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Human Genetics

Led by Prof Hugh Watkins, to span inherited diseases (gene discovery, phenotyping, disease mechanisms and clinical application of genetic testing) through to post-GWAS functional analyses, including model organism and cell biology approaches aiming to extract biological insight from genetically validated mechanisms.

The Human Genetics Theme of the Oxford BHF CRE aims to (i) advance the use of human genetic variation for diagnosis, prediction of individual risk, and disease stratification and (ii) to extract biological and therapeutic insight from genetically validated disease mechanisms. We will span the spectrum from rare diseases to complex traits and tackle some of the most important cardiovascular diseases.

Genetic and genomic approaches are uniquely powerful for proving causality, thus providing firm foundations for hypothesis-driven mechanistic exploration. Where genetic effects are large (either single variants or risk scores that combine multiple variants) there are also important benefits for diagnosis and patient stratification. Remarkable advances in sequencing technology and capacity are accelerating discovery across all of cardiovascular medicine; genome editing is transforming our ability to manipulate cell and model systems and holds promise for therapy. We believe that we are optimally placed to harness this transformation, not least because cardiovascular genetics in Oxford is notable for leading expertise in both rare, inherited disease and common, complex traits and there are increasing synergies across the genetic spectrum. This Theme will link closely with the Big Data Theme to advance the analysis of large genomic and phenotypic (e.g. imaging) data sets and with the Target Discovery Theme for downstream functional analyses, including cell and model organism approaches, reaching through to medicinal chemistry and high-throughput screens.

In rare/inherited diseases, the focus will be on cardiomyopathy and other sudden cardiac death (SCD) disorders, spanning gene discovery, phenotyping, disease mechanisms and clinical application of genetic testing. We will exploit Oxford’s analytical capability in interpretation of whole genome sequencing data, our largest single centre experience worldwide of genetic testing in inherited cardiac conditions, and our expertise in deriving new Magnetic Resonance imaging techniques to probe aspects of myocardial biology in patients. Functional analyses of known and newly implicated disease mechanisms will exploit state-of-the-art advances in high-throughput creation of genome-edited iPS-derived cardiomyocyte and mouse models. Experimental medicine trials of proposed disease-modifying therapies will include repurposed medicines, new small molecule and potentially nucleic acid therapies, in conjunction with the Target Discovery Theme; we will work towards studies on genotype-positive, preclinical, patient cohorts where the greatest chance of prevention lies.

In complex trait diseases, we will build on areas where we have already advanced genetic discovery through GWAS (coronary artery disease, stroke) and areas where we see new opportunities that build on local expertise (e.g. atrial fibrillation, vascular dementia, the interface between liver and heart disorders). We will seek to exploit new data modalities/measured intermediate phenotypes, building on links with the Big Data Theme. By combining genetic, epidemiological, and clinical phenotyping approaches we will ensure that the wealth of genetic susceptibility data gained from the GWAS era translates into therapeutic advances (for example through exploring utility of genetic risk scores and by deploying Mendelian Randomisation approaches). For functional analyses we will focus on areas where the CRE has leading expertise in related areas of biology, notably the genomics of coronary artery disease, where we will focus on genetic loci that implicate biological mechanisms within the vessel wall (for which there are currently few, if any, treatments).