Studies reveal new genetic roots of atrial fibrillation

Two studies led by researchers at the Broad Institute of MIT and Harvard and Mass General Brigham have greatly expanded the number of known genetic variants that boost the risk for atrial fibrillation (AF), a common heart condition marked by irregular heartbeat that can lead to stroke and heart failure.

In one effort, researchers analyzed results from dozens of large genetic studies and uncovered more than 350 common DNA variants associated with AF risk, doubling the number of common genetic risk factors for the condition. In another, scientists analyzed genetic sequencing data from thousands of individuals with AF and pinpointed rare changes in several genes, which underscore the genetic links between AF and structural abnormalities of the heart known as cardiomyopathies. The scientists say some of these genes may be at the root of AF and are potential targets for new drugs. The two studies also provide the most detailed look yet into the genetic architecture of this common arrhythmia.

Both papers appear in Nature Genetics and were from the lab of Patrick Ellinor, an institute member and director of the Cardiovascular Disease Initiative at the Broad, a professor of medicine at Harvard Medical School, and executive director of the Mass General Brigham Heart and Vascular Institute. Key Broad researchers who led the work include Carolina Roselli, co-first author on the meta-analysis of common variation, and Seung Hoan Choi and Sean Jurgens, co-first authors on the analysis of rare variants in sequencing data.

“Atrial fibrillation is an incredibly common disease, yet we have very limited pharmacologic therapies because we still have a primitive understanding of the molecular mechanisms involved,” said Ellinor, who is also a cardiologist. “These studies open up new potential targets for therapeutic development.”

AFIB INSIGHTS

More than 5 million Americans live with AF. Treatments focus on controlling symptoms and avoiding dangerous complications, rather than targeting the molecular origins of the arrhythmia. These include blood thinners to prevent clots that could lead to stroke and surgery to stop faulty electrical signals in the heart.

“There's high demand to fix atrial fibrillation,” said Ellinor, “but we're doing it with an invasive surgical procedure that reflects the fact that we do not have effective therapies.”

Over the past two decades, researchers have conducted genome-wide association studies to identify common DNA changes that raise the risk for developing AF. Those efforts yielded more than 140 genetic regions linked to AF risk, but it was clear there were more to find.

In one of the new efforts, members of the AFGen Consortium and the Ellinor lab gathered data from 68 studies from around the globe involving more than 180,000 individuals with AF and nearly 1.5 million people without the condition. Their “meta-analysis” highlighted more than 350 genomic sites associated with AF, doubling the previous total. In nearly 140 of these sites, the team found genes involved in muscle cell contraction and communication and heart muscle development. These genes are also more likely to be expressed in atrial heart muscle cells than other genes. Moreover, the team used a new polygenic score to calculate that these new genes likely have a stronger cumulative impact on AF risk than previously discovered ones.

“These findings solidify our fingerprint of the common variants for atrial fibrillation,” said Ellinor.

In the second study, Ellinor and colleagues took advantage of recently released genome sequencing datasets to explore uncommon variants that might have sizable impacts on AF risk. Compared to common DNA variants, which may only “tag” the genome region where the causal DNA misspelling lies, rare variants are more likely to be the DNA change that directly leads to cellular dysfunction.

They gathered whole-genome and whole-exome sequencing data from over 50,000 individuals with AF and more than 270,000 without, and discovered genetic misspellings in four genes never before linked to AF: MYBPC3, LMNA, PKP2, and KDM5B. They also observed large effects on risk from deletions in the CTNNA3 gene and from duplications, or extra bits of DNA, in the GATA4 gene. Some of these genes are also well known for their role in inherited cardiomyopathies, highlighting a shared biological basis with AF. To explore the effects of one of these genetic changes, the team used gene editing to turn off the KDM5B gene in stem-cell-derived atrial heart muscle cells, revealing the gene’s involvement in electrical activity in the heart’s atrium, a key process that goes awry in AF.

The researchers are now working to assess any prognostic implications of the results, such as impacts on heart disease risk in individuals carrying the variants. They are also conducting functional studies to uncover the mechanisms affected by the variants, and incorporating new sequencing datasets to find even more genes underlying AF risk.

“These two studies complement each other nicely, giving us a large number of genetic regions to explore further and a set of causal genes that could represent new starting points for therapeutic development,” said Ellinor.

He also acknowledged the role of collaboration across large consortia and biobanks in facilitating discovery, including the AFGen Consortium which has been critical for enabling these studies. “No single study is big enough to get meaningful results anymore, but by working together and sharing resources and data openly, we can achieve real progress towards improving care for patients.”