Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk

Area of Science:

• Cardiovascular Genetics
• Genomics
• Molecular Cardiology

Background:

• Atrial fibrillation (AF) is a widespread heart rhythm disorder with significant genetic underpinnings.
• Understanding the genetic architecture of AF is crucial for developing targeted therapies.

Purpose of the Study:

• To meta-analyze genome and exome sequencing data to identify novel genetic associations with AF.
• To investigate the functional impact of identified genetic variants on atrial cardiomyocyte function.

Main Methods:

• Meta-analysis of genome and exome sequencing data from 36 studies (52,416 AF cases, 277,762 controls).
• Burden tests for rare coding variation and analysis of rare structural variants.
• CRISPR gene editing in stem-cell-derived atrial cardiomyocytes to assess gene function.

Main Results:

• Identified novel associations between AF and rare coding variants in MYBPC3, LMNA, PKP2, FAM189A2, and KDM5B.
• Discovered associations between AF and rare structural variants (deletions in CTNNA3, duplications of GATA4).
• CRISPR knockout of KDM5B disrupted atrial cardiomyocyte action potential duration and gene expression.

Conclusions:

• Rare coding and structural genetic variants significantly contribute to AF risk.
• Genetic links between AF and cardiomyopathies are highlighted.
• Findings expand the understanding of rare variant contributions to AF etiology.