Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/44577
Title: Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.
Authors: Prins, BP
Mead, TJ
Brody, JA
Sveinbjornsson, G
Ntalla, I
Bihlmeyer, NA
van den Berg, M
Bork-Jensen, J
Cappellani, S
Van Duijvenboden, S
Klena, NT
Gabriel, GC
Liu, X
Gulec, C
Grarup, N
Haessler, J
Hall, LM
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, AV
Verweij, N
Warren, HR
Weiss, S
Alonso, A
Arnar, DO
Bots, ML
de Boer, RA
Dominiczak, AF
Eijgelsheim, M
Ellinor, PT
Guo, X
Felix, SB
Harris, TB
Hayward, C
Heckbert, SR
Huang, PL
Jukema, JW
Kähönen, M
Kors, JA
Lambiase, PD
Launer, LJ
Li, M
Linneberg, A
Nelson, CP
Pedersen, O
Perez, M
Peters, A
Polasek, O
Psaty, BM
Raitakari, OT
Rice, KM
Rotter, JI
Sinner, MF
Soliman, EZ
Spector, TD
Strauch, K
Thorsteinsdottir, U
Tinker, A
Trompet, S
Uitterlinden, A
Vaartjes, I
van der Meer, P
Völker, U
Völzke, H
Waldenberger, M
Wilson, JG
Xie, Z
Asselbergs, FW
Dörr, M
van Duijn, CM
Gasparini, P
Gudbjartsson, DF
Gudnason, V
Hansen, T
Kääb, S
Kanters, JK
Kooperberg, C
Lehtimäki, T
Lin, HJ
Lubitz, SA
Mook-Kanamori, DO
Conti, FJ
Newton-Cheh, CH
Rosand, J
Rudan, I
Samani, NJ
Sinagra, G
Smith, BH
Holm, H
Stricker, BH
Ulivi, S
Sotoodehnia, N
Apte, SS
van der Harst, P
Stefansson, K
Munroe, PB
Arking, DE
Lo, CW
Jamshidi, Y
First Published: 17-Jul-2018
Publisher: BMC (part of Springer Nature)
Citation: Genome Biology, 2018, 19:87
Abstract: 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.
DOI Link: 10.1186/s13059-018-1457-6
eISSN: 1474-760X
Links: https://genomebiology.biomedcentral.com/articles/10.1186/s13059-018-1457-6
http://hdl.handle.net/2381/44577
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2018. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Description: Summary statistics: The discovery summary statistics for both European and African-American ancestry meta-analyses are available at https://doi.org/10.17632/7jgbckpdr4.1 (DOI:https://doi.org/10.17632/7jgbckpdr4.1) and PhenoScanner [65] http://www.phenoscanner.medschl.cam.ac.uk/phenoscanner. Individual cohort data: Cardiovascular Health Study (CHS) Cohort: an NHLBI-funded observational study of risk factors for cardiovascular disease in adults aged 65 years or older. dbGaP. https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000287.v6.p1 [66].
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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