Abstract
ABSTRACTBackgroundGenome-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 reportedPITX2gene (chromosome 4q25, rs2723329,P=1.53×10−10) and two novel loci close toRAP1AandHNF4Ggenes (chromosome 1p13.2, rs7525578,P= 1.24×10−26; chromosome 8q21.13, rs2980218,P=2.19×10−9, respectively). They were further validated in a stage II replication population (P=4.60×10−9, 4.45×10−10and 6.97×10−5forRAP1A, PITX2andHNF4G, respectively). These 3 genes were also validated in the UK population. These 3 significant SNPs also show significant association with tissue expressions (RAP1Aexpression in thyroid,PITX2in testicular, andHNF4Gin lymphocyte tissues, respectively).ConclusionsGWAS in Taiwan revealed previously reportedPITX2and two novel AF genes (RAP1AandHNF4G) with the most significant locus inRAP1A.RAP1AandHNF4Ggenes may implicate fibrosis and metabolic pathways, respectively, in the mechanism of AF.
Publisher
Cold Spring Harbor Laboratory