Abstract

Large-scale, genome-wide studies have identified a plethora of genetic variants associated with cardiovascular diseases (e.g. coronary heart disease), and their risk factors (e.g. blood pressure and cholesterol levels), as well as related traits (e.g. blood cell traits). However, the molecular mechanisms underlying the majority of these genetic variants have remained elusive. There is a pressing need to translate genetic associations into biological mechanisms. This translation has the potential to empower clinical care through, for example, improved risk prediction, biomarker identification, disease sub-classification, drug development and dosing.

Many genetic variants identified through genome-wide association studies map outside protein-coding regions suggesting that the underlying functional variants may influence phenotype through regulation of gene expression. In the first part of my talk, I will address the formidable challenge of identifying functional variants at these regions, and interpreting their biological consequences. As proof-of-concept, I discuss the systematic functional translation of genetic loci associated with blood cell traits (Paul DS et al., PLOS Genet. 2011; HaemGen Consortium, Nature 2012; Paul DS et al., Genome Res. 2013).

In the second part of my talk, I will outline recently established and planned integrative genomics projects at the Cardiovascular Epidemiology Unit. These include (A) the characterisation of human induced pluripotent stem cell (hiPSC)-derived cell types that play a role in the pathobiology of cardiovascular diseases; and (B) the promise of recall-by-genotype studies using the 50,000-participant INTERVAL study as a bioresource to enable targeted deep-phenotyping of individuals carrying trait-associated genetic variants.