Abstract 11627: GWA Meta-Analysis on ST-T Wave Changes Identifies 12 Novel Loci for Human Cardiac Repolarization
Repolarization abnormalities of the heart have been linked to ventricular arrhythmias and sudden cardiac death. Duration of repolarization (QT interval) has been studied by genome wide association (GWA) studies. However, abnormalities of repolarization are not limited to changes in duration but concern changes in amplitudes as well. Therefore, we performed a GWA meta-analysis on amplitudes of the ST-segment and T-wave (ST-T wave) in 15,943 Dutch individuals from the general population. Amplitudes were measured trough the lateral, inferior, anterior, septal and aVR leads of the 12 lead electrocardiogram to define the spatial location. We evaluated 2 time points resulting in 10 traits: 5 for the ST segment (at 80ms after J point) and 5 for the T wave. Across 10 traits we identified 41 genotype-phenotype associations (P < 6.25E-9 based on 8 independent phenotypes) clustered within 17 independent loci. Twelve of the loci are novel determinants for cardiac repolarization. We observed that SNPs with P <6.25E-09 were 3.3 fold enriched for Dnase I hypersensitivity sites in human fetal heart (Z=3.2; compared to 337 other cell types and tissues) and >10 fold enriched for p300 enhancers in the human heart (P < 4E-7). This suggests that functional regulatory variants may contribute to several of the associations observed in this study. Furthermore the associations provide insights on the spatiotemporal contribution of genetic variation involved in cardiac repolarization: SNPs at KCND3, TNKS and KCNB1 showed specific associations with the ST-wave. Other loci (XPO1, KCNH2 and TBX3) were specific for the septal leads, possibly related to the function and location of structures such as the AV bundle and its branches. These analyses provide novel insights into the biology of cardiac repolarization and may help to elucidate diseases of cardiac repolarization.
Supported by the Netherlands Heart Foundation (grant NHS2010B280).
- © 2013 by American Heart Association, Inc.