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

Abstract

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 MRI 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 three 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 8,145 unrelated European-ancestry participants showed consistent effect sizes in all three 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 birthweight 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.

Heart-brain connections: phenotypic and genetic insights from 40,000 cardiac and brain magnetic resonance images

“…The majority of brain structural MRI traits are highly heritable (heritability ranges from 0.6 to 0.8) 29 and the heritability of brain functional connectivity is largely between 0.2 and 0.6 30 . A few recent genome-wide association study (GWAS) have been separately conducted on CMR [31][32][33][34][35][36] and brain MRI traits [37][38][39][40][41][42] . Although MRI is widely used in clinical research and genetic mapping, few studies have used multiorgan MRI to examine heart-brain connections and identify the heart's and brain's shared genetic signatures.…”

“…To evaluate the genetic determinates underlying heart-brain connections, we performed GWAS for the 82 CMR traits to uncover the genetic architecture of heart and aorta. In comparison to existing GWAS of CMR traits [31][32][33][34][35][36] , our study used a much broader group of cardiac and aortic traits, which allowed us to identify the shared genetic components with a wide variety of brain-related complex traits and disorders. For example, Pirruccello, et al 35 mainly focused on 9 measures of the right heart, Aung, et al 31 analyzed 6 LV traits, and Thanaj, et al 36 studied 3 traits of diastolic function.…”

Genomic and transcriptomic data analyses highlight KPNB1 and MYL4 as novel risk genes for congenital heart disease

“…The SNP rs11570508 associated with general CHD is located in a region that contains several genes linked to heart development, CHD and other cardiac phenotypes; MYL4, CDC27, GOSR2 and WNT9B (Goddard et al, 2017;Lahm et al, 2021;Orr et al, 2015;Sabour et al, 2018). A recent GWAS study on patients with anomalies of thoracic arteries and veins identified three significant SNPs within the GOSR2 locus in chromosome 17 close to rs11570508 (Lahm et al, 2021), and the chr17:45013271_T_C (rs17608766) variant in GOSR2 has been associated with a reduced aortic valve area (Córdova-Palomera et al, 2020) indicating importance of this locus in cardiac development.…”

Using Machine Learning to Elucidate the Spatial and Genetic Complexity of the Ascending Aorta

“…For example, SNPs near GOSR2 have previously been implicated in variations in aortic valve area, aortic root diameter, and other cardiac dimensions. [24][25][26][27] Further, PALMD has been implicated as a susceptibility gene for calcific aortic stenosis. 24,28,29 This agreement lends credence to interesting novel loci, such as aortic root diameter's association with SNP rs80036911 on MECOM, a gene previously associated with left ventricular trabeculation.…”