Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

In Memoriam: Herbert E Wright Jr 1917-2015

Herbert E Wright Jr was one of the foremost Quaternary scientists of the last century. He made wide ranging contributions to our understanding of the late-Quaternary of North and South America, Europe, Asia and Africa. This was based largely on reconstructing palaeoenvironments from lake sediments and included the important implications for glacial, vegetational, fire and climatic history, geoarchaeology and conservation. Many of his inter-disciplinary research projects involved fieldwork with his graduate students and co-workers from the University of Minnesota where he created and led the renowned Limnological Research Center. Perhaps his most outstanding contribution was as an instigator of the Co-operative Holocene Mapping Project (COHMAP). This triggered a paradigm shift in Holocene climatic research involving the comparison of climate-model simulations of past climates with palaeoclimatic data.