RATIONALE Genome-wide association studies have identified over 100 genetic loci for atrial fibrillation (AF); recent work described an association between loss-of-function (LOF) variants in TTN and early-onset AF. OBJECTIVE We sought to determine the contribution of rare and common genetic variation to AF risk in the general population. METHODS The UK Biobank is a population-based study of 500 000 individuals including a subset with genome-wide genotyping and exome sequencing. In this case-control study, we included AF cases and controls of genetically determined white-European ancestry; analyses were performed using a logistic mixed-effects model adjusting for age, sex, the first 4 principal components of ancestry, empirical relationships, and case-control imbalance. An exome-wide, gene-based burden analysis was performed to examine the relationship between AF and rare, high-confidence LOF variants in genes with ≥10 LOF carriers. A polygenic risk score for AF was estimated using the LDpred algorithm. We then compared the contribution of AF polygenic risk score and LOF variants to AF risk. RESULTS The study included 1546 AF cases and 41 593 controls. In an analysis of 9099 genes with sufficient LOF variant carriers, a significant association between AF and rare LOF variants was observed in a single gene, TTN (odds ratio, 2.71, P=2.50×10-8). The association with AF was more significant (odds ratio, 6.15, P=3.26×10-14) when restricting to LOF variants located in exons highly expressed in cardiac tissue (TTNLOF). Overall, 0.44% of individuals carried TTNLOF variants, of whom 14% had AF. Among individuals in the highest 0.44% of the AF polygenic risk score only 9.3% had AF. In contrast, the AF polygenic risk score explained 4.7% of the variance in AF susceptibility, while TTNLOF variants only accounted for 0.2%. CONCLUSIONS Both monogenic and polygenic factors contribute to AF risk in the general population. While rare TTNLOF variants confer a substantial AF penetrance, the additive effect of many common variants explains a larger proportion of genetic susceptibility to AF.

中文翻译：

---

心房颤动风险的单基因和多基因贡献：国家生物库的结果。

RATIONALE全基因组关联研究已经确定了100多个心房颤动（AF）的基因位点；最近的工作描述了TTN中功能丧失（LOF）变异与早发性AF之间的关联。目的我们试图确定普通人群中罕见和常见的遗传变异对房颤风险的影响。方法UK Biobank是一项基于人口的研究，研究对象为50万个人，其中包括具有全基因组基因分型和外显子组测序的子集。在本病例对照研究中，我们纳入了AF病例和遗传确定的白欧洲血统的对照。使用Logistic混合效应模型进行了分析，该模型针对年龄，性别，血统的前4个主要组成部分，经验关系和病例对照失衡进行了调整。在整个外显子组中 进行了基于基因的负担分析，以检查具有10个以上LOF携带者的基因中AF与罕见的高可信度LOF变异之间的关系。使用LDpred算法估算了AF的多基因风险评分。然后，我们比较了AF多基因风险评分和LOF变异对AF风险的贡献。结果该研究包括1546例AF病例和41 593例对照。在对具有足够LOF变异体载体的9099个基因进行分析时，在单个基因TTN中观察到了AF与罕见LOF变异体之间的显着关联（比值比为2.71，P = 2.50×10-8）。当局限于位于心脏组织中高度表达的外显子中的LOF变异体（TTNLOF）时，与AF的关联更显着（几率，6.15，P = 3.26×10-14）。总体而言，有0.44％的个体携带TTNLOF变体，其中14％患有房颤。在个人中排名最高的0。AF多基因风险评分的44％只有9.3％患有AF。相反，AF多基因风险评分解释了AF敏感性变异的4.7％，而TTNLOF变异仅占0.2％。结论单基因和多基因因素均对一般人群的房颤风险有影响。尽管罕见的TTNLOF变体具有显着的AF渗透能力，但许多常见变体的累加效应说明了遗传对AF的敏感性更高。