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Multi-ancestry GWAS Identifies 141 New Loci Underlying Cardiac Conduction

Key findings

  • To better understand the genetic and biological mechanisms of atrioventricular conduction, an international research team conducted a multi-ancestry meta-analysis of 40 genome-wide association studies (N=293,051)
  • 202 loci were significant, including 141 loci not previously reported, and in an analysis of the UK Biobank, these loci explained 62.6% of variant-based heritability of the PR interval
  • Further experiments underscored a central role of heart development and cytoskeletal components in atrioventricular conduction
  • Application of polygenic risk scores showed links between genetically determined PR interval duration and several adult-onset complex cardiovascular diseases, notably arrhythmias and conduction disorders

The PR interval on an electrocardiogram reflects conduction from the atria to the ventricles. Pathological variation in the PR interval may indicate elevated risk of atrial fibrillation (AF) and cardiovascular mortality. Genetic association studies have identified 64 PR interval loci, but their relationship to cardiac conduction has not been well understood. Lu-Chen Weng, PhD, of the Cardiovascular Research Center, Ioanna Ntalla, PhD, MSc, Gilead Sciences, Steven A. Lubitz, MD, MPH, cardiac electrophysiologist in the Cardiac Arrhythmia Service at Massachusetts General Hospital, and Patricia B. Monroe, MD, of the Queen Mary University of London, co-senior authors, published an international study that provides major insights into the polygenic basis of cardiac conduction and the genetic relationship between PR interval duration and arrhythmias. The study is published in Nature Communications.

Meta-analysis of GWASs

The researchers performed a meta-analysis of 40 genome-wide association studies (GWAS) that collectively included 293,051 individuals. The analysis was multi-ancestry: European (92.6%), Latino (4%), African (2.7%) and Brazilian (<1%). The team identified 202 genome-wide significant loci with links to PR interval duration, of which 141 had not been previously reported.

Heritability Analysis

Using data on 59,097 European participants in the UK Biobank, the researchers calculated the percentage of variant-based heritability of the PR interval. When they considered only the 64 previously reported loci, the percentage was 33.5%. However, when they considered all loci they discovered, the percentage was 62.6%.

Key Pathways

The researchers then investigated pathways and tissues/cell types where genes from the loci they identified are highly expressed. Several biological processes were found to underlie atrioventricular conduction:

  • Heart development
  • Actin cytoskeleton organization
  • Cell junction/cell signaling
  • Ion channel signaling (this association was already well known)

Polygenic Risk Scores

Lastly, the researchers examined relationships between cardiovascular diseases/conditions and genetic variants linked to PR interval duration. They performed a meta-analysis of multiple European GWASs and used the results to create a polygenic risk score for PR interval. They then applied the score to about 309,000 participants in the UK Biobank who had not been included in either the multi-ancestry or European meta-analysis.

Genetically determined PR interval prolongation was associated with:

  • Significantly higher risk of atrioventricular block and pacemaker implantation
  • Significantly reduced risk of AF
  • Marginally reduced risk of atrioventricular pre-excitation (Wolff–Parkinson–White syndrome)

Results were similar when the researchers derived a polygenic risk score from the multi-ancestry meta-analysis.

Looking Ahead

This new knowledge about the regulation of atrioventricular conduction may lead to potentially novel approaches to drug development for the prevention and treatment of heart disease. It may also prompt advanced screening methods to flag individuals at the greatest risk of arrhythmias and associated mortality.

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