Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6
Authors: 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
Journal: Genome biology (2018)

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. 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. Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.