Aims The present study aims to characterise the genetic risk architecture of bicuspid aortic valve (BAV) disease, the most common congenital heart defect. Methods and results We carried out a genome-wide association study (GWAS) including 2,236 BAV patients and 11,604 controls. This led to the identification of a new risk locus for BAV on chromosome 3q29. The single nucleotide polymorphism (SNP) rs2550262 was genome-wide significant BAV-associated (P = 3.49 × 10−08) and was replicated in an independent case-control sample. The risk locus encodes a deleterious missense variant in MUC4 (p.Ala4821Ser), a gene that is involved in epithelial-to-mesenchymal transformation. Mechanistical studies in zebrafish revealed that loss of Muc4 led to a delay in cardiac valvular development suggesting that loss of MUC4 may also play a role in aortic valve malformation. The GWAS also confirmed previously reported BAV risk loci at PALMD (P = 3.97 × 10−16), GATA4 (P = 1.61 × 10−09), and TEX41 (P = 7.68 × 10−04). In addition, the genetic BAV architecture was examined beyond the single-marker level revealing that a substantial fraction of BAV heritability is polygenic and approximately 20% of the observed heritability can be explained by our GWAS data. Furthermore, we used the largest human single cell atlas for foetal gene expression and show that the transcriptome profile in endothelial cells is a major source contributing to BAV pathology. Conclusion Our study provides a deeper understanding of the genetic risk architecture of BAV formation on the single-marker and polygenic level.

中文翻译：

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阐明二叶式主动脉瓣疾病的遗传原因


目的 本研究旨在描述二叶式主动脉瓣 (BAV) 疾病（最常见的先天性心脏病）的遗传风险结构。方法和结果 我们开展了一项全基因组关联研究 (GWAS)，包括 2,236 名 BAV 患者和 11,604 名对照者。这导致在染色体 3q29 上鉴定出 BAV 的新风险位点。单核苷酸多态性 (SNP) rs2550262 与全基因组显着的 BAV 相关 (P = 3.49 × 10−08)，并在独立的病例对照样本中进行了复制。该风险基因座编码 MUC4 (p.Ala4821Ser) 中的有害错义变异，该基因参与上皮间质转化。对斑马鱼的机制研究表明，Muc4 的缺失会导致心脏瓣膜发育延迟，这表明 MUC4 的缺失也可能在主动脉瓣畸形中发挥作用。 GWAS 还证实了先前报道的 PALMD (P = 3.97 × 10−16)、GATA4 (P = 1.61 × 10−09) 和 TEX41 (P = 7.68 × 10−04) 的 BAV 风险位点。此外，对遗传 BAV 结构的检查超出了单标记水平，表明 BAV 遗传力的很大一部分是多基因的，并且大约 20% 的观察到的遗传力可以通过我们的 GWAS 数据来解释。此外，我们使用最大的人类单细胞图谱进行胎儿基因表达，并表明内皮细胞的转录组谱是 BAV 病理学的主要来源。结论 我们的研究在单标记和多基因水平上更深入地了解了 BAV 形成的遗传风险结构。