Background:The aortic valve is an important determinant of cardiovascular physiology and anatomic location of common human diseases.Methods:From a sample of 34 287 white British ancestry participants, we estimated functional aortic valve area by planimetry from prospectively obtained cardiac magnetic resonance imaging sequences of the aortic valve. Aortic valve area measurements were submitted to genome-wide association testing, followed by polygenic risk scoring and phenome-wide screening, to identify genetic comorbidities.Results:A genome-wide association study of aortic valve area in these UK Biobank participants showed 3 significant associations, indexed by rs71190365 (chr13:50764607, DLEU1, P=1.8×10⁻⁹), rs35991305 (chr12:94191968, CRADD, P=3.4×10⁻⁸), and chr17:45013271:C:T (GOSR2, P=5.6×10⁻⁸). Replication on an independent set of 8145 unrelated European ancestry participants showed consistent effect sizes in all 3 loci, although rs35991305 did not meet nominal significance. We constructed a polygenic risk score for aortic valve area, which in a separate cohort of 311 728 individuals without imaging demonstrated that smaller aortic valve area is predictive of increased risk for aortic valve disease (odds ratio, 1.14; P=2.3×10⁻⁶). After excluding subjects with a medical diagnosis of aortic valve stenosis (remaining n=308 683 individuals), phenome-wide association of >10 000 traits showed multiple links between the polygenic score for aortic valve disease and key health-related comorbidities involving the cardiovascular system and autoimmune disease. Genetic correlation analysis supports a shared genetic etiology with between aortic valve area and birth weight along with other cardiovascular conditions.Conclusions:These results illustrate the use of automated phenotyping of cardiac imaging data from the general population to investigate the genetic etiology of aortic valve disease, perform clinical prediction, and uncover new clinical and genetic correlates of cardiac anatomy.

中文翻译：

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来自 34 287 名英国生物库参与者的主动脉瓣区域心脏成像揭示了新的遗传关联和与多种疾病表型的共同遗传共病

背景：主动脉瓣是心血管生理学和常见人类疾病解剖位置的重要决定因素。方法：我们从 34 287 名英国白人血统参与者的样本中，通过前瞻性获得的心脏磁共振成像序列的平面测量法估计功能性主动脉瓣面积。主动脉瓣。将主动脉瓣面积测量值提交给全基因组关联测试，然后进行多基因风险评分和全表型筛查，以确定遗传合并症。结果：这些英国生物库参与者的主动脉瓣面积全基因组关联研究显示 3 个显着关联, 由 rs71190365 (chr13:50764607, DLEU1 , P =1.8×10 ^-9 ), rs35991305 (chr12:94191968, CRADD ) 索引, P =3.4×10 ^-8 )，chr17:45013271:C:T ( GOSR2 , P =5.6×10 ^-8 )。尽管 rs35991305 不符合名义显着性，但对一组独立的 8145 名无关欧洲血统参与者的复制在所有 3 个基因座中显示出一致的效应大小。我们构建了主动脉瓣区域的多基因风险评分，在一个单独的 311 728 名没有影像学检查的个体队列中表明，较小的主动脉瓣面积可预测主动脉瓣疾病的风险增加（优势比，1.14；P =2.3×10 ^-6）。在排除医学诊断为主动脉瓣狭窄的受试者（剩余 n = 308 683 人）后，>10 000 个特征的全表型关联显示主动脉瓣疾病的多基因评分与涉及心血管系统的关键健康相关合并症之间存在多重联系和自身免疫性疾病。遗传相关分析支持主动脉瓣面积和出生体重以及其他心血管疾病之间的共同遗传病因。结论：这些结果说明使用来自普通人群的心脏成像数据的自动表型来研究主动脉瓣疾病的遗传病因，进行临床预测，并发现心脏解剖学的新临床和遗传相关性。