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

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.

SUBMITTER: Arking DE

PROVIDER: S-EPMC4124521 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Arking Dan E DE Pulit Sara L SL Crotti Lia L van der Harst Pim P Munroe Patricia B PB Koopmann Tamara T TT Sotoodehnia Nona N Rossin Elizabeth J EJ Morley Michael M Wang Xinchen X Johnson Andrew D AD Lundby Alicia A Gudbjartsson Daníel F DF Noseworthy Peter A PA Eijgelsheim Mark M Bradford Yuki Y Tarasov Kirill V KV Dörr Marcus M Müller-Nurasyid Martina M Lahtinen Annukka M AM Nolte Ilja M IM Smith Albert Vernon AV Bis Joshua C JC Isaacs Aaron A Newhouse Stephen J SJ Evans Daniel S DS Post Wendy S WS Waggott Daryl D Lyytikäinen Leo-Pekka LP Hicks Andrew A AA Eisele Lewin L Ellinghaus David D Hayward Caroline C Navarro Pau P Ulivi Sheila S Tanaka Toshiko T Tester David J DJ Chatel Stéphanie S Gustafsson Stefan S Kumari Meena M Morris Richard W RW Naluai Åsa T ÅT Padmanabhan Sandosh S Kluttig Alexander A Strohmer Bernhard B Panayiotou Andrie G AG Torres Maria M Knoflach Michael M Hubacek Jaroslav A JA Slowikowski Kamil K Raychaudhuri Soumya S Kumar Runjun D RD Harris Tamara B TB Launer Lenore J LJ Shuldiner Alan R AR Alonso Alvaro A Bader Joel S JS Ehret Georg G Huang Hailiang H Kao W H Linda WH Strait James B JB Macfarlane Peter W PW Brown Morris M Caulfield Mark J MJ Samani Nilesh J NJ Kronenberg Florian F Willeit Johann J Smith J Gustav JG Greiser Karin H KH Meyer Zu Schwabedissen Henriette H Werdan Karl K Carella Massimo M Zelante Leopoldo L Heckbert Susan R SR Psaty Bruce M BM Rotter Jerome I JI Kolcic Ivana I Polašek Ozren O Wright Alan F AF Griffin Maura M Daly Mark J MJ Arnar David O DO Hólm Hilma H Thorsteinsdottir Unnur U Denny Joshua C JC Roden Dan M DM Zuvich Rebecca L RL Emilsson Valur V Plump Andrew S AS Larson Martin G MG O'Donnell Christopher J CJ Yin Xiaoyan X Bobbo Marco M D'Adamo Adamo P AP Iorio Annamaria A Sinagra Gianfranco G Carracedo Angel A Cummings Steven R SR Nalls Michael A MA Jula Antti A Kontula Kimmo K KK Marjamaa Annukka A Oikarinen Lasse L Perola Markus M Porthan Kimmo K Erbel Raimund R Hoffmann Per P Jöckel Karl-Heinz KH Kälsch Hagen H Nöthen Markus M MM den Hoed Marcel M Loos Ruth J F RJ Thelle Dag S DS Gieger Christian C Meitinger Thomas T Perz Siegfried S Peters Annette A Prucha Hanna H Sinner Moritz F MF Waldenberger Melanie M de Boer Rudolf A RA Franke Lude L van der Vleuten Pieter A PA Beckmann Britt Maria BM Martens Eimo E Bardai Abdennasser A Hofman Nynke N Wilde Arthur A M AA Behr Elijah R ER Dalageorgou Chrysoula C Giudicessi John R JR Medeiros-Domingo Argelia A Barc Julien J Kyndt Florence F Probst Vincent V Ghidoni Alice A Insolia Roberto R Hamilton Robert M RM Scherer Stephen W SW Brandimarto Jeffrey J Margulies Kenneth K Moravec Christine E CE del Greco M Fabiola F Fuchsberger Christian C O'Connell Jeffrey R JR Lee Wai K WK Watt Graham C M GC Campbell Harry H Wild Sarah H SH El Mokhtari Nour E NE Frey Norbert N Asselbergs Folkert W FW Mateo Leach Irene I Navis Gerjan G van den Berg Maarten P MP van Veldhuisen Dirk J DJ Kellis Manolis M Krijthe Bouwe P BP Franco Oscar H OH Hofman Albert A Kors Jan A JA Uitterlinden André G AG Witteman Jacqueline C M JC Kedenko Lyudmyla L Lamina Claudia C Oostra Ben A BA Abecasis Gonçalo R GR Lakatta Edward G EG Mulas Antonella A Orrú Marco M Schlessinger David D Uda Manuela M Markus Marcello R P MR Völker Uwe U Snieder Harold H Spector Timothy D TD Ärnlöv Johan J Lind Lars L Sundström Johan J Syvänen Ann-Christine AC Kivimaki Mika M Kähönen Mika M Mononen Nina N Raitakari Olli T OT Viikari Jorma S JS Adamkova Vera V Kiechl Stefan S Brion Maria M Nicolaides Andrew N AN Paulweber Bernhard B Haerting Johannes J Dominiczak Anna F AF Nyberg Fredrik F Whincup Peter H PH Hingorani Aroon D AD Schott Jean-Jacques JJ Bezzina Connie R CR Ingelsson Erik E Ferrucci Luigi L Gasparini Paolo P Wilson James F JF Rudan Igor I Franke Andre A Mühleisen Thomas W TW Pramstaller Peter P PP Lehtimäki Terho J TJ Paterson Andrew D AD Parsa Afshin A Liu Yongmei Y van Duijn Cornelia M CM Siscovick David S DS Gudnason Vilmundur V Jamshidi Yalda Y Salomaa Veikko V Felix Stephan B SB Sanna Serena S Ritchie Marylyn D MD Stricker Bruno H BH Stefansson Kari K Boyer Laurie A LA Cappola Thomas P TP Olsen Jesper V JV Lage Kasper K Schwartz Peter J PJ Kääb Stefan S Chakravarti Aravinda A Ackerman Michael J MJ Pfeufer Arne A de Bakker Paul I W PI Newton-Cheh Christopher C

