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. 2018 Jul 17;19(1):87.
doi: 10.1186/s13059-018-1457-6.

Exome-chip Meta-Analysis Identifies Novel Loci Associated With Cardiac Conduction, Including ADAMTS6

Bram P Prins  1   2 Timothy J Mead  3 Jennifer A Brody  4 Gardar Sveinbjornsson  5 Ioanna Ntalla  6   7 Nathan A Bihlmeyer  8 Marten van den Berg  9 Jette Bork-Jensen  10 Stefania Cappellani  11 Stefan Van Duijvenboden  6   12 Nikolai T Klena  13 George C Gabriel  13 Xiaoqin Liu  13 Cagri Gulec  13 Niels Grarup  10 Jeffrey Haessler  14 Leanne M Hall  15   16 Annamaria Iorio  17 Aaron Isaacs  18   19 Ruifang Li-Gao  20 Honghuang Lin  21 Ching-Ti Liu  22 Leo-Pekka Lyytikäinen  23   24 Jonathan Marten  25 Hao Mei  26 Martina Müller-Nurasyid  27   28   29 Michele Orini  30   31 Sandosh Padmanabhan  32 Farid Radmanesh  33   34 Julia Ramirez  6   7 Antonietta Robino  11 Molly Schwartz  13 Jessica van Setten  35 Albert V Smith  36   37 Niek Verweij  34   38   39 Helen R Warren  6   7 Stefan Weiss  40   41 Alvaro Alonso  42 David O Arnar  5   43 Michiel L Bots  44 Rudolf A de Boer  38 Anna F Dominiczak  45 Mark Eijgelsheim  46 Patrick T Ellinor  47 Xiuqing Guo  48   49 Stephan B Felix  41   50 Tamara B Harris  51 Caroline Hayward  25 Susan R Heckbert  52 Paul L Huang  47 J W Jukema  53   54   55 Mika Kähönen  56   57 Jan A Kors  58 Pier D Lambiase  12   31 Lenore J Launer  51 Man Li  59 Allan Linneberg  60   61   62 Christopher P Nelson  15   16 Oluf Pedersen  10 Marco Perez  63 Annette Peters  29   64   65 Ozren Polasek  66 Bruce M Psaty  67   68 Olli T Raitakari  69   70 Kenneth M Rice  71 Jerome I Rotter  72 Moritz F Sinner  28   29 Elsayed Z Soliman  73 Tim D Spector  74 Konstantin Strauch  27   75 Unnur Thorsteinsdottir  5   76 Andrew Tinker  6   7 Stella Trompet  53   77 André Uitterlinden  78 Ilonca Vaartjes  44 Peter van der Meer  38 Uwe Völker  40   41 Henry Völzke  41   79 Melanie Waldenberger  29   64   80 James G Wilson  81 Zhijun Xie  82 Folkert W Asselbergs  35   83   84   85 Marcus Dörr  41   50 Cornelia M van Duijn  19 Paolo Gasparini  86   87 Daniel F Gudbjartsson  5   88 Vilmundur Gudnason  36   37 Torben Hansen  10 Stefan Kääb  28   29 Jørgen K Kanters  89 Charles Kooperberg  14 Terho Lehtimäki  23   24 Henry J Lin  48   90 Steven A Lubitz  49 Dennis O Mook-Kanamori  20   91 Francesco J Conti  92 Christopher H Newton-Cheh  34   93 Jonathan Rosand  33   34 Igor Rudan  94 Nilesh J Samani  15   16 Gianfranco Sinagra  17 Blair H Smith  95 Hilma Holm  5 Bruno H Stricker  96 Sheila Ulivi  11 Nona Sotoodehnia  97 Suneel S Apte  3 Pim van der Harst  38   83   98 Kari Stefansson  5   76 Patricia B Munroe  6   7 Dan E Arking  99 Cecilia W Lo  13 Yalda Jamshidi  100   101
Affiliations
Free PMC article

Exome-chip Meta-Analysis Identifies Novel Loci Associated With Cardiac Conduction, Including ADAMTS6

Bram P Prins et al. Genome Biol. .
Free PMC article

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.

Conflict of interest statement

Ethics approval and consent to participate

All participating studies received approval by their respective local institutional review boards and ensured that written informed consent was obtained from all study participants, following the recommendations of the Declaration of Helsinki.

Exome discovery and replication analyses

AGES: The study is approved by the Icelandic National Bioethics Committee, (VSN: 00–063) and the Data Protection Authority.

ARIC: Institutional Review Board approvals were obtained by each participating ARIC study center (the Universities of NC, MS, MN, and John Hopkins University) and the coordinating center (University of NC); the research was conducted in accordance with the principles described in the Helsinki Declaration. All participants in the ARIC study gave informed consent. For more information see dbGaP Study Accession: phs000280.v2.p1. JHSPH IRB number H.34.99.07.02.A1. Manuscript proposal number MS2572.

BRIGHT: All individuals in the BRIGHT study participated as volunteers and were recruited via hypertension registers from the MRC General Practice Framework in the UK. Ethics Committee approval was obtained from the multi-and local research committees of the partner institutes, and all participants gave written informed consent.

