BACKGROUND Genome-wide association studies (GWAS) have yielded variants at >30 loci that associate with atrial fibrillation (AF), including rare coding mutations in the sarcomere genes MYH6 and MYL4. OBJECTIVES The aim of this study was to search for novel AF associations and in doing so gain insights into the mechanisms whereby variants affect AF risk, using electrocardiogram (ECG) measurements. METHODS The authors performed a GWAS of 14,255 AF cases and 374,939 controls, using whole-genome sequence data from the Icelandic population, and tested novel signals in 2,002 non-Icelandic cases and 12,324 controls. They then tested the AF variants for effect on cardiac electrical function by using measurements in 289,297 ECGs from 62,974 individuals. RESULTS The authors discovered 2 novel AF variants, the intergenic variant rs72700114, between the genes LINC01142 and METTL11B (risk allele frequency = 8.1%; odds ratio [OR]: 1.26; p = 3.1 × 10-18), and the missense variant p.Gly4098Ser in PLEC (frequency = 1.2%; OR: 1.55; p = 8.0 × 10-10), encoding plectin, a cytoskeletal cross-linking protein that contributes to integrity of cardiac tissue. The authors also confirmed 29 reported variants. p.Gly4098Ser in PLEC significantly affects various ECG measurements in the absence of AF. Other AF variants have diverse effects on the conduction system, ranging from none to extensive. CONCLUSIONS The discovery of a missense variant in PLEC affecting AF combined with recent discoveries of variants in the sarcomere genes MYH6 and MYL4 points to an important role of myocardial structure in the pathogenesis of the disease. The diverse associations between AF variants and ECG measurements suggest fundamentally different categories of mechanisms contributing to the development of AF.

中文翻译：

---

PLEC 中的一个错义变异增加了心房颤动的风险

背景 全基因组关联研究 (GWAS) 已在超过 30 个与心房颤动 (AF) 相关的基因座上产生变异，包括肌节基因 MYH6 和 MYL4 中的罕见编码突变。目的 本研究的目的是寻找新的 AF 关联，并在此过程中使用心电图 (ECG) 测量深入了解变异影响 AF 风险的机制。方法 作者使用冰岛人群的全基因组序列数据对 14,255 名 AF 病例和 374,939 名对照进行了 GWAS，并在 2,002 名非冰岛病例和 12,324 名对照中测试了新信号。然后，他们通过使用来自 62,974 个人的 289,297 个心电图的测量结果来测试 AF 变体对心脏电功能的影响。结果 作者发现了 2 个新的 AF 变异，即基因间变异 rs72700114，基因 LINC01142 和 METTL11B（风险等位基因频率 = 8.1%；优势比 [OR]：1.26；p = 3.1 × 10-18）和 PLEC 中的错义变体 p.Gly4098Ser（频率 = 1.2%；OR：1.55； p = 8.0 × 10-10)，编码 plectin，一种有助于心脏组织完整性的细胞骨架交联蛋白。作者还确认了 29 个报告的变异。在没有 AF 的情况下，PLEC 中的 p.Gly4098Ser 显着影响各种 ECG 测量。其他 AF 变体对传导系统有不同的影响，从无到广泛。结论 PLEC 中影响 AF 的错义变异的发现，结合最近发现的肌节基因 MYH6 和 MYL4 中的变异，表明心肌结构在该疾病的发病机制中具有重要作用。