Arking, DE;
Pulit, SL;
Crotti, L;
van der Harst, P;
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(2014)
Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.
Nature Genetics, 46 (8).
pp. 826-836.
ISSN 1546-1718
https://doi.org/10.1038/ng.3014
SGUL Authors: Behr, Elijah Raphael Jamshidi, Yalda Whincup, Peter Hynes
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Abstract
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.
Item Type: |
Article
|
Additional Information: |
Author’s manuscript is made available for academic research only, and cannot be used for commercial purposes without prior permission of the copyright holders. Made available here with permission from the publisher. |
Keywords: |
Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Electrocardiography, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Male, Middle Aged, Myocardium, Polymorphism, Single Nucleotide, Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, CHRONIC HEART-FAILURE, GENOME-WIDE ASSOCIATION, COMMON VARIANTS, CARDIAC REPOLARIZATION, SARCOPLASMIC-RETICULUM, QRS DURATION, PR INTERVAL, LOCI, TRPM7, MODEL, Developmental Biology, 11 Medical And Health Sciences, 06 Biological Sciences |
SGUL Research Institute / Research Centre: |
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cardiac (INCCCA) Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS) Academic Structure > Population Health Research Institute (INPH) |
Journal or Publication Title: |
Nature Genetics |
ISSN: |
1546-1718 |
Language: |
eng |
Dates: |
Date | Event |
---|
August 2014 | Published |
|
Projects: |
Project ID | Funder | Funder ID |
---|
CZB/4/710 | Chief Scientist Office | UNSPECIFIED | G0701863 | Medical Research Council | UNSPECIFIED | G9521010 | Medical Research Council | UNSPECIFIED | K23 HL080025 | NHLBI NIH HHS | UNSPECIFIED | MC_U106179471 | Medical Research Council | UNSPECIFIED | MC_UU_12015/1 | Medical Research Council | UNSPECIFIED | MR/K006584/1 | Medical Research Council | UNSPECIFIED | MR/K013351/1 | Medical Research Council | UNSPECIFIED | NF-SI-0512-10113 | Department of Health | UNSPECIFIED | NF-SI-0512-10135 | Department of Health | UNSPECIFIED | NF-SI-0611-10170 | Department of Health | UNSPECIFIED | P30 DK063491 | NIDDK NIH HHS | UNSPECIFIED | P30 DK072488 | NIDDK NIH HHS | UNSPECIFIED | PG/12/38/29615 | British Heart Foundation | UNSPECIFIED | R01 HL098283 | NHLBI NIH HHS | UNSPECIFIED | R01 HL105756 | NHLBI NIH HHS | UNSPECIFIED | R01 HL111267 | NHLBI NIH HHS | UNSPECIFIED | R01 HL113933 | NHLBI NIH HHS | UNSPECIFIED | R01 HL120393 | NHLBI NIH HHS | UNSPECIFIED | RG/10/12/28456 | British Heart Foundation | UNSPECIFIED | T32 GM007753 | NIGMS NIH HHS | UNSPECIFIED | U01 DK094157 | NIDDK NIH HHS | UNSPECIFIED | U01 DK094176 | NIDDK NIH HHS | UNSPECIFIED | UL1 TR000114 | NCATS NIH HHS | UNSPECIFIED | UL1 TR000124 | NCATS NIH HHS | UNSPECIFIED |
|
PubMed ID: |
24952745 |
Web of Science ID: |
WOS:000339704400010 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/107365 |
Publisher's version: |
https://doi.org/10.1038/ng.3014 |
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