Large-scale integrative genomic studies of high-dimensional traits in cardiovascular diseases (renewal)

Through large-scale integrative genomic studies of high-dimensional traits, we will advance understanding of CVD aetiology and contribute to new medicines development. First, we will discover genetic risk factors for CVDs by: whole-exome sequencing patients with early-onset myocardial infarction in understudied populations (eg, South Asians); investigating mitochondrial DNA parameters (an under-explored type of DNA variation); and large-scale genomic analysis of understudied CVDs (eg, stroke subtypes, venous thromboembolic events). Second, we will identify causal pathways through analysis of the “expressed genome” (eg, RNA, proteins, metabolites, blood cell traits) to help elucidate the molecular chain of events that link genetic variation with clinical CVD outcomes. Third, we will identify human genetic “knockouts” in populations enriched for autozygosity (which are valuable models of pharmacological inhibition), and then characterise their molecular and clinical phenotypes to help identify and validate novel therapeutic targets. Fourth, as a complementary approach to therapeutic target prioritisation, we will use a comprehensive framework based on Mendelian randomisation (MR) principles to evaluate potential targets for clinical utility, informing trial design.