Genetic basis and causal relationship between atrial fibrillation and sinus node dysfunction: Evidence from...

Area of Science:

• Cardiovascular Genetics
• Electrophysiology
• Genomic Epidemiology

Background:

• Atrial fibrillation (AF) and sinus node dysfunction (SND) frequently coexist clinically.
• The underlying genetic architecture and causal links between AF and SND remain largely unexplored.

Purpose of the Study:

• To investigate the genetic correlation and shared genetic factors between AF and SND.
• To identify novel pleiotropic and functional genes implicated in both conditions.
• To elucidate the causal relationship between AF and SND using Mendelian randomization.

Main Methods:

• Utilized LDSC and HESS for global and local genetic correlation analyses.
• Performed cross-trait meta-analyses and colocalization to identify shared SNPs and pleiotropic genes.
• Employed LDSC-SEG, MAGMA, SMR, TSMR, and MVMR for gene enrichment, functional gene identification, and causal inference.

Main Results:

• Demonstrated a significant positive genetic correlation between AF and SND.
• Identified shared genetic loci, including prominent regions on chr4 and chr11.
• Discovered ENPEP and PITX2 as novel pleiotropic genes and CEP68 and BEST3 as potential functional genes.
• Mendelian randomization analysis revealed that AF causally increases the risk of SND.

Conclusions:

• Provides robust genetic evidence for an increased risk of SND associated with AF.
• Highlights shared genetic risk loci and tissue enrichment patterns.
• Identifies novel pleiotropic and functional genes, advancing understanding of AF-SND interplay.