multiple sclerosis (MS) is primarily driven by neuronal and axonal loss. While genome-wide association (GWAS) studies have begun identifying genetic variants associated with the clinical course of MS, the variants underpinning pathological severity have not been described. Understanding these novel variants and their influence on the clinical course of MS can be used to further develop our knowledge of this heterogenous disease.Aims: To uncover genetic variants and describe the expression of mapped genes that associate with the pathological severity of MS.Methods: Using data from an integrated GWAS expression quantitative trait loci COLOCation (eQTL COLOC) analysis of progressive MS (n = 310), we investigated the association between gene variant status and neuron density, extent of demyelination and retrospectively determined clinical milestones. In situ hybridisation (ISH) revealed gene expression and localisation in a subset of MS and controls (n = 20).Results: Previously described variant rs7289446 (SEZ6L) was not associated with quantitative measures of neuron density, demyelination or clinical outcomes. A 2nd variant mapping to DYSF:CYP26B1 (rs7564433), which represents the first GWAS validated mapped gene (rs10191329), was associated with higher neuron density, lower demyelination, slower disease progression and an older age at death in heterozygote allele carriers (p < 0.05). Independent single nucleotide polymorphisms (SNPs), mapping to PCSK5 and COMMD10, genes not previously linked to MS, were associated with increased neuron density in the thalamus, pons (p < 0.05; PCSK5) and frontal cortex (p <0.05; COMMD10), specifically among heterozygous carriers. The average age of onset was 4.6 yrs lower in COMMD10 major allele carriers compared to heterozygotes.COMMD10 and PCSK5 neuronal and glial expression was elevated in normal MS grey matter (GM) compared to control and lesion GM.Summary: We describe gene variants that associate with neuron density and show the altered expression of mapped genes in MS. Our findings provide insights into biological mechanisms underlying MS severity, offering potential opportunities for targeted therapies and personalised MS care.
published_date 2025-09-01T05:25:03Z
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