Yuan Yalin, Zheng Xin, Zhang Wenjing, Ren Zhaoyu, Liang Bin
Shanxi Medical University Taiyuan Shanxi China.
Department of Cardiovascular Medicine Second Hospital of Shanxi Medical University Taiyuan Shanxi China.
J Arrhythm. 2025 May 22;41(3):e70097. doi: 10.1002/joa3.70097. eCollection 2025 Jun.
Atrial fibrillation (AF), the most common cardiac arrhythmia, has been linked to numerous loci identified by genome-wide association studies (GWAS). However, the causal genes and underlying mechanisms remain unclear.
We conducted a cross-tissue transcriptome-wide association studies (TWAS) using the unified test for molecular signatures (UTMOST), integrating genetic data from the FinnGen R11 cohort (287 805 individuals) with gene expression profiles from the genotype-tissue expression (GTEx) project. To enhance reliability, we applied functional summary-based imputation (FUSION), fine-mapping of causal gene sets (FOCUS), and multi-marker analysis of GenoMic annotation (MAGMA) for gene prioritization, followed by Mendelian randomization (MR) and colocalization analyses. GeneMANIA was used to explore gene functions.
By integrating four TWAS approaches, this study identified five novel susceptibility genes significantly associated with AF risk. MR analysis further revealed that the gene expression levels of FKBP7, CEP68, and CAMK2D were positively associated with AF risk, while SPATS2L exhibited a significant protective effect. Colocalization analysis demonstrated that CEP68 and SPATS2L share causal variants with AF. Through comprehensive evaluation of multidimensional functional annotations and existing biological evidence, this study highlighted SPATS2L and CEP68 as potential functional candidate genes in AF pathogenesis.
This cross-tissue TWAS identified five novel AF susceptibility genes (CAMK2D, SPAST2L, CEP68, FKBP7, and SHRMOO3). Elevated expression of FKBP7, CEP68, and CAMK2D increases AF risk, while SPATS2L showed a protective effect, with colocalization analysis implicating CEP68 and SPATS2L as prioritized candidates. The integration of multi-omics approaches effectively unravels AF's genetic mechanisms.
心房颤动（AF）是最常见的心律失常，已与全基因组关联研究（GWAS）确定的众多基因座相关联。然而，因果基因和潜在机制仍不清楚。
我们使用分子特征统一检验（UTMOST）进行了跨组织全转录组关联研究（TWAS），将来自芬兰基因研究R11队列（287805人）的遗传数据与基因型-组织表达（GTEx）项目的基因表达谱相结合。为提高可靠性，我们应用基于功能摘要的插补（FUSION）、因果基因集精细定位（FOCUS）和基因组注释多标记分析（MAGMA）对基因进行优先级排序，随后进行孟德尔随机化（MR）和共定位分析。使用GeneMANIA探索基因功能。
通过整合四种TWAS方法，本研究确定了五个与AF风险显著相关的新的易感基因。MR分析进一步表明，FKBP7、CEP68和CAMK2D的基因表达水平与AF风险呈正相关，而SPATS2L具有显著的保护作用。共定位分析表明，CEP68和SPATS2L与AF共享因果变异。通过对多维功能注释和现有生物学证据的综合评估，本研究强调SPATS2L和CEP68是AF发病机制中潜在的功能候选基因。
这项跨组织TWAS确定了五个新的AF易感基因（CAMK2D、SPAST2L、CEP68、FKBP7和SHRMOO3）。FKBP7、CEP68和CAMK2D的表达升高会增加AF风险，而SPATS2L显示出保护作用，共定位分析表明CEP68和SPATS2L是优先候选基因。多组学方法的整合有效地揭示了AF的遗传机制。
