Cardiac Imaging of Aortic Valve Area From 34 287 UK Biobank Participants Reveals Novel Genetic Associations and Shared Genetic Comorbidity With Multiple Disease Phenotypes

Circ Genom Precis Med. 2020 Dec;13(6):e003014. doi: 10.1161/CIRCGEN.120.003014. Epub 2020 Oct 30.


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.

Keywords: aortic valve; birth weight; humans; molecular epidemiology; odds ratio.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aortic Valve / diagnostic imaging*
  • Aortic Valve / pathology
  • Aortic Valve Stenosis / diagnostic imaging
  • Aortic Valve Stenosis / genetics
  • Biological Specimen Banks*
  • Cardiovascular Diseases / diagnostic imaging*
  • Cardiovascular Diseases / genetics*
  • Comorbidity
  • Female
  • Genome, Human
  • Genome-Wide Association Study*
  • Humans
  • Magnetic Resonance Imaging*
  • Male
  • Middle Aged
  • Multifactorial Inheritance / genetics
  • Phenomics
  • Phenotype
  • Survival Analysis
  • United Kingdom