CHS: CHS was approved by institutional review committees at each site, the participants gave informed consent, and those included in the present analysis consented to the use of their genetic information for the study of cardiovascular disease. It is the position of the UW IRB that these studies of de-identified data, with no patient contact, do not constitute human subjects research. Therefore, we have neither an approval number, nor an exemption.

deCODE: The deCODE Electrocardiogram (ECG) study was approved by the Data Protection Commission of Iceland and the National Bioethics Committee of Iceland (VSNb2015030024/03.01). Written informed consent was obtained from individuals donating samples. Personal identifiers associated with medical information and samples were encrypted with a third-party encryption system as provided by the Data Protection Commission of Iceland.

ERF: The Medical Ethics Committee of the Erasmus University Medical Center approved the ERF study protocol and all participants, or their legal representatives, provided written informed consent.

FHS: The Boston University Medical Campus Institutional Review Board approved the FHS genome-wide genotyping (protocol number H-226671).

Generation Scotland: Data were collected for GS:SFHS during 2006–2011 with ethical approval from the NHS Tayside Committee on Medical Research Ethics A (ref 05/S1401/89). All participants gave written informed consent. 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.

Competing interests

MGH-CAMP: Dr. Ellinor is the PI on a grant from Bayer HealthCare to the Broad Institute focused on the genetics and therapeutics of atrial fibrillation.

CHS: Dr. Bruce Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson.

deCODE: G. Sveinbjornsson, D.O. Arnar, U. Thorsteinsdottir, D.F.Gudbjartsson, H. Holm, K. Stefansson are employed by deCODE genetics/Amgen, Inc.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Adamts6 cardiac expression, sequence conservation, and cardiac anomalies in Adamts6-deficient mice. ad Adamts6 (red punctate signal) is expressed in the outflow tract (a, blue arrowhead), heart valves (ayellow arrowhead), atria (agreen arrowhead), and ventricular myocardium (aorange arrowhead, b-d). e, f Diagram of the two Adamts6 mutant alleles recovered: Met1Ile and Ser149Arg. The sequence alignment shows conservation of the Ser149 residue in ADAMTS6 across species. gl Congenital heart defects observed in Adamts6 Ser149Arg (Adamts6m/m) mutant embryos. A WT mouse heart with normal atrial, ventricular, and outflow tract anatomy (g), an intact atrioventricular septum (d), and normal ventricular myocardium (i). Homozygous Adamts6 Ser149Arg mutants (Adamts6m/m) exhibit a spectrum of congenital heart defects, such as a double outlet right ventricle (j, in which the aorta and pulmonary artery both arise from the right ventricle; see Additional file 3: Video S1) or an atrioventricular septal defect (AVSD) (k, in which the atrial and ventricular septa fail to form). Thickening of the ventricular wall is commonly observed, indicating ventricular hypertrophy (l). These mutant hearts (jl) are shown at embryonic day (E)16.5 but their development is delayed, giving an appearance similar to WT hearts at E14.5 (as shown in (gi)). Ao aorta, AVSD atrioventricular septal defect, LA left atrium, LV left ventricle, Pa pulmonary artery, RA right atrium, RV right ventricle. Scale bar: (a) 500 μm; (bd) 50 μm; (gl) 1 mm
Fig. 2
Fig. 2
Reduction of Cx43 intercalated disk gap junction staining in Adamts6-deficient mice. a, b Cx43 staining (green) (a) is reduced throughout ventricular myocardium in embryonic day (E) 14.5 Adamts6m/m embryos and 6-week and 12-month Adamts6m/+ mice and quantified in (b). DAPI (blue) was used to visualize cell nuclei. c, d Representative western blot (c) and quantification (d) shows reduced Cx43 in three pairs of 6-week Adamts6m/+ and WT myocardium controls. Gapdh was used as a loading control. e No change in Gja1 RNA level in 6-week and 12-month Adamts6m/+ myocardium as compared to control. Scale bar: 50 μm. *P ≤ 0.01. E embryonic, W weeks, M months
Fig. 3
Fig. 3
A mouse Adamts6 ENU mutant and predicted damaging ADAMTS6 variants have impaired secretion. a, b Representative western blots using anti-Myc antibody show a major molecular species of 150 kDa in HEK293F cell lysates, corresponding to the ADAMTS6 zymogen (Z). In contrast, the culture medium of cells transfected with WT ADAMTS6 shows a 130 kDa species, corresponding to mature (M, i.e. furin-processed) ADAMTS6. a The p.Ser149Arg murine variant is not secreted into the culture medium. b The predicted damaging human variants, p.Ser90Leu and p.Arg603Trp, have reduced secretion, whereas the predicted benign variants, p.Ser210Leu and p.Met752Val, are secreted normally. Lysate and medium of HEK293F cells transfected with an empty vector (EV) lack immunoreactivity. The membrane was subsequently re-blotted using an anti-GAPDH monoclonal antibody to demonstrate comparable sample loading. c, d Densitometry of ADAMTS6 signal in lysates (c) and medium (d) shows reduced secretion of p.Ser90Leu and p.Arg603Trp variants and normal secretion of p.Ser210Leu and p.Met752Val into the medium, relative to the WT control (*P ≤ 0.01 for n = 3 transfections of each vector)

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