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

IF 7.4 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Europace Pub Date : 2025-03-28 DOI:10.1093/europace/euaf042
Guan-Wei Lee, Jien-Jiun Chen, Chih-Hsien Wang, Sheng-Nan Chang, Fu-Chun Chiu, Pang-Shuo Huang, Su-Kiat Chua, Eric Y Chuang, Chia-Ti Tsai
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引用次数: 0

Abstract

Aims: 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.

Methods and results: 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.

Conclusion: 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.

通过全基因组和转录组关联研究鉴定台湾人群心房颤动的新基因位点。
背景:全基因组关联研究(GWASs)在100多个与房颤(AF)相关的基因组区域中发现了常见的单核苷酸多态性(snp)。我们的目的是通过多阶段GWAS鉴定台湾人群中新的房颤基因。方法:在探索阶段,我们对516名来自国立台湾大学房颤登记中心(NTUAFR)的房颤患者和5160名来自台湾生物库的正常窦性心律对照者进行了全基因组基因型(4,512,191个snp)的GWAS。在1002名独立患者和2003名对照以及UK biobank中复制了重要的基因座。我们进行了表达数量性状位点(eQTL)定位和转录组全关联研究(TWAS),以了解其功能意义。结果:I期GWAS发现3个与AF相关的位点,且具有全基因组显著性水平,其中1个位点靠近PITX2基因(染色体4q25, rs2723329,次要等位基因频率[MAF] 0.50 vs 0.41, P=1.53×10-10), 1个位点靠近RAP1A基因(也与先前的KCND3;染色体1p13.2, rs7525578, MAF 0.17 vs 0.07, P= 1.24×10-26)和一个接近HNF4G基因的新位点(染色体8q21.13, rs2980218, MAF 0.44 vs 0.35, P=2.19×10-9)。它们在II期人群中得到了验证。eQTL分析显示,成纤维细胞中表达RAP1A基因的1p13.2位点和淋巴细胞中表达HNF4G基因的8q21.13位点存在显著共定位。结论:台湾地区GWAS在成纤维细胞中发现了PITX2、RAP1A/KCND3位点和新的AF位点(HNF4G),其中RAP1A位点最显著。RAP1A和HNF4G基因在房颤的发病机制中可能涉及纤维化、代谢和神经发生途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Europace
Europace 医学-心血管系统
CiteScore
10.30
自引率
8.20%
发文量
851
审稿时长
3-6 weeks
期刊介绍: EP - Europace - European Journal of Pacing, Arrhythmias and Cardiac Electrophysiology of the European Heart Rhythm Association of the European Society of Cardiology. The journal aims to provide an avenue of communication of top quality European and international original scientific work and reviews in the fields of Arrhythmias, Pacing and Cellular Electrophysiology. The Journal offers the reader a collection of contemporary original peer-reviewed papers, invited papers and editorial comments together with book reviews and correspondence.
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