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dc.contributor.authorPrins, Bram P
dc.contributor.authorMead, Timothy J
dc.contributor.authorBrody, Jennifer A
dc.contributor.authorSveinbjornsson, Gardar
dc.contributor.authorNtalla, Ioanna
dc.contributor.authorBihlmeyer, Nathan A
dc.contributor.authorvan den Berg, Marten
dc.contributor.authorBork-Jensen, Jette
dc.contributor.authorCappellani, Stefania
dc.contributor.authorVan Duijvenboden, Stefan
dc.contributor.authorKlena, Nikolai T
dc.contributor.authorGabriel, George C
dc.contributor.authorLiu, Xiaoqin
dc.contributor.authorGulec, Cagri
dc.contributor.authorGrarup, Niels
dc.contributor.authorHaessler, Jeffrey
dc.contributor.authorHall, Leanne M
dc.contributor.authorIorio, Annamaria
dc.contributor.authorIsaacs, Aaron
dc.contributor.authorLi-Gao, Ruifang
dc.contributor.authorLin, Honghuang
dc.contributor.authorLiu, Ching-Ti
dc.contributor.authorLyytikäinen, Leo-Pekka
dc.contributor.authorMarten, Jonathan
dc.contributor.authorMei, Hao
dc.contributor.authorMüller-Nurasyid, Martina
dc.contributor.authorOrini, Michele
dc.contributor.authorPadmanabhan, Sandosh
dc.contributor.authorRadmanesh, Farid
dc.contributor.authorRamirez, Julia
dc.contributor.authorRobino, Antonietta
dc.contributor.authorSchwartz, Molly
dc.contributor.authorvan Setten, Jessica
dc.contributor.authorSmith, Albert V
dc.contributor.authorVerweij, Niek
dc.contributor.authorWarren, Helen R
dc.contributor.authorWeiss, Stefan
dc.contributor.authorAlonso, Alvaro
dc.contributor.authorArnar, David O
dc.contributor.authorBots, Michiel L
dc.contributor.authorde Boer, Rudolf A
dc.contributor.authorDominiczak, Anna F
dc.contributor.authorEijgelsheim, Mark
dc.contributor.authorEllinor, Patrick T
dc.contributor.authorGuo, Xiuqing
dc.contributor.authorFelix, Stephan B
dc.contributor.authorHarris, Tamara B
dc.contributor.authorHayward, Caroline
dc.contributor.authorHeckbert, Susan R
dc.contributor.authorHuang, Paul L
dc.contributor.authorJukema, J. W
dc.contributor.authorKähönen, Mika
dc.contributor.authorKors, Jan A
dc.contributor.authorLambiase, Pier D
dc.contributor.authorLauner, Lenore J
dc.contributor.authorLi, Man
dc.contributor.authorLinneberg, Allan
dc.contributor.authorNelson, Christopher P
dc.contributor.authorPedersen, Oluf
dc.contributor.authorPerez, Marco
dc.contributor.authorPeters, Annette
dc.contributor.authorPolasek, Ozren
dc.contributor.authorPsaty, Bruce M
dc.contributor.authorRaitakari, Olli T
dc.contributor.authorRice, Kenneth M
dc.contributor.authorRotter, Jerome I
dc.contributor.authorSinner, Moritz F
dc.contributor.authorSoliman, Elsayed Z
dc.contributor.authorSpector, Tim D
dc.contributor.authorStrauch, Konstantin
dc.contributor.authorThorsteinsdottir, Unnur
dc.contributor.authorTinker, Andrew
dc.contributor.authorTrompet, Stella
dc.contributor.authorUitterlinden, André
dc.contributor.authorVaartjes, Ilonca
dc.contributor.authorvan der Meer, Peter
dc.contributor.authorVölker, Uwe
dc.contributor.authorVölzke, Henry
dc.contributor.authorWaldenberger, Melanie
dc.contributor.authorWilson, James G
dc.contributor.authorXie, Zhijun
dc.contributor.authorAsselbergs, Folkert W
dc.contributor.authorDörr, Marcus
dc.contributor.authorvan Duijn, Cornelia M
dc.contributor.authorGasparini, Paolo
dc.contributor.authorGudbjartsson, Daniel F
dc.contributor.authorGudnason, Vilmundur
dc.contributor.authorHansen, Torben
dc.contributor.authorKääb, Stefan
dc.contributor.authorKanters, Jørgen K
dc.contributor.authorKooperberg, Charles
dc.contributor.authorLehtimäki, Terho
dc.contributor.authorLin, Henry J
dc.contributor.authorLubitz, Steven A
dc.contributor.authorMook-Kanamori, Dennis O
dc.contributor.authorConti, Francesco J
dc.contributor.authorNewton-Cheh, Christopher H
dc.contributor.authorRosand, Jonathan
dc.contributor.authorRudan, Igor
dc.contributor.authorSamani, Nilesh J
dc.contributor.authorSinagra, Gianfranco
dc.contributor.authorSmith, Blair H
dc.contributor.authorHolm, Hilma
dc.contributor.authorStricker, Bruno H
dc.contributor.authorUlivi, Sheila
dc.contributor.authorSotoodehnia, Nona
dc.contributor.authorApte, Suneel S
dc.contributor.authorvan der Harst, Pim
dc.contributor.authorStefansson, Kari
dc.contributor.authorMunroe, Patricia B
dc.contributor.authorArking, Dan E
dc.contributor.authorLo, Cecilia W
dc.contributor.authorJamshidi, Yalda
dc.date.accessioned2018-07-17T06:04:34Z
dc.date.available2018-07-17T06:04:34Z
dc.date.issued2018-07-17
dc.identifier.citationGenome Biology. 2018 Jul 17;19(1):87
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/278148
dc.description.abstractAbstract Background Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. Results Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. Conclusions Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.
dc.titleExome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6
dc.typeJournal Article
dc.date.updated2018-07-17T06:04:29Z
dc.language.rfc3066en
dc.rights.holderThe Author(s).
dc.identifier.doi10.17863/CAM.25493
rioxxterms.versionofrecord10.1186/s13059-018-1457-6


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