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

Background: The interventricular septum (IVS) plays a primary role in cardiovascular physiology and a large proportion of genetic risk remains unexplained for structural heart disease involving the IVS such as hypertrophic cardiomyopathy (HCM) and ventricular septal defects (VSD). Objectives: We sought to develop a reproducible proxy of IVS structure from standard medical imaging, discover novel genetic determinants of IVS structure, and relate these loci to two rare diseases of the IVS. Methods: We performed machine learning to estimate the cross-sectional area of the interventricular septum (IVS.csad) obtained from the 4-chamber view of cardiac MRI in 32,219 individuals from the UK Biobank. Using these extracted measurement of IVS.csad we performed phenome-wide association to relate this proxy measure to relevant clinical phenotypes, followed by genome-wide association studies and Mendelian Randomization. Results: Automated measures of IVS.csad were highly accurate, and strongly correlated with anthropometric measures, blood pressure, and diagnostic codes related to cardiovascular physiology. A Single nucleotide polymorphism in the intron of CDKN1A was associated with IVS.csad (rs2376620, Beta 8.4 mm2, 95% confidence intervals (CI) 5.8 to 11.0, p=2.0e-10), and a common inversion incorporating KANSL1 predicted to disrupt local chromatin structure was associated with an increase in IVS.csad (Beta 8.6 mm2, 95% CI 6.3-10.9, p=1.3e-13). Mendelian Randomization suggested that inheritance of a larger IVS.csad was causal for HCM (Beta 2.45 log odds ratio (OR) HCM per increase in SD of IVS.csad, standard error (SE) 0.48, pIVW = 2.8e-7) while inheritance of a smaller IVS.csad was causal for VSD (Beta -2.06 log odds ratio (OR) VSD per decrease in SD of IVS.csad, SE 0.75, pIVW = 0.006) Conclusion: Automated derivation of the cross sectional area of the IVS from the 4-chamber view allowed discovery of loci mapping to genes related to cardiac development and Mendelian disease. Inheritance of a genetic liability for either large or small interventricular septum, appears to confer risk for HCM or VSD respectively, which suggests that a considerable proportion of risk for structural and congenital heart disease may be localized to the common genetic determinants of cardiovascular anatomy.