Lee Guan-Wei, Chen Jien-Jiun, Wang Chih-Hsien, Chang Sheng-Nan, Chiu Fu-Chun, Huang Pang-Shuo, Chua Su-Kiat, Chuang Eric Y, Tsai Chia-Ti
Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 106, Taiwan.
Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital Yun-Ling Branch, Dou-Liu City, Taiwan.
Europace. 2025 Mar 28;27(4). doi: 10.1093/europace/euaf042.
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.
全基因组关联研究（GWAS）已在100多个与心房颤动（AF）相关的基因组区域中鉴定出常见的单核苷酸多态性（SNP）。我们旨在通过多阶段GWAS在台湾人群中鉴定新的AF基因。
在探索阶段，我们对来自台湾大学AF登记处的516例AF患者和来自台湾生物银行的5160例正常窦性心律对照进行了全基因组基因型（4512191个SNP）的GWAS。显著位点在1002例独立患者和2003例对照以及英国生物银行中得到重复验证。进行了表达数量性状位点（eQTL）定位和全转录组关联研究（TWAS）以阐明功能意义。第一阶段GWAS揭示了三个与AF相关且具有全基因组显著性水平的位点，包括一个靠近PITX2基因（染色体4q25，rs2723329，次要等位基因频率[MAF] 0.50对0.41，P = 1.53×10-10），另一个靠近RAP1A基因（也靠近先前的KCND3；染色体1p13.2，rs7525578，MAF 0.17对0.07，P = 1.24×10-26），以及一个靠近HNF4G基因的新位点（染色体8q21.13，rs2980218，MAF 0.44对0.35，P = 2.19×10-9）。它们在第二阶段人群中得到验证。eQTL分析显示1p13.2位点与成纤维细胞中RAP1A基因表达以及8q21.13位点与淋巴细胞中HNF4G表达存在显著共定位。在TWAS中，成纤维细胞中的RAP1A基因表达和淋巴细胞及大脑中的HNF4G与AF存在显著关联。
台湾的全基因组关联研究揭示了PITX2和RAP1A/KCND3位点以及新的AF位点（HNF4G），其中RAP1A位点最为显著。RAP1A和HNF4G基因可能在AF发病机制中涉及纤维化、代谢和神经源性途径。
