Veterans Affairs (VA) Palo Alto Healthcare System, Palo Alto, CA, USA.
Department of Surgery, Stanford University School of Medicine, Palo Alto, CA, USA.
Nat Genet. 2023 Jul;55(7):1106-1115. doi: 10.1038/s41588-023-01420-z. Epub 2023 Jun 12.
The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size.
目前对胸主动脉瘤和夹层（TAAD）遗传决定因素的认识主要是通过对罕见的孟德尔形式疾病的研究得出的。在这里，我们对 TAAD 进行了全基因组关联研究（GWAS），在百万退伍军人计划中对 8626 名有和 453043 名无 TAAD 的参与者以及来自六个队列的 4459 名有和 512463 名无 TAAD 的独立样本中进行了测试，检测了约 2500 万个 DNA 序列变体。我们确定了 21 个 TAAD 风险位点，其中 17 个以前没有报道过。我们利用多种下游分析方法来确定因果 TAAD 风险基因和细胞类型，并提供人类遗传证据表明，TAAD 是一种非动脉粥样硬化性主动脉疾病，与其他形式的血管疾病不同。我们的研究结果表明，TAAD 的遗传结构与其他复杂特征相似，并且它不仅仅通过大效应尺寸的蛋白改变变体遗传。
