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

Bram P Prins; Timothy J Mead; Jennifer A Brody; Gardar Sveinbjornsson; Ioanna Ntalla; Nathan A Bihlmeyer; Marten van den Berg; Jette Bork-Jensen; Stefania Cappellani; Stefan Van Duijvenboden; Nikolai T Klena; George C Gabriel; Xiaoqin Liu; Cagri Gulec; Niels Grarup; Jeffrey Haessler; Leanne M Hall; Annamaria Iorio; Aaron Isaacs; Ruifang Li-Gao; Honghuang Lin; Ching-Ti Liu; Leo-Pekka Lyytikäinen; Jonathan Marten; Hao Mei; Martina Müller-Nurasyid; Michele Orini; Sandosh Padmanabhan; Farid Radmanesh; Julia Ramirez; Antonietta Robino; Molly Schwartz; Jessica van Setten; Albert V Smith; Niek Verweij; Helen R Warren; Stefan Weiss; Alvaro Alonso; David O Arnar; Michiel L Bots; Rudolf A de Boer; Anna F Dominiczak; Mark Eijgelsheim; Patrick T Ellinor; Xiuqing Guo; Stephan B Felix; Allan Linneberg; Oluf Pedersen; Torben Hansen; Jørgen K Kanters; et al.

doi:10.1186/s13059-018-1457-6

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

Bram P Prins, Timothy J Mead, Jennifer A Brody, Gardar Sveinbjornsson, Ioanna Ntalla, Nathan A Bihlmeyer, Marten van den Berg, Jette Bork-Jensen, Stefania Cappellani, Stefan Van Duijvenboden, Nikolai T Klena, George C Gabriel, Xiaoqin Liu, Cagri Gulec, Niels Grarup, Jeffrey Haessler, Leanne M Hall, Annamaria Iorio, Aaron Isaacs, Ruifang Li-GaoHonghuang Lin, Ching-Ti Liu, Leo-Pekka Lyytikäinen, Jonathan Marten, Hao Mei, Martina Müller-Nurasyid, Michele Orini, Sandosh Padmanabhan, Farid Radmanesh, Julia Ramirez, Antonietta Robino, Molly Schwartz, Jessica van Setten, Albert V Smith, Niek Verweij, Helen R Warren, Stefan Weiss, Alvaro Alonso, David O Arnar, Michiel L Bots, Rudolf A de Boer, Anna F Dominiczak, Mark Eijgelsheim, Patrick T Ellinor, Xiuqing Guo, Stephan B Felix, Allan Linneberg, Oluf Pedersen, Torben Hansen, Jørgen K Kanters, et al.

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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.

Original language	English
Article number	87
Journal	Genome Biology
Volume	19
Number of pages	17
ISSN	1474-7596
DOIs	https://doi.org/10.1186/s13059-018-1457-6
Publication status	Published - 17 Jul 2018

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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., ... et al. (2018). Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. Genome Biology, 19, [87]. https://doi.org/10.1186/s13059-018-1457-6

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, Linneberg, A , Pedersen, O , Hansen, T , Kanters, JK & et al. 2018, 'Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6', Genome Biology, vol. 19, 87. https://doi.org/10.1186/s13059-018-1457-6

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title = "Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6",

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.",

author = "Prins, {Bram P} and Mead, {Timothy J} and Brody, {Jennifer A} and Gardar Sveinbjornsson and Ioanna Ntalla and Bihlmeyer, {Nathan A} and {van den Berg}, Marten and Jette Bork-Jensen and Stefania Cappellani and {Van Duijvenboden}, Stefan and Klena, {Nikolai T} and Gabriel, {George C} and Xiaoqin Liu and Cagri Gulec and Niels Grarup and Jeffrey Haessler and Hall, {Leanne M} and Annamaria Iorio and Aaron Isaacs and Ruifang Li-Gao and Honghuang Lin and Ching-Ti Liu and Leo-Pekka Lyytik{\"a}inen and Jonathan Marten and Hao Mei and Martina M{\"u}ller-Nurasyid and Michele Orini and Sandosh Padmanabhan and Farid Radmanesh and Julia Ramirez and Antonietta Robino and Molly Schwartz and {van Setten}, Jessica and Smith, {Albert V} and Niek Verweij and Warren, {Helen R} and Stefan Weiss and Alvaro Alonso and Arnar, {David O} and Bots, {Michiel L} and {de Boer}, {Rudolf A} and Dominiczak, {Anna F} and Mark Eijgelsheim and Ellinor, {Patrick T} and Xiuqing Guo and Felix, {Stephan B} and Allan Linneberg and Oluf Pedersen and Torben Hansen and Kanters, {J{\o}rgen K} and {et al.}",

year = "2018",

month = jul,

day = "17",

doi = "10.1186/s13059-018-1457-6",

language = "English",

volume = "19",

journal = "Genome Biology (Online Edition)",

issn = "1474-7596",

publisher = "BioMed Central Ltd.",

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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

SN - 1474-7596

VL - 19

JO - Genome Biology (Online Edition)

JF - Genome Biology (Online Edition)

M1 - 87

ER -

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

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