The results of research by scientists at University College London (UCL), Imperial College London, and the MRC Laboratory of Medical Sciences, indicate that a potentially life-changing heart condition, dilated cardiomyopathy (DCM), can be caused by the cumulative influence of hundreds or thousands of genes and not just by a single aberrant genetic variant, as has previously been thought.
The new study found that about a quarter to a third of the risk of DCM could be accounted for by the small effects of many thousands of genetic differences scattered throughout the genome. The researchers developed a polygenic risk score to assess an individual’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 risk among individuals with an average risk score.
In addition, the study 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. Research co-lead Tom Lumbers, MD, PhD, at 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.” The study, Lumbers added, “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.”
Lumbers is co-senior author of the team’s published paper in Nature Genetics, titled “Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy,” in which the investigators concluded, “Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics.|
DCM is a disorder in which the heart becomes progressively enlarged and weakened, reducing its ability to pump blood efficiently. “Dilated cardiomyopathy (DCM) describes a spectrum of heart muscle diseases that are characterized by impaired left ventricular (LV) myocardial contractility and dilatation, in the absence of coronary artery disease (CAD) or abnormal loading conditions,” the authors explained. The condition affects perhaps one in every 250 individuals in the U.K., and is the leading cause of heart transplantation.
Previously, it was thought that DCM 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. “Pathogenic mutations in relevant genes can cause DCM via monogenic disease mechanisms; however, recent evidence suggests direct and indirect effects of polygenic background on DCM risk,” the authors continued.
For their newly reported study, the research teams worked with collaborators from around the world to collect and analyze the results of 16 existing studies alongside new data, comparing the genomes of thousands of people who had DCM with more than a million people who did not have the disease. “We performed a meta-analysis of a case–control genome-wide association study (GWAS) comprising 14,256 DCM cases and 1,199,156 controls from 16 studies participating in the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) Consortium,” the investigators explained.
By comparing the genomes of those with and without DCM the team identified 80 areas of the genome with a likely link to the disorder—the majority of which had not been previously reported—as well as 62 specific genes within those areas that may be involved. “We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L, and SSPN),” they wrote. “We then used single-nucleus transcriptomics to identify cellular states, biological pathways, and intercellular communications that drive pathogenesis.”
The investigators developed a polygenic risk score, based on the genome association scan, and applied it to a separate dataset of 347,585 individuals in the U.K. 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 with those individuals whose risk score was in the lowest 20%.
In their report, the authors concluded, “These findings provide mechanistic insights into the genetic causes underlying DCM pathogenesis and may inform therapeutic strategies for DCM patients and at-risk individuals.”
James Ware, MD, PhD, at Imperial College London & MRC Laboratory of Medical Sciences, said, “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 … 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 the next steps, Ware noted, will be 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.
“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,” added Lumbers. “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.”
Metin Avkiran, PhD, director of international partnerships and special programs at the British Heart Foundation, one of the organizations supporting the research, 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 personalized monitoring and care, as well as revealing potential targets for the development of new treatments.”
