Prioritisation of genes and variants underlying hypertrophic cardiomyopathy GWAS loci using computational approaches

Thesis

Hypertrophic cardiomyopathy (HCM) is a common heart condition, affecting at least 1 in 200 to 500 individuals, and a leading cause of sudden cardiac death. HCM has traditionally been recognised as a monogenic disorder caused by rare variants in sarcomere genes. This scenario does however only account for ~40% of HCM cases and so the majority of patients’ causal variants do not get identified and the current applied clinical protocol needs reviewing.   

In this thesis, the polygenic aspects of HCM are explored with the central aim being to identify plausible causal variants and their likely target gene(s). Prior to this thesis, HCM GWASs comprising of data from seven cohorts were combined into an overarching meta-analysis and a multitrait analysis of genome-wide association summary statistics (MTAG) which identified 68 (50 novel) loci. Following this availability of HCM genome wide association data, a two-fold approach of gene prioritisation followed by functional variant prioritisation ensued. The former entailed employing existing gene prioritisation tools, leveraging expression data, and conducting case-control rare variant burden analyses all for the identification of plausible (and tractable) genes. The latter utilised machine learning approaches to gain insight into the chromatin landscape of the heart so as to pinpoint significant common susceptibility variants at a regulatory level. The final stage of this thesis attempted to draw a link between the shortlist of both prioritised genes and variants to best define probable routes of pathogenicity. Twenty-six of the 68 HCM loci were resolved to likely causal gene(s). Machine learning prioritised 53 variants, 24 of which were shown to open up and 29 to close the chromatin. Case studies linking prioritised variants to their genes computationally highlighted the detrimental effects of MTSS1 in the context of HCM; identified an inversion disrupting interactions between KANSL1 and other genes in an otherwise puzzling locus; fine-tuned the TBX3 locus with this gene being the sole likely target; added weight to PXN through its functional common variant being assigned the most significant impact score. 

Collectively, these analyses put forward a list of implicated genes and functional common variants to be investigated in vitro for greater insight into the disease mechanisms associated with common variants and HCM.

Authors: West, DM

• DOI: 10.5287/ora-5z1yoxk1e
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English