National Heart and Lung Institute, Imperial College London, Programme in Cardiovascular Genetics and Genomics, London, UK.
Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, SW3 6NP, UK.
Nat Commun. 2022 Aug 3;13(1):4505. doi: 10.1038/s41467-022-32219-x.
Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-β, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.
升主动脉和降主动脉的弹性和面积是主动脉瘤和夹层以及其他心脑血管疾病的关键风险因素。我们利用英国生物库中多达 32590 名白种人的心脏磁共振成像（MRI）数据，进行了升主动脉和降主动脉弹性及面积的全基因组关联研究。我们鉴定出 102 个位点（包括 27 个新的关联），这些位点标记了与心血管发育、细胞外基质产生、平滑肌收缩和遗传性主动脉疾病相关的基因。功能分析突出了与主动脉弹性相关的四个信号通路（TGF-β、IGF、VEGF 和 PDGF）。我们还发现了与主动脉特征有关的性别特异性关联。我们构建了与主动脉特征相关的共表达网络，并应用表型广泛的孟德尔随机化（MR-PheWAS），为主动脉弹性在主动脉瘤发展中的因果作用提供了证据。多变量 MR 表明，主动脉弹性与脑白质高信号之间存在因果关系，从机制上联系了主动脉特征和脑小血管疾病。
