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Title: The genetic architecture of hypertrophic cardiomyopathy
Author: Harper, Andrew Robert
ISNI:       0000 0004 9356 6096
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2020
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Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disorder, affecting at least 1 in 500 individuals, and a leading cause of sudden death. Genetic testing for rare, causal, genetic variants in sarcomere genes is the standard of care and conducted at scale. However, more than half of HCM patients do not carry identifiable pathogenic variants and, in those that do, there is substantial variation in penetrance and disease expression. Here, the genetic architecture of HCM is further evaluated, under a central hypothesis that the genetic aetiology of HCM extends beyond known rare variant contributions. Through a series of case-control analyses monogenic, oligogenic and polygenic models of disease were assessed. Burden testing analyses support prior knowledge regarding the monogenic basis to HCM. Quantitative analyses directed towards quantifying the penetrance and expressivity of disease-causing HCM variants were largely underpowered. Similarly, systematic evaluation for oligogenicity was underpowered. However, haplotype analysis of a candidate variant (MYBPC3�25) presumed to be of importance to oligogenicity revealed synthetic association with a rare pathogenic variant (MYBPC3 c.1224-52G > A), quelling this specific oligogenic hypothesis. Polygenicity was evaluated through genome wide association analyses. The additive effects of common variants explained 34.0±2.4% of phenotypic variance in sarcomere-negative HCM, and 15.8±3.8% in sarcomere-positive HCM. Meta-analysis revealed 28 loci (13 independent genome-wide significant variants (p-value < 5×10−8) and 16 < 5% local false discovery rate variants (p-value < 1.82×10−6)). A genetic risk score (GRS) assessed the aggregate impact of these independent common variants: HCM risk was halved for individuals in the lowest quintile and more than doubled for those in the highest quintile. Collectively, these analyses reject the null hypothesis that the genetic aetiology of HCM is restricted to known rare variant contributions and extend understanding regarding the genetic architecture of HCM.
Supervisor: Farrall, Martin ; Watkins, Hugh ; Goel, Anuj Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Genomics ; Medicine ; Genetics ; Cardiology