Meet the team

Cardiovascular genomics precision medicine Research

“Why do some heart conditions run in families?”

We are working to understand more about the causes of heart conditions that run in families, and particularly cardiomyopathies – a range of conditions that affect the heart muscle, which can become thickened, stiff, scarred, or too thin.

Cardiomyopathy can reduce the ability of the heart to effectively pump blood around the body, and can lead to dangerous heart rhythm changes, with symptoms worsening over time.

Many of the commonest heart problems are caused by problems with the blood supply to the heart – coronary artery disease –  or problems with the heart valves which can become damaged over time.  Cardiomyopathy refers to an intrinsic problem with the heart muscle itself, when the blood supply is normal.  Cardiomyopathy can be environmental, with some caused by viral infections, medications, or lifestyle choices, but often they are genetic, and can be caused by a faulty copy of a gene inherited from parents.

We have been very interested in the Titin gene, which encodes the largest human protein and a key component of human muscle. It has been identified as the most important cause of dilated cardiomyopathy, but many people in the wider population also carry faulty copies of the Titin gene.  We are working to understand why some people develop serious cardiomyopathy, while others do not.  We believe that that are additional factors that either trigger heart disease, or protect against heart disease, in people with a genetic predisposition.

Through our work, we aim to uncover new mechanisms, diagnostics and therapeutic targets for cardiomyopathy.

We analyse and combine large data sets from patients, trials, and wider research programmes to help identify new patterns.

We employ a range of approaches combining analyses of genomic data, medical imaging, and evaluating electronic health records to make new insights into human cardiovascular disease.

Cardiomyopathy can vary in severity. It can lead to heart failure and result in death, regardless of age or health. Our research findings are providing diagnostic answers to affected families and helping to identify new therapeutic targets.

“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 cardiovascular disease.

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.

Software

Web resources, software, and other tools developed by the group are available at cvgenetics.org/resources.

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

Our research is supported by

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Jules Thorn logo
BHF
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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 individualsNature 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 CardiomyopathyCirculation, 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 humansNature, 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 CardiomyopathyCirculation, 140:31–41.

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

Ware JS, Cook SA. (2018). Titin cardiomyopathy: from DNA variant to patient stratificationNature 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 genesEuropean 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 cardiomyopathiesNew 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 DeficitsScience 350, 1262.

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