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. W. 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 M. Rice; Jerome I. Rotter; Moritz F. Sinner; Elsayed Z. Soliman; Tim D. Spector; Konstantin Strauch; Unnur Thorsteinsdottir; Andrew Tinker; Stella Trompet; André 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 H. Newton-Cheh; Jonathan Rosand; Igor Rudan; Nilesh J. Samani; Gianfranco Sinagra; Blair H. Smith; Hilma Holm; Bruno H. 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. W. 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 M. Rice, Jerome I. Rotter, Moritz F. Sinner, Elsayed Z. Soliman, Tim D. Spector, Konstantin Strauch, Unnur Thorsteinsdottir, Andrew Tinker, Stella Trompet, André 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 H. Newton-Cheh, Jonathan Rosand, Igor Rudan, Nilesh J. Samani, Gianfranco Sinagra, Blair H. Smith, Hilma Holm, Bruno H. 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

School of Medicine

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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 (US)
Article number	87
Journal	Genome biology
Volume	19
Issue number	1
DOIs	https://doi.org/10.1186/s13059-018-1457-6
State	Published - Jul 17 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/s13059-018-1457-6

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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), [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, CT, Lyytikäinen, LP, 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 2018, 'Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6', Genome biology, vol. 19, no. 1, 87. https://doi.org/10.1186/s13059-018-1457-6

@article{956fb9048910423e9d0325c10eaca549,

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 Liu, {Ching Ti} and Lyytik{\"a}inen, {Leo Pekka} 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. W.} 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 Rice, {Kenneth M.} 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 Andr{\'e} Uitterlinden 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 Newton-Cheh, {Christopher H.} and Jonathan Rosand and Igor Rudan and Samani, {Nilesh J.} and Gianfranco Sinagra and Smith, {Blair H.} and Hilma Holm and Stricker, {Bruno H.} 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",

note = "Funding Information: GS:SFHS is now a Research Tissue Bank approved by the East of Scotland Research Ethics Service (ref 15/ES/0040). GOCHA: The Institutional Review Board at MGH reviewed and approved the study. Participants or their next of kin provided informed consent at the time of enrolment. GRAPHIC: GRAPHIC was approved by the Leicestershire Research Ethics Committee (LREC Ref no. 6463). Inter99: Written informed consent was obtained from all participants and the study was approved by the Scientific Ethics Committee of the Capital Region of Denmark (KA98155, H-3-2012-155) and was in accordance with the principles of the Declaration of Helsinki II. KORA: Written informed consent was obtained from all participants and the study was approved by the local ethics committee (Bayerische Landes{\"a}rztekammer). KORCULA: Ethical approval was given for recruitment of all Korcula study participants by ethics committees in both Scotland and Croatia. All volunteers gave informed consent before participation. Lifelines: The Lifelines study followed the recommendations of the Declaration of Helsinki and was in accordance with research code of the University Medical Center Groningen (UMCG). The LifeLines study is approved by the medical ethical committee of the UMCG, the Netherlands. All participants signed an informed consent form before they received an invitation for the physical examination. For a comprehensive overview of the data collection, please visit the LifeLines catalog at https:// catalogue.lifelines.nl/menu/main/protocolviewer. MGH CAMP: The Institutional Review Board at MGH reviews the study protocol annually. Each participant provided written, informed consent before enrolment. NEO: The Netherlands Epidemiology of obesity (NEO) study is supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Center, and by the Leiden University, Research Profile Area Vascular and Regenerative Medicine. All participants gave written informed consent and the Medical Ethical Committee of the Leiden University Medical Center (LUMC) approved the study design. RS: The Rotterdam Study has been approved by the medical ethics committee according to the Population Study Act Rotterdam Study, executed by the Ministry of Health, Welfare and Sports of the Netherlands. Written informed consent was obtained from all participants. SHIP: The SHIP study followed the recommendations of the Declaration of Helsinki. The study protocol of SHIP was approved by the medical ethics committee of the University of Greifswald. Written informed consent was obtained from each of the study participants. The SHIP study is described in PMID: 20167617. TwinsUK: The study has ethical approval from the NRES Committee London–Westminster, London, UK (EC04/015). Written consent was obtained from all participants. Research was carried out in accordance with the Helsinki declaration. UKBB: The UKB study has approval from the North West Multi-Centre Research Ethics Committee and all participants provided informed consent. UHP: The Utrecht Health Project has been approved by the Medical Ethics Committee of the University Medical Centre Utrecht. All participants give written informed consent. The masking of all personal data for researchers and for other possible users of UHP has been regulated in a legal document. WHI: All WHI participants provided written and informed consent. All study sites received approval to conduct this research from local Institutional Review Boards at the Fred Hutchinson Cancer research Center. YFS: The Young Finns Study was approved by the local ethics committees (University Hospitals of Helsinki, Turku, Tampere, Kuopio, and Oulu) and was conducted following the guidelines of the Declaration of Helsinki. All participants gave their written informed consent. In vivo mouse work Cleveland Clinic Lerner Research Institute: All mouse experiments were approved by the Cleveland Clinic Institutional Animal Care and Use Committee (protocol no. 2015–1458, IACUC number: 18052990), and by the University of Pittsburgh Institutional Animal Care and Use Committee. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = jul,

day = "17",

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

language = "English (US)",

volume = "19",

journal = "Genome Biology",

issn = "1474-7596",

publisher = "BioMed Central",

number = "1",

}

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. W.

