Identification of a new genetic locus associated with atrial fibrillation in the Taiwanese population by genome-wide and transcriptome-wide association studies

Genome-wide association studies (GWASs) identified common single-nucleotide polymorphisms (SNPs) in more than 100 genomic regions associated with atrial fibrillation (AF). We aimed to identify novel AF genes in Taiwanese population by multi-stage GWAS.

In exploratory stage, we did GWAS with whole-genome genotypes (4 512 191 SNPs) in 516 patients with AF from the National Taiwan University AF Registry and 5160 normal sinus rhythm controls from the Taiwan Biobank. Significant loci were replicated in 1002 independent patients and 2003 controls and in the UK Biobank. Expression quantitative trait locus (eQTL) mapping and transcriptome-wide association study (TWAS) were performed to implicate functional significance. Stage I GWAS revealed three loci associated with AF with a genome-wide significance level, including one close to PITX2 gene (chromosome 4q25, rs2723329, minor allele frequency [MAF] 0.50 vs. 0.41, P = 1.53 × 10⁻¹⁰), another close to RAP1A gene (also to previous KCND3; chromosome 1p13.2, rs7525578, MAF 0.17 vs. 0.07, P = 1.24 × 10⁻²⁶), and one novel locus close to HNF4G gene (chromosome 8q21.13, rs2980218, MAF 0.44 vs. 0.35, P = 2.19 × 10⁻⁹). They were validated in Stage II population. The eQTL analyses showed significant colocalization of 1p13.2 locus with RAP1A gene expression in fibroblasts and 8q21.13 locus with HNF4G expression in lymphocytes. There is a significant association of RAP1A gene expression in fibroblasts and HNF4G in lymphocytes and brain with AF in TWAS.

Genome-wide association study in Taiwan revealed PITX2 and RAP1A/KCND3 loci and novel AF locus (HNF4G) with the most significant locus in the RAP1A locus. RAP1A and HNF4G genes may implicate fibrosis, metabolic, and neurogenic pathways in pathogenesis of AF.