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

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

Description

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.
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Year of publication

2018

Authors

Leo-Pekka Lyytikäinen - Contributor

Mika Kähönen - Creator

Terho Lehtimäki - Creator

Unknown organization

Cagri Gulec - Contributor

Ching-Ti Liu - Contributor

Cornelia M. van Duijn - Contributor

Elsayed Z. Soliman - Contributor

Gardar Sveinbjornsson - Contributor

J.W. Jukema - Contributor

Jessica van Setten - Contributor

Marten van den Berg - Contributor

Nilesh J. Samani - Contributor

Peter van der Meer - Contributor

Pim van der Harst - Contributor

Rudolf A. de Boer - Contributor

Ruifang Li-Gao - Contributor

Sandosh Padmanabhan - Contributor

Stefan Van Duijvenboden - Contributor

Suneel S. Apte - Contributor

Xiaoqin Liu - Contributor

Xiuqing Guo - Contributor

Yalda Jamshidi - Contributor

Zhijun Xie - Contributor

Aaron Isaacs - Creator

Albert V. Smith - Creator

Allan Linneberg - Creator

Alvaro Alonso - Creator

Andrew Tinker - Creator

André Uitterlinden - Creator

Anna F. Dominiczak - Creator

Annamaria Iorio - Creator

Annette Peters - Creator

Antonietta Robino - Creator

Blair H. Smith - Creator

Bram P. Prins - Creator

Bruce M. Psaty - Creator

Bruno H. Stricker - Creator

Caroline Hayward - Creator

Cecilia W. Lo - Creator

Charles Kooperberg - Creator

Christopher H. Newton-Cheh - Creator

Christopher P. Nelson - Creator

Dan E. Arking - Creator

Daniel F. Gudbjartsson - Creator

David O. Arnar - Creator

Dennis O. Mook-Kanamori - Creator

Farid Radmanesh - Creator

Folkert W. Asselbergs - Creator

Francesco J. Conti - Creator

George C. Gabriel - Creator

Gianfranco Sinagra - Creator

Hao Mei - Creator

Helen R. Warren - Creator

Henry J. Lin - Creator

Henry Völzke - Creator

Hilma Holm - Creator

Honghuang Lin - Creator

Igor Rudan - Creator

Ilonca Vaartjes - Creator

Ioanna Ntalla - Creator

James G. Wilson - Creator

Jan A. Kors - Creator

Jeffrey Haessler - Creator

Jennifer A. Brody - Creator

Jerome I. Rotter - Creator

Jette Bork-Jensen - Creator

Jonathan Marten - Creator

Jonathan Rosand - Creator

Julia Ramirez - Creator

Jørgen K. Kanters - Creator

Kari Stefansson - Creator

Kenneth M. Rice - Creator

Konstantin Strauch - Creator

Leanne M. Hall - Creator

Lenore J. Launer - Creator

Man Li - Creator

Marco Perez - Creator

Marcus Dörr - Creator

Mark Eijgelsheim - Creator

Martina Müller-Nurasyid - Creator

Melanie Waldenberger - Creator

Michele Orini - Creator

Michiel L. Bots - Creator

Molly Schwartz - Creator

Moritz F. Sinner - Creator

Nathan A. Bihlmeyer - Creator

Niek Verweij - Creator

Niels Grarup - Creator

Nikolai T. Klena - Creator

Nona Sotoodehnia - Creator

Olli T. Raitakari - Creator

Oluf Pedersen - Creator

Ozren Polasek - Creator

Paolo Gasparini - Creator

Patricia B. Munroe - Creator

Patrick T. Ellinor - Creator

Paul L. Huang - Creator

Pier D. Lambiase - Creator

Sheila Ulivi - Creator

Stefan Kääb - Creator

Stefan Weiss - Creator

Stefania Cappellani - Creator

Stella Trompet - Creator

Stephan B. Felix - Creator

Steven A. Lubitz - Creator

Susan R. Heckbert - Creator

Tamara B. Harris - Creator

Tim D. Spector - Creator

Timothy J. Mead - Creator

Torben Hansen - Creator

Unnur Thorsteinsdottir - Creator

Uwe Völker - Creator

Vilmundur Gudnason - Creator

figshare - Publisher

Other information

Fields of science

Genetics, developmental biology, physiology; Medical biotechnology

Language

English

Open access

Open

License

Creative Commons Attribution 4.0 International (CC BY 4.0)

Keywords

Medical biotechnology, Genetics developmental biology physiology
Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6 - Research.fi