Identification of two new genetic loci associated with atrial fibrillation in the Taiwanese population- implication of metabolism and fibrosis in atrial fibrillation mechanism

BackgroundGenome-wide association studies (GWASs) have identified common single nucleotide polymorphisms (SNPs) in more than 100 genomic regions associated with atrial fibrillation (AF). Genes for AF identified by GWAS in the Caucasian populations may show ethnic differences in the Asian populations. We sought to identify other novel AF genes in the Taiwanese population by multi-stage GWAS. MethodsIn exploratory stage, GWAS with whole genome genotypes (4,512,191 SNPs) were done in 516 young AF Patients (58.1{+/-}8.7 years-old, 438 men [84.9%]) from the National Taiwan University AF registry (NTUAFR) and 5160 normal sinus rhythm controls (57.8 {+/-}8.7 years-old, 2460 men [47.7%]) from Taiwan Biobank. Significant loci were replicated in 1002 independent AF patients and 2003 NSR controls, and also in UK biobank (5630 AF cases and 24000 NSR controls). Quantitative trait locus mapping was performed to implicate functional significance. ResultsStage I GWAS revealed 3 loci associated with AF with the genome-wide significance level, which included locus close to previously reported PITX2 gene (chromosome 4q25, rs2723329, P=1.53x10-10) and two novel loci close to RAP1A and HNF4G genes (chromosome 1p13.2, rs7525578, P= 1.24x10-26; chromosome 8q21.13, rs2980218, P=2.19x10-9, respectively). They were further validated in a stage II replication population (P=4.60x10-9, 4.45x10-10 and 6.97x10-5 for RAP1A, PITX2 and HNF4G, respectively). These 3 genes were also validated in the UK population. These 3 significant SNPs also show significant association with tissue expressions (RAP1A expression in thyroid, PITX2 in testicular, and HNF4G in lymphocyte tissues, respectively). ConclusionsGWAS in Taiwan revealed previously reported PITX2 and two novel AF genes (RAP1A and HNF4G) with the most significant locus in RAP1A. RAP1A and HNF4G genes may implicate fibrosis and metabolic pathways, respectively, in the mechanism of AF.