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; Tamara B. Harris; Caroline Hayward; Susan R. Heckbert; Paul L. Huang; J. Wouter Jukema; Mika  Kähönen; Jan A. Kors; Pier D. Lambiase; Lenore J. Launer; Man Li; Allan Linneberg; Christopher P. Nelson; Oluf Pedersen; Marco Perez; Annette Peters; Ozren Polasek; Bruce M. Psaty; Olli T. Raitakari; Kenneth Rice; Jerome I. Rotter; Moritz F. Sinner; Elsayed Z. Soliman; Tim D. Spector; Konstantin Strauch; Unnur Thorsteinsdottir; Andrew Tinker; Stella Trompet; André G. Uitterlinden; Ilonca Vaartjes; Peter van der Meer; Uwe Völker; Henry Völzke; Melanie Waldenberger; James G. Wilson; Zhijun Xie; Folkert W. Asselbergs; Marcus Dörr; Cornelia M. van Duijn; Paolo Gasparini; Daniel F. Gudbjartsson; Vilmundur Gudnason; Torben Hansen; Stefan Kääb; Jørgen K Kanters; Charles Kooperberg; Terho Lehtimäki; Henry J Lin; Steven A. Lubitz; Dennis O. Mook-Kanamori; Francesco J. Conti; Christopher Newton-Cheh; Jonathan Rosand; Igor Rudan; Nilesh J. Samani; Gianfranco Sinagra; Blair Smith; Hilma Holm; Bruno H. C. Stricker; Sheila Ulivi; Nona Sotoodehnia; Suneel S. Apte; Pim van der Harst; Kari Stefansson; Patricia B. Munroe; Dan E. Arking; Cecilia W. Lo; Yalda Jamshidi

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, Tamara B. Harris, Caroline Hayward, Susan R. Heckbert, Paul L. Huang, J. Wouter Jukema, Mika Kähönen, Jan A. Kors, Pier D. Lambiase, Lenore J. Launer, Man Li, Allan Linneberg, Christopher P. Nelson, Oluf Pedersen, Marco Perez, Annette Peters, Ozren Polasek, Bruce M. Psaty, Olli T. Raitakari, Kenneth Rice, Jerome I. Rotter, Moritz F. Sinner, Elsayed Z. Soliman, Tim D. Spector, Konstantin Strauch, Unnur Thorsteinsdottir, Andrew Tinker, Stella Trompet, André G. Uitterlinden, Ilonca Vaartjes, Peter van der Meer, Uwe Völker, Henry Völzke, Melanie Waldenberger, James G. Wilson, Zhijun Xie, Folkert W. Asselbergs, Marcus Dörr, Cornelia M. van Duijn, Paolo Gasparini, Daniel F. Gudbjartsson, Vilmundur Gudnason, Torben Hansen, Stefan Kääb, Jørgen K Kanters, Charles Kooperberg, Terho Lehtimäki, Henry J Lin, Steven A. Lubitz, Dennis O. Mook-Kanamori, Francesco J. Conti, Christopher Newton-Cheh, Jonathan Rosand, Igor Rudan, Nilesh J. Samani, Gianfranco Sinagra, Blair Smith, Hilma Holm, Bruno H. C. Stricker, Sheila Ulivi, Nona Sotoodehnia, Suneel S. Apte, Pim van der Harst, Kari Stefansson, Patricia B. Munroe, Dan E. Arking, Cecilia W. Lo, Yalda Jamshidi (Lead / Corresponding author)

Population Health and Genomics

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42 Citations (Scopus)

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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
Pages (from-to)	1-17
Number of pages	17
Journal	Genome Biology
Volume	19
DOIs	https://doi.org/10.1186/s13059-018-1457-6
Publication status	Published - 17 Jul 2018

Keywords

ADAMTS6
Conduction
Exome chip
Meta-analysis

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Genetics
Cell Biology

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10.1186/s13059-018-1457-6Licence: CC BY

Final Published VersionFinal published version, 2.69 MBLicence: CC BY

Smith, Blair, FRSE MD MEd FRCGP FHEA FFPMRCA FRCP Edin
- Population Health and Genomics - Clinical Professor (Teaching and Research) of Population Health Science
Person: Academic

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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., ... Jamshidi, Y. (2018). Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. Genome Biology, 19, 1-17. Article 87. https://doi.org/10.1186/s13059-018-1457-6

