2023年6月12日出版的《自然—遗传学》杂志发表了美国宾夕法尼亚大学Scott M. Damrauer和斯坦福大学医学院Derek Klarin团队的最新成果，他们揭示了百万退伍军人项目中与胸主动脉瘤和主动脉夹层（TAAD）有关的全基因组关联研究。

研究人员对TAAD进行了一项全基因组关联研究（GWAS），在百万退伍军人项目中测试了8626名参与者和453043名没有TAAD参与者的2500万个DNA序列变异，并在包含4459名个体和512463名没有TAAD的独立样本中重复了该结果。研究人员确定了21个TAAD风险位点，其中17个是之前没有报告过的。研究人员利用多种下游分析方法来识别致病TAAD风险基因和细胞类型，并提供人类遗传证据，证明TAAD是一种不同于其他形式血管疾病的非动脉粥样硬化性主动脉疾病。

该研究结果表明，TAAD的遗传结构反映了其他复杂性状的遗传结构，并且它不仅仅通过蛋白质改变变异遗传。

据介绍，目前对TAAD遗传决定因素的理解很大程度上是通过对罕见孟德尔疾病的研究所获得。

附：英文原文

Title: Genome-wide association study of thoracic aortic aneurysm and dissection in the Million Veteran Program

Author: Klarin, Derek, Devineni, Poornima, Sendamarai, Anoop K., Angueira, Anthony R., Graham, Sarah E., Shen, Ying H., Levin, Michael G., Pirruccello, James P., Surakka, Ida, Karnam, Purushotham R., Roychowdhury, Tanmoy, Li, Yanming, Wang, Minxian, Aragam, Krishna G., Paruchuri, Kaavya, Zuber, Verena, Shakt, Gabrielle E., Tsao, Noah L., Judy, Renae L., Vy, Ha My T., Verma, Shefali S., Rader, Daniel J., Do, Ron, Bavaria, Joseph E., Nadkarni, Girish N., Ritchie, Marylyn D., Burgess, Stephen, Guo, Dong-chuan, Ellinor, Patrick T., LeMaire, Scott A., Milewicz, Dianna M., Willer, Cristen J., Natarajan, Pradeep, Tsao, Philip S., Pyarajan, Saiju, Damrauer, Scott M.

Issue&Volume: 2023-06-12

Abstract: 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. A genome-wide association study of thoracic aortic aneurysms and dissections (TAAD) in the Million Veteran Program identifies 17 new risk loci and demonstrates that the genetic architecture of TAAD mirrors that of other complex traits.

DOI: 10.1038/s41588-023-01420-z

Source: https://www.nature.com/articles/s41588-023-01420-z