Abstract 11789: Genetic Determinants of Interventricular Septal Anatomy and Risk of Congenital Heart Disease

Background: A large proportion of genetic risk remains unexplained for structural heart disease involving the interventricular septum (IVS) including hypertrophic cardiomyopathy (HCM) and ventricular septal defects (VSD). Methods: We performed machine learning to estimate the cross-sectional area of the interventricular septum (IVS.csad) from the 4-chamber view of cardiac MRI in 32,219 individuals from the UK Biobank. We related IVS.csad to relevant clinical phenotypes, and performed 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 an 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 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 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 allowed discovery of loci related to cardiac development and Mendelian disease. Inheritance of genetic liability for either large or small interventricular septum, appears to confer risk for HCM or VSD respectively, suggesting that a proportion of risk for structural and congenital heart disease may localize to the common genetic determinants of cardiovascular anatomy.