@article{e7136e4d8f2c4e93b4ca91d75a04e28c,

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.",

keywords = "ADAMTS6, Conduction, Exome chip, Meta-analysis",

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 Harris, {Tamara B.} and Caroline Hayward and Heckbert, {Susan R.} and Huang, {Paul L.} and Jukema, {J. Wouter} and Mika K{\"a}h{\"o}nen and Kors, {Jan A.} and Lambiase, {Pier D.} and Launer, {Lenore J.} and Man Li and Allan Linneberg and Nelson, {Christopher P.} and Oluf Pedersen and Marco Perez and Annette Peters and Ozren Polasek and Psaty, {Bruce M.} and Raitakari, {Olli T.} and Kenneth Rice and Rotter, {Jerome I.} and Sinner, {Moritz F.} and Soliman, {Elsayed Z.} and Spector, {Tim D.} and Konstantin Strauch and Unnur Thorsteinsdottir and Andrew Tinker and Stella Trompet and Uitterlinden, {Andr{\'e} G.} and Ilonca Vaartjes and {van der Meer}, Peter and Uwe V{\"o}lker and Henry V{\"o}lzke and Melanie Waldenberger and Wilson, {James G.} and Zhijun Xie and Asselbergs, {Folkert W.} and Marcus D{\"o}rr and {van Duijn}, {Cornelia M.} and Paolo Gasparini and Gudbjartsson, {Daniel F.} and Vilmundur Gudnason and Torben Hansen and Stefan K{\"a}{\"a}b and Kanters, {J{\o}rgen K} and Charles Kooperberg and Terho Lehtim{\"a}ki and Lin, {Henry J} and Lubitz, {Steven A.} and Mook-Kanamori, {Dennis O.} and Conti, {Francesco J.} and Christopher Newton-Cheh and Jonathan Rosand and Igor Rudan and Samani, {Nilesh J.} and Gianfranco Sinagra and Blair Smith and Hilma Holm and Stricker, {Bruno H. C.} and Sheila Ulivi and Nona Sotoodehnia and Apte, {Suneel S.} and {van der Harst}, Pim and Kari Stefansson and Munroe, {Patricia B.} and Arking, {Dan E.} and Lo, {Cecilia W.} and Yalda Jamshidi",

year = "2018",

month = jul,

day = "17",

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

language = "English",

volume = "19",

pages = "1--17",

journal = "Genome Biology",

issn = "1474-7596",

publisher = "BioMed Central Ltd.",

}

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, K, Rotter, JI, Sinner, MF, Soliman, EZ, Spector, TD, Strauch, K, Thorsteinsdottir, U, Tinker, A, Trompet, S, Uitterlinden, AG, 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, C, Rosand, J, Rudan, I, Samani, NJ, Sinagra, G, Smith, B, Holm, H, Stricker, BHC, Ulivi, S, Sotoodehnia, N, Apte, SS, van der Harst, P, Stefansson, K, Munroe, PB, Arking, DE, Lo, CW & Jamshidi, Y 2018, 'Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6', Genome Biology, vol. 19, 87, pp. 1-17. https://doi.org/10.1186/s13059-018-1457-6

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 - Harris, Tamara B.

AU - Hayward, Caroline

AU - Heckbert, Susan R.

AU - Huang, Paul L.

AU - Jukema, J. Wouter

AU - Kähönen, Mika

AU - Kors, Jan A.

AU - Lambiase, Pier D.

AU - Launer, Lenore J.

AU - Li, Man

AU - Linneberg, Allan

AU - Nelson, Christopher P.

AU - Pedersen, Oluf

AU - Perez, Marco

AU - Peters, Annette

AU - Polasek, Ozren

AU - Psaty, Bruce M.

AU - Raitakari, Olli T.

AU - Rice, Kenneth

AU - Rotter, Jerome I.

AU - Sinner, Moritz F.

AU - Soliman, Elsayed Z.

AU - Spector, Tim D.

AU - Strauch, Konstantin

AU - Thorsteinsdottir, Unnur

AU - Tinker, Andrew

AU - Trompet, Stella

AU - Uitterlinden, André G.

AU - Vaartjes, Ilonca

AU - van der Meer, Peter

AU - Völker, Uwe

AU - Völzke, Henry

AU - Waldenberger, Melanie

AU - Wilson, James G.

AU - Xie, Zhijun

AU - Asselbergs, Folkert W.

AU - Dörr, Marcus

AU - van Duijn, Cornelia M.

AU - Gasparini, Paolo

AU - Gudbjartsson, Daniel F.

AU - Gudnason, Vilmundur

AU - Hansen, Torben

AU - Kääb, Stefan

AU - Kanters, Jørgen K

AU - Kooperberg, Charles

AU - Lehtimäki, Terho

AU - Lin, Henry J

AU - Lubitz, Steven A.

AU - Mook-Kanamori, Dennis O.

AU - Conti, Francesco J.

AU - Newton-Cheh, Christopher

AU - Rosand, Jonathan

AU - Rudan, Igor

AU - Samani, Nilesh J.

AU - Sinagra, Gianfranco

AU - Smith, Blair

AU - Holm, Hilma

AU - Stricker, Bruno H. C.

AU - Ulivi, Sheila

AU - Sotoodehnia, Nona

AU - Apte, Suneel S.

AU - van der Harst, Pim

AU - Stefansson, Kari

AU - Munroe, Patricia B.

AU - Arking, Dan E.

AU - Lo, Cecilia W.

AU - Jamshidi, Yalda

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.

KW - ADAMTS6

KW - Conduction

KW - Exome chip

KW - Meta-analysis

U2 - 10.1186/s13059-018-1457-6

DO - 10.1186/s13059-018-1457-6

M3 - Article

C2 - 30012220

SN - 1474-7596

VL - 19

SP - 1

EP - 17

JO - Genome Biology

JF - Genome Biology

M1 - 87

ER -

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

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Smith, Blair, FRSE MD MEd FRCGP FHEA FFPMRCA FRCP Edin

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