Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, yet current therapeutic strategies often fail to address key biological mechanisms underlying disease onset and progression. This project aims to use the UK Biobank’s large-scale genotypic and phenotypic data to discover novel therapeutic targets and elucidate disease mechanisms for major CVDs, including myocardial infarction, aortic aneurysm, atrial fibrillation, and ischemic stroke.
The research integrates hypothesis-driven and data-driven approaches to explore both known and novel biological pathways. We will combine genome-wide association studies (GWAS), Mendelian Randomization (MR), phenome-wide scans (PheWAS), and transcriptome/proteome-based functional annotation to achieve three key aims:
1. Target Discovery: Identify genetic variants that influence intermediate phenotypes (e.g., circulating cytokines such as IL-6, CRP) and evaluate their causal impact on cardiovascular endpoints via MR.
2. Mechanistic Exploration: Use multi-omic integration (e.g., eQTL, pQTL, colocalization, and pathway enrichment) to investigate molecular pathways that mediate genetic effects on CVD, including inflammation, lipid metabolism, vascular remodeling, and cardiac electrophysiology.
3. Patient Stratification: Examine heterogeneity in genetic risk and causal effects across demographic subgroups (e.g., sex, age, comorbidities), identifying population-specific mechanisms or treatment opportunities.
The scientific rationale is that identifying genetically supported mechanisms increases the likelihood of successful drug development and can inform precision medicine strategies. Insights from this study will support target prioritization and the development of mechanism-informed interventions for patients with unmet clinical needs in cardiovascular care.
