Single‐Cell Transcriptomics and Mendelian Randomization Analysis Reveal Key Genes in Atrial Fibrillation

BACKGROUND: Atrial fibrillation (AF) is one of the most common cardiac arrhythmias. It reduces quality of life and increases the risk of complications such as stroke. Although progress has been made in understanding its pathogenesis, the key cellular subtypes and therapeutic targets remain unclear. METHODS: We applied single-cell transcriptomics to identify critical cellular subtypes in AF. High-dimensional weighted gene co-expression network analysis (hdWGCNA) and machine learning were used to screen AF-related genes. Mendelian randomization (MR) and colocalization analyses were performed to assess causal relationships between these genes and AF. RESULTS: Single-cell analysis showed a significant increase in macrophages in AF, especially SPP1-expressing macrophages, which may drive AF onset and progression. HdWGCNA identified AF-related gene modules. Three genes, LRCH1, RSRC2 and VAMP2, were found to be causally associated with AF. MR analysis confirmed their significant causal effects. CONCLUSIONS: The accumulation of SPP1-expressing macrophages may drive the onset and progression of AF. Furthermore, LRCH1, RSRC2, and VAMP2 were identified as key causal genes for AF, providing novel insights into its molecular mechanisms and potential therapeutic targets.