Nature genetics 20140622 8

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 ...[more]

PMID: 24952745

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Project description:Genome-wide association studies (GWAS) have suggested that sequence variation in cis-regulatory elements (CREs) modulate common disease risk and trait variation. However, identification of the majority of these causal variants and their mechanism of action have remained significant challenges. We used reporter assays for all common variants at the QT interval associated SCN5A GWAS locus with the goal of identifying causal variants for the association. A target region of ~500kb containing SCN5A was defined based on recombination hotspots (rate>10cM/Mb; estimated from HapMap) flanking the 5 independent QT interval GWAS hits. Within this region, all common variants (minor allele frequency >5%), from the 1000 Genomes European ancestry populations, in moderate linkage disequilibrium (LD; r2>0.3) with any of the 5 sentinel hits, were selected for analyses. Of a total 121 variants selected, 112 variants in 104 amplicons passed primer design (amplicon size 256-617bp; median 397bp), with both alleles of 106 variants successfully cloned along with flanking sequences into 98 amplicons upstream of a minimal promoter-driven firefly luciferase gene in pGL4.23. Cardiomyocyte cells, AC16 (human) and HL1 (mouse), were transfected with test constructs and Renilla luciferase vector (for transfection normalization) in triplicate; luciferase assays were performed 24h later. All cloning and reporter assays were performed in 96- and 24-well plates. In reporter assays across the two cell lines, compared to empty vector, 37 amplicons showed enhancer activity (z-score>99 %tile), with a concordance rate of ~70%. Of these 37 enhancer CREs, 9 overlapped open chromatin regions (DNase-seq peaks) observed in adult human heart tissue, largest among all human tissues evaluated by the RoadMap Epigenomics project. Of these 37 enhancer CREs, 12 showed allelic difference in reporter activity (P<0.05), thus identifying at least one enhancer CRE variant in high-to-moderate LD with each of the 5 sentinel hits. Using GTEx heart left ventricle (n=190) gene expression data, we showed correlation between SCN5A expression and the number of QT interval prolonging alleles across the 5 index SNPs. We are currently assessing the binding of cardiac nuclear factors at the 12 enhancer CRE variants by gel-shift assays and the effect of CRISPR-Cas9 mediated CRE deletion on SCN5A expression in AC16 and HL1 cells, an analyses helped by evaluation of AC16 and HL1 cells by RNA-seq, ATAC-seq and karyotyping. Thus, independent of the publicly available epigenomic data, which are of limited cell-type relevance, an unbiased in vitro reporter screen for CREs overlapping all common variants associated with QT interval at the SCN5A GWAS locus identified 12 common cis-regulatory variants that map to cardiac open chromatin regions and correlate with SCN5A cardiac expression.

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

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

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