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Prins, B.P.* ; Mead, T.J.* ; Brody, J.A.* ; Sveinbjornsson, G.* ; Ntalla, I.* ; Bihlmeyer, N.A.* ; van den Berg, M.* ; Bork-Jensen, J.* ; Cappellani, S.* ; Van Duijvenboden, S.* ; Klena, N.T.* ; Gabriel, G.C.* ; Liu, X.* ; Gulec, C.* ; Grarup, N.* ; Haessler, J.* ; Hall, L.M.* ; Iorio, A.* ; Isaacs, A.* ; Li-Gao, R.* ; Lin, H.* ; Liu, C.-T.* ; Lyytikäinen, L.-P.* ; Marten, J.* ; Mei, H.* ; Müller-Nurasyid, M. ; Orini, M.* ; Padmanabhan, S.* ; Radmanesh, F.* ; Ramirez, J.* ; Robino, A.* ; Schwartz, M.* ; van Setten, J.* ; Smith, A.V.* ; Verweij, N.* ; Warren, H.R.* ; Weiss, S.* ; Alonso, A.* ; Arnar, D.O.* ; Bots, M.L.* ; de Boer, R.A.* ; Dominiczak, A.F.* ; Eijgelsheim, M.* ; Ellinor, P.T.* ; Guo, X.* ; Felix, S.B.* ; Harris, T.B.* ; Hayward, C.* ; Heckbert, S.R.* ; Huang, P.L.* ; Strauch, K. ; Jamshidi, Y.* ; Kors, J.A.* ; Lambiase, P.D.* ; Launer, L.J.* ; Li, M.* ; Linneberg, A.* ; Nelson, C.P.* ; Pedersen, O.* ; Perez, M.L.* ; Peters, A. ; Polasek, O.* ; Psaty, B.M.* ; Raitakari, O.T.* ; Rice, K.M.* ; Rotter, J.I.* ; Sinner, M.F.* ; Soliman, E.Z.* ; Spector, T.D.* ; Waldenberger, M. ; Lo, C.W.*

Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.

Genome Biol. 19:87 (2018)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Adamts6 ; Conduction ; Exome Chip ; Meta-analysis
Sprache englisch
Veröffentlichungsjahr 2018
HGF-Berichtsjahr 2018
ISSN (print) / ISBN 1474-760X
e-ISSN 1465-6906
Zeitschrift Genome Biology
Quellenangaben Band: 19, Heft: 1, Seiten: , Artikelnummer: 87 Supplement: ,
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology (EPI)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30202 - Environmental Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-504100-001
G-504000-001
G-504091-001
DOI 10.1186/s13059-018-1457-6
Scopus ID 85050161703
PubMed ID 30012220
Erfassungsdatum 2018-07-27
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