Genome and Transcriptome-Wide Analyses Identify Multiple Candidate Genes and a Significant Polygenic Contribution in Bicuspid Aortic Valve.

Despite this, only a limited number of genes have been associated with the disease, and the molecular mechanisms remain unexplained in most cases.

尽管如此，与该疾病相关的基因数量有限，而且在大多数情况下，分子机制仍然无法解释。

This study aimed to further understand the genetic architecture of BAV.

本研究旨在进一步了解主动脉瓣二叶畸形（BAV）的遗传结构。

Methods

A genome-wide association study meta-analysisincluding 9631 cases among 65 677 participants was performed.

本研究进行了包括65,677名参与者中的9631例病例的全基因组关联研究荟萃分析。

Genes were prioritized using transcriptomic analyses based on RNA sequencing in relevant tissues, including human fetal and adult aortic valves.

通过在相关组织中进行转录组分析，基于RNA测序，对基因进行了优先排序，包括人类胎儿和成人主动脉瓣膜。

The impact of the knockdown or knockout of 4 candidate genes on cardiac development was verified in zebrafish.

在斑马鱼中验证了敲低或敲除4个候选基因对心脏发育的影响。

A polygenic risk score was developed, its association with BAV was evaluated in an independent cohort, and its association with a wide range of phenotypes (n=976) was evaluated in UK Biobank (n=355 618 individuals).

开发了一种多基因风险评分，其与主动脉瓣狭窄（BAV）的关联在一个独立队列中得到评估，并在英国生物银行（n=355,618人）中评估了其与广泛表型（n=976）的关联。

Results

Thirty-six genomic loci were identified, including 32 that were not described previously.

确定了36个基因组位点，包括32个之前未描述过的。

Among the prioritized genes, KANK2 and ERBB4 were identified as potentially causal through transcriptomic analyses, colocalization, and Mendelian randomization based on gene expression in human aortic valves (n=484), whereas PRDM6 and STRN were prioritized using similar analyses from aortic (n=326) and left ventricular tissues (n=326), respectively.

在优先考虑的基因中，通过转录组分析、共定位和基于人类主动脉瓣（n=484）基因表达的孟德尔随机化，KANK2和ERBB4被识别为潜在的因果基因，而PRDM6和STRN则分别通过类似的分析从主动脉（n=326）和左心室组织（n=326）中被优先考虑。

Targeting 4 candidate genes (WNT4, LEF1, STRN, and KANK2) in zebrafish led to disruption in cardiac development.

在斑马鱼中针对4个候选基因（WNT4、LEF1、STRN和KANK2）的靶向导致了心脏发育的中断。

A polygenic risk score was associated with an odds ratio of 2.07 (95% CI, 1.90-2.25; P=5.43×10-62) per SD for BAV and significantly associated with thoracic aortic aneurysm and atrial fibrillation in UK Biobank.

多基因风险评分与主动脉瓣狭窄（BAV）的比值比为2.07（95%置信区间，1.90-2.25；P=5.43×10^-62），每标准差增加，且在英国生物银行中与胸主动脉瘤和房颤显著相关。

Conclusions

This study supports a significant polygenic contribution to BAV, where the combination of multiple common variants in genes involved in heart morphogenesis disrupts aortic valve development.

本研究支持多基因对主动脉瓣狭窄（BAV）有显著贡献，其中涉及心脏形态发生基因的多个常见变异的组合干扰了主动脉瓣的发育。