Cardiac imaging of aortic valve area from 26,142 UK Biobank participants reveal novel genetic associations and shared genetic comorbidity with multiple disease phenotypes

Abstract

The aortic valve is an important determinant of cardiovascular physiology and anatomic location of common human diseases. From a sample of 26,142 European-ancestry participants, we estimated functional aortic valve area by planimetry from prospectively obtained cardiac MRI sequences of the aortic valve. A genome-wide association study of aortic valve area in these UK Biobank participants showed two significant associations indexed by rs71190365 (chr13:50764607, DLEU1, p=1.8e-9) and rs35991305 (chr12:94191968, CRADD, p=3.4e-8). From the GWAS findings 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 0.88, p=2.3e-6). After excluding subjects with a medical diagnosis of aortic valve stenosis (remaining n=310,546 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 size and birthweight along with other cardiovascular conditions. 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.

Computational estimates of mitral annular diameter in systole and diastole cardiac cycle reveal novel genetic determinants of valve function and disease

“…Previously identified in GWAS of blood pressure(37, 38) and aortic root diameter(38), the two variants in GOSR2 identified in systole (rs6504673) and diastole (rs533030436) display essentially no linkage in European populations (R2 0.02) and arise from different haplotypes [Figure S9]. The variant rs533030436 identified in diastolic measures is in strong linkage with rs11874 (R 2 0.84) recently identified in congenital cardiovascular malformations(39) as well as rs17608766 (R 2 0.76) identified in Aortic valve stenosis(27) in the same UK Biobank MRI dataset. The cusps and annulus of the mitral valve are composed primarily of endothelial cells and valvular interstitial cells which may differentiate to myofibroblasts in disease states(40).…”

“…We performed a phenome-wide association studies (PheWAS) to highlight clinical associations with up to 1,240 ICD-10 aggregated clinical phenotypes defined as phecodes(26). Methods are as previously described(27). For PheWAS results reported here, we excluded phenotypes with less than 50 individuals (for continuous traits) or less than 50 cases (for binary-coded traits) were excluded, and we corrected for multiple testing using a Bonferroni adjustment.…”

Progress and Research Priorities in Imaging Genomics for Heart and Lung Disease: Summary of an NHLBI Workshop

“…Several groups have recently developed DL models to derive clinically relevant phenotypic data from these images. [85][86][87] In addition, DL algorithms can identify diabetic retinopathy from retinal images with a higher risk of vision loss in individuals with diabetes. 88 There are several potential challenges in developing effective DL algorithms for phenotypic characterization, however.…”

Genetic determinants of interventricular septal anatomy and the risk of ventricular septal defects and hypertrophic cardiomyopathy

“…Given that IVS.csad is not a standard clinical measurement, using previously described methods 14 we performed a phenome-wide association studies (PheWAS) to highlight clinical associations with 67 cardiovascular phenotypes aggregated from ICD-10 codes as phecodes 15 .…”