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

• Type of Material: Article
• Authors: Bram P. Prins, St. George's University of London; Timothy J. Mead, Cleveland Clinic; Jennifer A. Brody, University of Washington; Gardar Sveinbjornsson, deCODE Genet/Amgen, Inc.; Ioanna Ntalla, Queen Mary University of London; Nathan A. Bihlmeyer, Johns Hopkins University; Marteen van den Berg, Erasmus MC University Medical Center; Jette Bork-Jensen, University of Copenhagen; Stefania Cappellani, Institute for Maternal and Child Health; Stefan Van Duijvenboden, Queen Mary University of London; Nikolai T. Klena, University of Pittsburgh; George C. Gabriel, University of Pittsburgh; Xiaoqin Liu, University of Pittsburgh; Cagri Gulec, University of Pittsburgh; Niels Grarup, University of Copenhagen; Jeffrey Haessler, Fred Hutchinson Cancer Research Center; Leanne M. Hall, University of Leicester; Annamaria Iorio, Ospedali Riuniti and University of Trieste; Aaron Isaacs, Maastricht University; Ruifang Li-Gao, Leiden University; Honghuang Lin, Boston University; Ching-Ti Liu, Boston University; Leo-Pekka Lyytikainen, Fimlab Laboratories; Jonathan Marten, University of Edinburgh; Hao Mei, University of Mississippi; Martina Mueller-Nurasyid, German Research Center for Environmental Health; Michele Orini, University College London; Sandosh Padmanabhan, University of Glasgow; Farid Radmanesh, Massachusetts General Hospital; Alvaro Alonso, Emory University
• Language: English
• Date: 2018-07-17
• Publisher: BMC (part of Springer Nature)
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s). 2018
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13059-018-1457-6
• Title of Journal or Parent Work: Genome Biology
• ISSN: 1474-7596
• Volume: 19
• Issue: 1
• Start Page: 87
• End Page: 87
• Grant/Funding Information: See publication for full funding statements from: AGES, ARIC, BRIGHT, CHS, ERF, FHS, Generation Scotland, GOCHA, GRAPHIC, INGI-FVG, INTER99, JHS, KORA, Korcula, LifeLines, UHP, MGH-CAMP, NEO, RS-I, SHIP, TWINSUK, UKBB, YFS, Cell culture and biochemistry, and Mutant mouse model.; This work was funded by a grant to YJ from the British Heart Foundation (PG/12/38/29615).
• Keywords: POPULATION; Meta-analysis; ARRHYTHMIC DEATH; Genetics & Heredity; QRS DURATION; Biotechnology & Applied Microbiology; VENTRICULAR CONDUCTION; COMMON VARIANTS; PR INTERVAL; GENOME-WIDE ASSOCIATION; ELECTROCARDIOGRAPHIC PARAMETERS; Exome chip; ADAMTS6; Science & Technology; Conduction; MORTALITY; WORSENING HEART-FAILURE; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Epidemiology; Engineering, Biomedical; Health Sciences, Medicine and Surgery

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.