Cardiovascular Genomics and Precision Medicine

“We aim to understand the genetic basis of cardiovascular disease in order to both reveal disease mechanisms, thereby identifying new therapeutic targets, and to interpret genomic information for application in patient care.”

Research areas

Understanding the genetic architecture of cardiomyopathies – we are using genetic and genomic approaches to understand the genetic underpinnings of heritable heart muscle diseases in humans.  We are using exome and genome sequencing approaches to find genes that cause Mendelian (single-gene) forms of these diseases and are also exploring the role of more common genetic and environmental factors that modulate disease risk and severity.  These studies both provide diagnostic answers to affected families, and also identify potential new therapeutic targets.

Variant interpretation – all of us carry rare variants that alter important genes.  Distinguishing between those that cause disease and those that are innocent bystanders is a key challenge in contemporary clinical genetics.  We are developing and applying new methods to address this challenge and collaborating globally to refine our understanding of variation in genes associated with heart disease.

Functional genomics -central to our work is the integration of genome data with cutting-edge phenotypic characterisation. We leverage cardiac magnetic resonance (CMR) imaging, machine-based image processing and quantitative multi-dimensional feature extraction techniques, transciptomics and translatomics, and other large data sets including electronic health records, to make new insights into human cardiovasculardisease.

Precision medicine – we are evaluating the use of genetic and other biomarkers to stratify patients and predict their response to therapy and long-term outcomes.  Ultimately, we are working to interpret genome information so that it can be used to optimise treatment choice for our patients.

Titin – we have a particular focus on the Titin gene, which encodes the largest human protein, a key component of muscles throughout the body.  Recently identified as the most important cause of inherited dilated cardiomyopathy, we are working to understand the effects of Titin variants on the heart, their mechanisms of action, and their clinical significance.

These studies are complemented by RNA sequencing of the human heart and protein-protein interactomes that enable us to build gene networks and define biological pathways, with the aim of uncovering novel mechanisms, diagnostics and therapeutic targets.

Software – web resources, software, and other tools developed by the group are available at

Semi-transparent, space-filled PDB 5TBY IHM structure depicting the impact of HCM variants, when exposed to different IHM environments.

Selected Publications

Whiffin N, Karczewski KJ, Zhang X, Chothani S, Smith MJ, Evans DG, Roberts AM, Quaife NM, Schafer S, Rackham O, Alfoldi J, O’Donnell-Luria AH, Franciolo LC, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, Cook SA, Barton PJR, MacArthur DG, Ware JS. (2020). Characterising the loss-of-function impact of 5′ untranslated region variants in 15,708 individuals. Nature Communications, 11, 2523.

Mazzarotto F, Taya Ul, Buchan RJ, Midwinter W, Wilk A, Whiffin N, Govind R, Mazaika E, de Marvao A, Dawes TJW, Felkin LE, Ahmad M, Theotokis PI, Edwards E, Ing AY, Thomson KL, Chan LLH, Sim D, Baksi AJ, Pantazi As, Roberts AM, Watkins H, Funke B, O’Regan DP, Olivotto I, Barton PJR, Prasad SK, Cook SA, Ware JS, Walsh R. (2020). Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy. Circulation, 141:387–398

Meyer HV, Dawes TJW, Serrani M, Bai W, Tokarczuk P, Cai J, de Marvao A, Henry A, Lumbers RT, Gierten J, Thumberger T, Wittbrodt J, Ware JS, Rueckert D, Matthews PM, Prasad SK, Costantino ML, Cook SA, Birney E, O’Regan DP. (2020). Genetic and functional insights into the fractal structure of the heartNature, 584; 589–594.

Karczewski KJ, Franciolo LC, Tiao G, [63 authors], Daly MJ, MacArthur DG. (2020). The mutational constraint spectrum quantified from variation in 141,456 humans. Nature, 581, 434–443.

Garcia-Pavia P, Kim Y, Restrepo-Cordoba MA, [47 authors], Ware JS, Seidman CE. (2019). Genetic Variants Associated With Cancer Therapy–Induced Cardiomyopathy. Circulation, 140:31–41.

Ware JS, Amor-Salamanca A, [26 authors], Barton PJ, Garcia-Pavia P. (2018). Genetic Etiology for Alcohol-Induced Cardiac Toxicity, Journal of the American College of Cardiology, 71 (20), 2293-2302.

Ware JS, Cook SA. (2018). Titin cardiomyopathy: from DNA variant to patient stratification, Nature Review Cardiology (invited review) 15(4), 241. 10.1038/nrcardio.2017.190.

Walsh R, Buchan R, Wilk A, John S, Felkin LE, Thomson KL, Chiaw TH, Loong CCW, Pua CJ, Raphael C, Prasad S, Barton PJ, Funke B, Watkins H, Ware JS, Cook SA. (2017). Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcometric genes, European Heart Journal, 38(42) 3119-3121.

Whiffin N, Minikel E, Walsh R, O’Donnell-Luria AH, Karczewski K, Ing AY, Barton PJR, Funke B, Cook SA, MacArthur DG, Ware JS. (2017). Using high-resolution variant frequencies to empower clinical genome interpretation. Genet Med 19, 1151.

Schafer S, de Marvao A, [32 authors], Ware JS (joint senior), Hubner N, Cook SA. (2017). Titin truncating variants affect heart function in disease cohorts and the general population. Nature Genetics 49, 46.

Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, [69 authors], Daly MJ, MacArthur DG, Exome Aggregation Consortium. (2016). Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285.

Ware JS, Li J, Mazaika E, [29 authors], Seidman CS, Seidman JG, Arany Z. (2016). Shared genetic predisposition in peripartum and dilated cardiomyopathies. New England Journal of Medicine 374, 233.

Homsy J, Zaidi S, Shen Y, Ware JS (joint first author), [35 authors], Seidman C, Chung W. (2015). Genetic Causes for Congenital Heart Disease with Neurodevelopmental and other Deficits. Science 350, 1262.