Whole genome sequencing approach to identifying genetic risk factors underlying anterior cruciate ligament injuries in a twin family study
type: CreativeWork
description: Background: Predisposition to ACL rupture is multifactorial, resulting from a complex interplay of intrinsic and extrinsic risk factors. Variation in the genome is now considered a key intrinsic risk factor, but the majority of currently implicated loci have been identified through case-control genetic association studies, which are limited by a candidate gene approach and insufficient statistical power. The primary aim of this thesis was to use a whole genome sequencing (WGS) approach within the context of a twin family study to identify novel or previously implicated genetic loci contributing to ACL rupture predisposition (Chapter 2). Additionally, this research aimed to explore prioritised genetic polymorphisms previously associated with ACL rupture and functioning in key biological pathways implicated through the WGS analyses, independently and as a collective, with ACL rupture predisposition in a large combined ACL rupture dataset (Chapter 3 and 4). Methods: The complete genomes of all family members in two unrelated families, each with affected twins were sequenced. Variants with potential loss of function effect were prioritised, and explored for probable biological function in the ACL rupture risk pathway. Furthermore, identity by descent analysis (IBD) was performed to identify potential disease causing mutations, on chromosomal regions shared between family members, and across families. Enriched biological pathway analyses were further explored to prioritise potential candidate genes. Two biological networks were prioritised which highlighted the angiogenesis and proteoglycan family of proteins. Specific polymorphisms within previously investigated candidate genes were further explored in case-control genetic association studies conducted in a large collective data set, including participants from three independent (Sweden, Poland and Australia) cohorts, combined with previously published South African and Polish data. The anterior cruciate ligament (ACL) …
abstract: Background: Predisposition to ACL rupture is multifactorial, resulting from a complex interplay of intrinsic and extrinsic risk factors. Variation in the genome is now considered a key intrinsic risk factor, but the majority of currently implicated loci have been identified through case-control genetic association studies, which are limited by a candidate gene approach and insufficient statistical power. The primary aim of this thesis was to use a whole genome sequencing (WGS) approach within the context of a twin family study to identify novel or previously implicated genetic loci contributing to ACL rupture predisposition (Chapter 2). Additionally, this research aimed to explore prioritised genetic polymorphisms previously associated with ACL rupture and functioning in key biological pathways implicated through the WGS analyses, independently and as a collective, with ACL rupture predisposition in a large combined ACL rupture dataset (Chapter 3 and 4). Methods: The complete genomes of all family members in two unrelated families, each with affected twins were sequenced. Variants with potential loss of function effect were prioritised, and explored for probable biological function in the ACL rupture risk pathway. Furthermore, identity by descent analysis (IBD) was performed to identify potential disease causing mutations, on chromosomal regions shared between family members, and across families. Enriched biological pathway analyses were further explored to prioritise potential candidate genes. Two biological networks were prioritised which highlighted the angiogenesis and proteoglycan family of proteins. Specific polymorphisms within previously investigated candidate genes were further explored in case-control genetic association studies conducted in a large collective data set, including participants from three independent (Sweden, Poland and Australia) cohorts, combined with previously published South African and Polish data. The anterior cruciate ligament (ACL) …
author: Feldmann, Daneil
keywords: human biology
date published: 2022
date modified: 2026-07-22T22:23:23Z
provider: University of Cape Town
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Department of Human Biology

PropertyValue
property ID: Handle
value: http://hdl.handle.net/11427/36615