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.
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.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.Circ Cardiovasc Genet. 2014 Jun;7(3):365-73. doi: 10.1161/CIRCGENETICS.113.000098. Circ Cardiovasc Genet. 2014. PMID: 24951663 Free PMC article.
Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.Hum Mol Genet. 2016 Oct 1;25(19):4350-4368. doi: 10.1093/hmg/ddw284. Epub 2016 Aug 29. Hum Mol Genet. 2016. PMID: 27577874 Free PMC article.
Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants.Heart Rhythm. 2013 Mar;10(3):401-8. doi: 10.1016/j.hrthm.2012.11.014. Epub 2012 Nov 24. Heart Rhythm. 2013. PMID: 23183192 Free PMC article. Clinical Trial.
Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.Nat Genet. 2010 Dec;42(12):1068-76. doi: 10.1038/ng.716. Epub 2010 Nov 14. Nat Genet. 2010. PMID: 21076409 Free PMC article.
Discovery of novel heart rate-associated loci using the Exome Chip.Hum Mol Genet. 2017 Jun 15;26(12):2346-2363. doi: 10.1093/hmg/ddx113. Hum Mol Genet. 2017. PMID: 28379579 Free PMC article.
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- Mentz RJ, Greiner MA, DeVore AD, Dunlay SM, Choudhary G, Ahmad T, et al. Ventricular conduction and long-term heart failure outcomes and mortality in African Americans: insights from the Jackson heart study. Circ Heart Fail. 2015;8:243–251. doi: 10.1161/CIRCHEARTFAILURE.114.001729. - DOI - PMC - PubMed
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