Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. / Prins, Bram P; Mead, Timothy J; Brody, Jennifer A; Sveinbjornsson, Gardar; Ntalla, Ioanna; Bihlmeyer, Nathan A; van den Berg, Marten; Bork-Jensen, Jette; Cappellani, Stefania; Van Duijvenboden, Stefan; Klena, Nikolai T; Gabriel, George C; Liu, Xiaoqin; Gulec, Cagri; Grarup, Niels; Haessler, Jeffrey; Hall, Leanne M; Iorio, Annamaria; Isaacs, Aaron; Li-Gao, Ruifang; Lin, Honghuang; Liu, Ching-Ti; Lyytikäinen, Leo-Pekka; Marten, Jonathan; Mei, Hao; Müller-Nurasyid, Martina; Orini, Michele; Padmanabhan, Sandosh; Radmanesh, Farid; Ramirez, Julia; Robino, Antonietta; Schwartz, Molly; van Setten, Jessica; Smith, Albert V; Verweij, Niek; Warren, Helen R; Weiss, Stefan; Alonso, Alvaro; Arnar, David O; Bots, Michiel L; de Boer, Rudolf A; Dominiczak, Anna F; Eijgelsheim, Mark; Ellinor, Patrick T; Guo, Xiuqing; Felix, Stephan B; Linneberg, Allan; Pedersen, Oluf; Hansen, Torben; Kanters, Jørgen K; et al.
I: Genome Biology, Bind 19, 87, 17.07.2018.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6
AU - Prins, Bram P
AU - Mead, Timothy J
AU - Brody, Jennifer A
AU - Sveinbjornsson, Gardar
AU - Ntalla, Ioanna
AU - Bihlmeyer, Nathan A
AU - van den Berg, Marten
AU - Bork-Jensen, Jette
AU - Cappellani, Stefania
AU - Van Duijvenboden, Stefan
AU - Klena, Nikolai T
AU - Gabriel, George C
AU - Liu, Xiaoqin
AU - Gulec, Cagri
AU - Grarup, Niels
AU - Haessler, Jeffrey
AU - Hall, Leanne M
AU - Iorio, Annamaria
AU - Isaacs, Aaron
AU - Li-Gao, Ruifang
AU - Lin, Honghuang
AU - Liu, Ching-Ti
AU - Lyytikäinen, Leo-Pekka
AU - Marten, Jonathan
AU - Mei, Hao
AU - Müller-Nurasyid, Martina
AU - Orini, Michele
AU - Padmanabhan, Sandosh
AU - Radmanesh, Farid
AU - Ramirez, Julia
AU - Robino, Antonietta
AU - Schwartz, Molly
AU - van Setten, Jessica
AU - Smith, Albert V
AU - Verweij, Niek
AU - Warren, Helen R
AU - Weiss, Stefan
AU - Alonso, Alvaro
AU - Arnar, David O
AU - Bots, Michiel L
AU - de Boer, Rudolf A
AU - Dominiczak, Anna F
AU - Eijgelsheim, Mark
AU - Ellinor, Patrick T
AU - Guo, Xiuqing
AU - Felix, Stephan B
AU - Linneberg, Allan
AU - Pedersen, Oluf
AU - Hansen, Torben
AU - Kanters, Jørgen K
AU - et al.
PY - 2018/7/17
Y1 - 2018/7/17
N2 - 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.
AB - 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.
U2 - 10.1186/s13059-018-1457-6
DO - 10.1186/s13059-018-1457-6
M3 - Journal article
C2 - 30012220
VL - 19
JO - Genome Biology (Online Edition)
JF - Genome Biology (Online Edition)
SN - 1474-7596
M1 - 87
ER -
ID: 202032143