A hidden genetic threat may trigger atrial fibrillation decades early, raising the risk of stroke before symptoms appear.
Atrial fibrillation (AFib) occurs when chaotic electrical signals cause the heart’s upper chambers to beat irregularly and out of sync with the lower chambers. Blood can then collect inside the heart, creating clots that may travel to the brain.
Recent estimates suggest that at least 10.55 million American adults, roughly one in 22, have AFib, making it far more common than previously believed. Although the condition is strongly associated with aging, high blood pressure, diabetes, and heart disease, inherited risk can bring it on much earlier.
“For many people, their first symptom of AFib is a stroke,” said Dawood Darbar, the new chair of the Department of Medicine at Penn State College of Medicine, who has spent his career investigating abnormal heart rhythms. “If we can prevent even one stroke, the impact on that person and their family would be huge.”
When Genetic Risks Combine to Disrupt the Heart
Darbar led a multi-institutional study published in Nature Communications that investigated why a rare mutation does not affect everyone who inherits it in the same way. The researchers found that its effects can be intensified by numerous common DNA differences, each of which contributes only a small amount of risk on its own. In an analysis of the U.K. Biobank, people carrying a heavy burden of these common risk variants had about twice the likelihood of developing early-onset AFib.
The team examined a rare mutation in LMNA, a gene that helps organize DNA inside cells. The mutation changed how tightly parts of the genome were packaged, making it harder for cells to access and activate genes that help regulate the heart’s electrical rhythm. Common genetic variants further weakened this control, showing how rare and widespread forms of genetic risk can combine to produce disease much earlier in life.
In this Q&A, Darbar explains how heart cells generate a coordinated beat, why inherited mutations alone do not tell the entire story, and how combining different forms of genetic risk could eventually help doctors identify vulnerable patients before AFib leads to a stroke.
Q. What happens when the heart beats? What breaks down during AFib?
Darbar: Every heartbeat begins with an electrical impulse generated by specialized cells in the heart’s natural pacemaker. This impulse travels through the upper heart chamber, or atria, causing the heart muscle cells to contract in a coordinated fashion and pump blood into the bottom heart chambers, known as ventricles. The electrical signal then passes through the ventricles, producing the heartbeat that pumps blood throughout the body.
In AFib, this orderly electrical system breaks down. Instead of a single, coordinated electrical impulse, multiple abnormal signals spread through the atria simultaneously. As a result, the atria “quiver” rather than contract effectively, leading to an irregular heartbeat and increasing the risk of stroke, heart failure, and other cardiovascular complications.
Q: AFib is usually described as a disease of aging. Where do genetics come in?
Darbar: Most AFib is related to high blood pressure, diabetes, and heart disease. But roughly 20% is genetic. Some people inherit a rare genetic mutation that substantially increases their risk of developing AFib at an early age. However, in our recent study in Nature Communications, we saw that these mutations do not act in isolation.
Each of us also carries hundreds or even thousands of common genetic variants — or single-nucleotide polymorphisms (SNPs), pronounced “snips” — that individually have only a very small effect on AFib risk. But when many of these common variants occur together, they can amplify the impact of a rare AFib-causing mutation. It’s the interaction between rare and common genetic variants that appears to matter.
We refer to this as “additive” risk because rare and common genetic variants work together to provide a more complete picture of a person’s likelihood of developing AFib than either type of variant alone. In our analysis of the U.K. Biobank, a health and genetic database that includes more than 500,000 participants, individuals with a high burden of common genetic risk variants had approximately twice the risk of developing early-onset AFib.
Q. What is an example of this additive effect?
Darbar: Some families carry a rare mutation in a gene called LMNA, which helps organize DNA inside the cell. LMNA mutations have been linked to inherited forms of heart disease and AFib. In our study, the mutation altered how tightly certain regions of DNA were packaged, which in turn affected how easily those regions could be accessed and regulated.
Using blood samples—donated by individuals with and without AFib—to generate personalized human heart cell models, we found that the rare LMNA mutation and SNPs converged on many of the same DNA regulatory pathways. Several of those SNPs were located within regions of DNA whose accessibility had been altered by the LMNA mutation. One of these regions helps regulate the movement of sodium ions into heart cells, a process that is essential for generating and conducting the electrical signals that produce a normal heartbeat.
This provides a concrete example of additive genetic risk: the rare LMNA mutation creates a vulnerable cellular environment, while a person’s background of common genetic variants can further increase or modify that risk. Together, these factors may help explain why some people develop AFib much earlier than others. It also suggests that predicting AFib risk may require looking beyond a single harmful mutation and considering a patient’s broader genetic landscape.
Q: What does this all mean for a patient sitting in your clinic?
Darbar: These studies were conducted in laboratory-based cell models, so the findings are not yet ready to guide routine clinical care. What they do provide is a clearer understanding of how rare and common genetic risk factors can converge to disrupt the heart’s electrical system. With additional research, including studies in patients, this knowledge could eventually help us identify who is at greatest risk for developing AFib at a young age.
Genetic testing is already an important part of evaluating patients with inherited heart rhythm disorders and their families because it can identify people who may be at increased risk before symptoms appear. In the future, combining information about a rare disease-associated mutation with a person’s broader genetic background may allow us to estimate risk more accurately, for example, identifying someone who may be more likely to develop AFib in their 30s or 40s.
Our findings also suggest that LMNA should be considered in genetic testing panels for inherited arrhythmia syndromes. LMNA has traditionally been associated with cardiomyopathy and heart failure, but our work shows that some individuals with LMNA variants may first present with AFib, before structural heart disease becomes apparent. Identifying these patients earlier could lead to closer monitoring, earlier treatment, and screening of family members who may also be at risk.
The long-term goal is to move from reacting to complications to preventing them. For example, if we can identify a high-risk individual early, we might use a wearable heart monitor to detect AFib before it causes a stroke. That would be a very different and much more proactive conversation than the one we are often able to have with patients today.
Reference: “Gene-gene interactions between a LMNA variant and common polymorphisms drive early-onset atrial fibrillation” by Asia Owais, Hanna Chen, Hammad Farooq, Prisca K. Thami, Kathryn A. McGurk, George J. Powell, Jaime DeSantiago, Talla Abbas, Arvind Sridhar, Arif Pavel, Gregory Webster, Bradley Merrill, James S. Ware, Fu Siong Ng and Dawood Darbar, 19 May 2026, Nature Communications.
DOI: 10.1038/s41467-026-73113-0
This work was supported in part by the National Institutes of Health’s National Heart Lung and Blood Institute under award numbers R01 HL148444, T32 HL139439 and R01 HL164773; the U.S. Department of Veterans Affairs under Merit Award 2I01BX004268; and the American Heart Association under award numbers 25CDA1447820 and 24PRE1178922.
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