New genetic explanation for heart condition revealed

Dilated cardiomyopathy (DCM) is a condition in which the heart becomes progressively enlarged and weakened, reducing its ability to pump blood efficiently. It is estimated to affect up to 260,000 people in the UK (one in every 250 individuals) and is the leading cause of heart transplantation.

Previously, it was thought that dilated cardiomyopathy was mostly caused by faulty copies of a single gene that can be passed down through families, even though in more than half of patients no faulty gene is identified.

The new study, published in the journal Nature Genetics, found that about a quarter to a third of the risk of dilated cardiomyopathy could be accounted for by the small effects of many thousands of genetic differences scattered throughout the genome.

Importantly, the researchers also developed a polygenic risk score to assess a person's likelihood of developing dilated cardiomyopathy based on the many small effects of these genes.

They found that those with the highest genetic risk score (in the top 1%) had a fourfold risk of developing dilated cardiomyopathy compared to those with an average risk score.

In addition, the researchers found that these cumulative small genetic effects provided an important explanation for the puzzle that some people with a faulty gene copy develop cardiomyopathy, while others don't.

Co-senior author Dr Tom Lumbers (UCL Institute of Health Informatics) said: "When cardiomyopathy runs in a family, it can be very worrying for family members who don't know whether they are going to develop disease. Our findings could allow clinicians to better predict disease risk for patients and their families.

"Our study also heralds a new way of thinking about the genetics of this heart disease. Instead of being caused by a single genetic spelling mistake, in some patients the condition is more like common diseases such as coronary artery disease, where many genetic differences collectively contribute to risk.

"Understanding the small effects of many genes across the genome also helps us to identify those patients carrying a faulty gene copy at highest risk of developing the disease. This higher-risk group can be followed more closely, and offered early opportunities to participate in clinical trials testing preventive treatments. Identifying people at the highest risk has been challenging until now."

Professor James Ware (Imperial College London & MRC Laboratory of Medical Sciences) added: "We expect that our findings will improve the precision of clinical genetic testing and will increase the number of patients to whom a genetic explanation can be given."

For the study, the research teams worked with collaborators from around the world to collect and analyse the results of 16 existing studies alongside new data, comparing the genomes of 14,256 people who had dilated cardiomyopathy with more than a million people who did not have the disease.

By comparing the genomes of those with and without the disease, the team were able to identify 80 areas of the genome with a likely link to the disease, the majority of which had not been previously reported, as well as 62 specific genes within those areas that likely had a link to the disease.

They developed a polygenic risk score, based on the genome association scan, and applied it to a separate dataset of 347,585 individuals in UK Biobank. They found that people with a rare disease-causing variant were four times more likely to develop disease (7.3% to 1.7%) if their polygenic risk score was in the top 20% compared to those whose risk score was in the lowest 20%.

Professor Ware said: "We still have a lot of work to do to understand how these specific newly identified genes influence the risk of developing cardiomyopathy, but they are already shedding light on biological processes underlying the condition, and we hope that some will give new leads on possible treatments.

"One of our next steps is to explore integrating polygenic risk scores into genetic testing, to provide more people with a genetic explanation for their disease and a more precise assessment of disease risk."

Professor Metin Avkiran, Director of International Partnerships and Special Programmes at the British Heart Foundation, said: "Dilated cardiomyopathy is a debilitating condition with few treatment options once it has developed.

"This study is a big step forward in our understanding of the genetics of DCM, providing a clearer picture of individual risk in people who do not carry a known disease-causing mutation in a single gene. These promising early findings could lay the foundation for more personalised monitoring and care, as well as revealing potential targets for the development of new treatments."

The research team are supported by funding from the Medical Research Council, Sir Jules Thorn Charitable Trust, British Heart Foundation including their Big Beat Challenge award to CureHeart, Wellcome Trust, the National Institute for Health Research (NIHR) Imperial College Biomedical Research Centre, NIHR Royal Brompton Cardiovascular Biomedical Research Unit, National Heart Lung Institute Foundation; Royston Centre for Cardiomyopathy Research, Rosetrees Trust, GenMED LABEX, the UCL British Heart Foundation Research Accelerator and the NIHR University College London Hospital Biomedical Research Centre.