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Abstract：
Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 × 10-18) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 × 10-11) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.
摘要：
心房颤动(房颤)是一种常见的心律失常,是脑卒中的主要危险因素。心力衰竭,过早死亡。房颤的发病机制仍然知之甚少，这导致了目前缺乏高效的治疗方法。为了了解AF的遗传变异和生物学基础，我们对来自挪威的6,337例房颤个体和61,607例无房颤个体进行了全基因组关联研究(GWAS),包括30,679例房颤个体和278,895例无房颤个体的复制。通过全基因组测序的基因分型和密集插补作图，我们在整个基因组中测试了近900万个遗传变异，并确定了七个风险位点，包括两个新颖的基因座。一个新的基因座（前导单核苷酸变体[SNV]rs12614435;p=6.76×10-18）包含内含子和位于I-中的几个高度相关的错义变体，A-,和肌动蛋白的M波段，它是人类中最大的蛋白质，负责心脏和骨骼肌的被动弹性。另一个新的基因座（前导SNVrs56202902;p=1.54×10-11）覆盖了一个大的，以前与心脏传导有关的基因密集的1号染色体区域。途径和功能富集分析表明，许多与AF相关的遗传变异是通过胎儿心脏发育过程中肌细胞分化和组织形成受损的机制起作用的。
