Why Does Atrial Fibrillation Strike 40 Years Early in Some People? Gene Study Finds a Clue

Atrial fibrillation (AFib), the most common heart rhythm disorder, occurs when chaotic electrical signals cause the heart's upper chambers to beat irregularly and out of sync with the lower chambers, allowing blood to pool and form clots that can travel to the brain. Recent estimates suggest at least 10.55 million American adults -- roughly one in 22 -- have AFib. While the condition is strongly linked to aging, high blood pressure, diabetes and heart disease, inherited risk can bring it on decades earlier.

'For many people, their first symptom of AFib is a stroke,' said Dawood Darbar, chair of the Department of Medicine at Penn State College of Medicine, who led a multi-institutional study published in Nature Communications on why a rare AFib-causing mutation does not affect everyone who inherits it the same way. The researchers found its effects can be intensified by many common DNA differences called single-nucleotide polymorphisms, or SNPs, each of which raises risk only slightly on its own. In an analysis of the UK Biobank, a health and genetic database of more than 500,000 participants, people carrying a heavy burden of these common variants had about twice the likelihood of developing early-onset AFib.

The team focused on a rare mutation in a gene called LMNA, which helps organize DNA inside cells. The mutation changed how tightly certain regions of the genome were packaged, making it harder for cells to access and activate genes that regulate the heart's electrical rhythm. Using blood samples from people with and without AFib to build personalized human heart cell models, the researchers found that the rare LMNA mutation and the common SNPs converged on many of the same DNA regulatory pathways, with several SNPs located in regions whose accessibility the mutation had altered.

One of those regions helps regulate the movement of sodium ions into heart cells, a process essential for generating and conducting the electrical signals that produce a normal heartbeat -- showing how a rare mutation and a person's broader background of common genetic variants can combine to raise AFib risk.