This project will dissect the complex pathobiology of cardiomyopathy, heart failure, and myocardial infarction using a deeply integrated multi-omics and lifestyle data framework within the UK Biobank. While GWAS have identified numerous risk loci, the molecular mechanisms linking genetic variation to clinical disease remain largely unresolved. A critical knowledge gap exists in understanding how genetic predispositions are translated through intermediate molecular phenotypes (proteins, metabolites) and modulated by environmental factors.
Our central hypothesis is that integrating genomics with proteomics, metabolomics, and objective lifestyle data can reveal causal biological pathways and gene-environment interactions that are invisible to genomic analysis alone.
Our objectives are to:
1. Expand the genetic atlas: Utilize whole-genome/exome sequencing and structural variation data to identify novel common and rare genetic determinants for these cardiac conditions.
2. Map genotype-to-phenotype pathways: Integrate proteomics and metabolomics data to identify circulating biomarkers that mediate the effects of genetic variants on cardiac structure and function. This will bridge the gap from statistical association to biological causation.
3. Quantify gene-lifestyle interplay: Leverage accelerometer data for objective physical activity measurement, enabling a robust analysis of how lifestyle factors modify genetic risk.
4. Elucidate shared and distinct mechanisms: Investigate the multi-omic architecture to understand the substantial genetic and phenotypic overlaps across different forms of cardiac disease.
By creating a comprehensive, multi-layered biological map from gene to cell to behavior, this research will uncover novel therapeutic targets and lay the groundwork for a new era of precision cardiology.
