Integrative analysis of transcriptome-wide association study data and mRNA expression profiles identified candidate genes and pathways associated with atrial fibrillation.

Abstract

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia characterized by extensive structural, contractile and electrophysiological remodeling. The genetic basis of AF remained elusive until now. Transcriptome-wide association study (TWAS) was conducted by FUSION tool using gene expression weights of 7 tissues combined with a large-scale genome-wide association study (GWAS) dataset of AF, totally involving 8180 AF cases and 28,612 controls. Significant genes identified by TWAS were then subjected to gene ontology (GO) and pathway enrichment analysis. The genome-wide mRNA gene expression profiling of AF was compared with the results of TWAS to detect common genes shared by TWAS and mRNA expression profiling of AF. TWAS detected a group of candidate genes with PTWAS values < 0.05 across the seven tissues for AF, such as CMAH (PTWAS = 3.15 × 10-25 for whole blood), INCENP (PTWAS = 1.77 × 10-22 for artery aorta), CMAHP (PTWAS = 4.57 × 10-20 for artery aorta). Pathway enrichment analysis identified multiple candidate pathways, such as protein K48-linked ubiquitination (P value = 0.0124), positive regulation of leukocyte chemotaxis (P value = 0.0046) and fatty acid degradation (P value = 0.0295). Further comparing the GO results of TWAS and mRNA expression profiling, 2 common GO terms were identified, including actin binding (PTWAS = 0.0446, PmRNA = 7.00 × 10-4) and extracellular matrix (PTWAS = 0.0037, PmRNA = 3.00 × 10-6). We detected multiple novel candidate genes, GO terms and pathways for AF, providing novel clues for understanding the genetic mechanism of AF.