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 M.

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

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 H.

AU - Rosand, Jonathan

AU - Rudan, Igor

AU - Samani, Nilesh J.

AU - Sinagra, Gianfranco

AU - Smith, Blair H.

AU - Holm, Hilma

AU - Stricker, Bruno H.

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

N1 - Funding Information: GS:SFHS is now a Research Tissue Bank approved by the East of Scotland Research Ethics Service (ref 15/ES/0040). GOCHA: The Institutional Review Board at MGH reviewed and approved the study. Participants or their next of kin provided informed consent at the time of enrolment. GRAPHIC: GRAPHIC was approved by the Leicestershire Research Ethics Committee (LREC Ref no. 6463). Inter99: Written informed consent was obtained from all participants and the study was approved by the Scientific Ethics Committee of the Capital Region of Denmark (KA98155, H-3-2012-155) and was in accordance with the principles of the Declaration of Helsinki II. KORA: Written informed consent was obtained from all participants and the study was approved by the local ethics committee (Bayerische Landesärztekammer). KORCULA: Ethical approval was given for recruitment of all Korcula study participants by ethics committees in both Scotland and Croatia. All volunteers gave informed consent before participation. Lifelines: The Lifelines study followed the recommendations of the Declaration of Helsinki and was in accordance with research code of the University Medical Center Groningen (UMCG). The LifeLines study is approved by the medical ethical committee of the UMCG, the Netherlands. All participants signed an informed consent form before they received an invitation for the physical examination. For a comprehensive overview of the data collection, please visit the LifeLines catalog at https:// catalogue.lifelines.nl/menu/main/protocolviewer. MGH CAMP: The Institutional Review Board at MGH reviews the study protocol annually. Each participant provided written, informed consent before enrolment. NEO: The Netherlands Epidemiology of obesity (NEO) study is supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Center, and by the Leiden University, Research Profile Area Vascular and Regenerative Medicine. All participants gave written informed consent and the Medical Ethical Committee of the Leiden University Medical Center (LUMC) approved the study design. RS: The Rotterdam Study has been approved by the medical ethics committee according to the Population Study Act Rotterdam Study, executed by the Ministry of Health, Welfare and Sports of the Netherlands. Written informed consent was obtained from all participants. SHIP: The SHIP study followed the recommendations of the Declaration of Helsinki. The study protocol of SHIP was approved by the medical ethics committee of the University of Greifswald. Written informed consent was obtained from each of the study participants. The SHIP study is described in PMID: 20167617. TwinsUK: The study has ethical approval from the NRES Committee London–Westminster, London, UK (EC04/015). Written consent was obtained from all participants. Research was carried out in accordance with the Helsinki declaration. UKBB: The UKB study has approval from the North West Multi-Centre Research Ethics Committee and all participants provided informed consent. UHP: The Utrecht Health Project has been approved by the Medical Ethics Committee of the University Medical Centre Utrecht. All participants give written informed consent. The masking of all personal data for researchers and for other possible users of UHP has been regulated in a legal document. WHI: All WHI participants provided written and informed consent. All study sites received approval to conduct this research from local Institutional Review Boards at the Fred Hutchinson Cancer research Center. YFS: The Young Finns Study was approved by the local ethics committees (University Hospitals of Helsinki, Turku, Tampere, Kuopio, and Oulu) and was conducted following the guidelines of the Declaration of Helsinki. All participants gave their written informed consent. In vivo mouse work Cleveland Clinic Lerner Research Institute: All mouse experiments were approved by the Cleveland Clinic Institutional Animal Care and Use Committee (protocol no. 2015–1458, IACUC number: 18052990), and by the University of Pittsburgh Institutional Animal Care and Use Committee. Publisher Copyright: © 2018 The Author(s).

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

UR - http://www.scopus.com/inward/record.url?scp=85050161703&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85050161703&partnerID=8YFLogxK

U2 - 10.1186/s13059-018-1457-6

DO - 10.1186/s13059-018-1457-6

M3 - Article

C2 - 30012220

AN - SCOPUS:85050161703

SN - 1474-7596

VL - 19

JO - Genome Biology

JF - Genome Biology

IS - 1

M1 - 87

ER -

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

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