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
Genome Biol 2018 07 17;19(1):87. Epub 2018 Jul 17.
Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, SW17 0RE, UK.
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.
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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Source |
|---|---|
| http://dx.doi.org/10.1186/s13059-018-1457-6 | DOI Listing |
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048820 | PMC |
July 2018
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