Research Spotlight: Identifying Genetic Variants Associated with Common Cardiac Rhythm Disorders

Lu-Chen Weng, PhD and Shaan Khurshid, MD, MPH are co-first authors and Patrick T. Ellinor, MD, PhD and Steven A. Lubitz, MD, MPH, of the Cardiovascular Research Center and Telemachus and Irene Demoulas Family Foundation Center for Cardiac Arrhythmias at Massachusetts General Hospital, are co-senior authors of a paper published in Nature Genetics, “Common and rare variant contributions to bradyarrhythmias.”

How would you summarize your study for a lay audience?

Bradyarrhythmias are a common cardiovascular disorder where the heart beats at a slower rate and represents a major public health problem, affecting at least 1% of adults over age 65 years. It’s believed bradyarrhythmias may be heritable. To treat serious cases of bradyarrhythmias, pacemakers are inserted in patients to help the heart maintain a normal, steady heart rate. However, pacemakers are invasive and place the patient at risk for complications.

We sought to identify genetic variants associated with bradyarrhythmia risk to better understand the genetic mechanisms behind bradyarrhythmias and potentially identify individuals at elevated risk.

What approach did you use?

We combined data from nine diverse genetic studies to identify both common and rare genetic variants associated with major subtypes of bradyarrhythmias: sinus node dysfunction, distal conduction disease and any bradyarrhythmia resulting in a pacemaker implant.

What did you find?

We identified 13, 31, and 21 common genes for sinus node dysfunction (SND), distal conduction disease (DCD), and pacemaker implantation (PM), respectively. Four key genetic regions were shared between SND and DCD, while others were more specific for either SND or DCD. We also identified several rare genetic variants that affect cardiac structure and function (such as LMNA, SMAD6, TTN, and MYBPC3) as well as ion channels (SCN5A). Our analysis suggests that certain modifiable risk factors, such as being overweight or having high blood pressure, may increase the risk of bradyarrhythmia. Finally, we developed a genetic risk score that can predict the likelihood of needing a pacemaker in the future.

What are the implications?

Our results demonstrate that variation in multiple genetic pathways (e.g., ion channel function, cardiac developmental programs, sarcomeric structure and cellular homeostasis) appear to be critical to the development of bradyarrhythmias. Our findings identify specific genes and respective pathways (e.g., SCN5A, SMAD6), as well as potentially causal risk factors (e.g., weight and blood pressure), which may represent targets for interventions designed to more effectively prevent and treat bradyarrhythmias.

What are the next steps?

Future experimental work to elucidate specific mechanisms by which candidate genes may affect bradyarrhythmia development is warranted.

Authorship: In addition to Weng, Khurshid, Ellinor and Lubitz, Mass General Brigham authors include Victor Nauffal, J. Michael Gaziano, Kelly Cho, and Aarno Palotie.

Paper cited: Weng L et al., “Common and rare variant contributions to bradyarrhythmias,” Nature Genetics DOI: 10.1038/s41588-024-01978-2

Funding: This work was supported by grants from the National Institutes of Health including R01HL139731 and R01HL157635. Part of this research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by award MVP001.

Disclosures: Lubitz is employed by Novartis as of July 2022. Previously, Lubitz received sponsored research support from Bristol Myers Squibb / Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, IBM, Medtronic, and Premier Inc., and consulted for Bristol Myers Squibb / Pfizer, Bayer AG, Blackstone Life Sciences, and Invitae. Ellinor has received sponsored research support from Bayer AG, IBM Research, Bristol Myers Squibb, Pfizer and Novo Nordisk; he has also served on advisory boards or consulted for Bayer AG and MyoKardia.