Journal
NATURE GENETICS
Volume 46, Issue 8, Pages 826-836Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3014
Keywords
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Categories
Funding
- British Heart Foundation [RG/13/16/30528, RG/10/12/28456, PG/12/38/29615] Funding Source: Medline
- Medical Research Council [MC_PC_U127592696, MR/K006584/1, MR/K013351/1, G9521010, MC_UU_12015/1, MC_PC_U127561128, G0701863, MC_U106179471] Funding Source: Medline
- NCATS NIH HHS [UL1 TR000114, UL1 TR000124, UL1 TR000142] Funding Source: Medline
- NHGRI NIH HHS [R01 HG004037, T32 HG002295] Funding Source: Medline
- NHLBI NIH HHS [R01 HL120393, K23 HL080025, R01 HL111267, R01 HL098283, R01 HL105993, R01 HL113933, R01 HL117626, R01 HL105756] Funding Source: Medline
- NIDDK NIH HHS [U01 DK094176, P30 DK072488, P30 DK063491] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007753, R01 GM104469] Funding Source: Medline
- Chief Scientist Office [CZB/4/710] Funding Source: Medline
- British Heart Foundation [PG/12/38/29615, RG/10/12/28456, RG/13/16/30528] Funding Source: researchfish
- Chief Scientist Office [CZB/4/710] Funding Source: researchfish
- Economic and Social Research Council [ES/K005774/1, ES/J023299/1, ES/H029745/1, ES/K005146/1] Funding Source: researchfish
- Medical Research Council [MR/K013351/1, MC_PC_U127561128, G0701863, MR/K006584/1, G9521010, MC_U106179471, MC_PC_U127592696, MC_UU_12015/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10170, NF-SI-0512-10113] Funding Source: researchfish
- Division Of Mathematical Sciences
- Direct For Mathematical & Physical Scien [1228248] Funding Source: National Science Foundation
- Div Of Biological Infrastructure
- Direct For Biological Sciences [0644282] Funding Source: National Science Foundation
- ESRC [ES/K005774/1, ES/H029745/1, ES/J023299/1, ES/K005146/1] Funding Source: UKRI
- MRC [MR/K013351/1, G9521010, MC_PC_U127561128, MC_PC_U127592696, G0701863, MC_UU_12015/1] Funding Source: UKRI
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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 similar to 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.
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