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

Prins, B. P. et al. (2018) Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. Genome Biology, 19, 87. (doi:10.1186/s13059-018-1457-6) (PMID:30012220) (PMCID:PMC6048820)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna
Authors: Prins, B. P., Mead, T. J., Brody, J. A., Sveinbjornsson, G., Ntalla, I., Bihlmeyer, N. A., van den Berg, M., Bork-Jensen, J., Cappellani, S., Van Duijvenboden, S., Klena, N. T., Gabriel, G. C., Liu, X., Gulec, C., Grarup, N., Haessler, J., Hall, L. M., Iorio, A., Isaacs, A., Li-Gao, R., Lin, H., Liu, C.-T., Lyytikäinen, L.-P., Marten, J., Mei, H., Müller-Nurasyid, M., Orini, M., Padmanabhan, S., Radmanesh, F., Ramirez, J., Robino, A., Schwartz, M., van Setten, J., Smith, A. V., Verweij, N., Warren, H. R., Weiss, S., Alonso, A., Arnar, D. O., Bots, M. L., de Boer, R. A., Dominiczak, A. F., Eijgelsheim, M., Ellinor, P. T., Guo, X., Felix, S. B., Harris, T. B., Hayward, C., Heckbert, S. R., Huang, P. L., Jukema, J.W., Kähönen, M., Kors, J. A., Lambiase, P. D., Launer, L. J., Li, M., Linneberg, A., Nelson, C. P., Pedersen, O., Perez, M., Peters, A., Polasek, O., Psaty, B. M., Raitakari, O. T., Rice, K. M., Rotter, J. I., Sinner, M. F., Soliman, E. Z., Spector, T. D., Strauch, K., Thorsteinsdottir, U., Tinker, A., Trompet, S., Uitterlinden, A., Vaartjes, I., van der Meer, P., Völker, U., Völzke, H., Waldenberger, M., Wilson, J. G., Xie, Z., Asselbergs, F. W., Dörr, M., van Duijn, C. M., Gasparini, P., Gudbjartsson, D. F., Gudnason, V., Hansen, T., Kääb, S., Kanters, J. K., Kooperberg, C., Lehtimäki, T., Lin, h. J., Lubitz, S. A., Mook-Kanamori, D. O., Conti, F. J., Newton-Cheh, C. H., Rosand, J., Rudan, I., Samani, N. J., Sinagra, G., Smith, B. H., Holm, H., Stricker, B. H., Ulivi, S., Sotoodehnia, N., Apte, S. S., van der Harst, P., Stefansson, K., Munroe, P. B., Arking, D. E., Lo, C. W., and Jamshidi, Y.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Genome Biology
Publisher:BioMed Central
ISSN:1474-760X
ISSN (Online):1465-6906
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Genome Biology 19: 87
Publisher Policy:Reproduced under a Creative Commons License
Data DOI:10.17632/7jgbckpdr4.1

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
348311The British genetics of hypertension study - application to enhance TDT and control recruitment for fine mapping genes for hypertensionAnna DominiczakBritish Heart Foundation (BHF)PG/02/128 MCPG1A9RRI CARDIOVASCULAR & MEDICAL SCIENCES
464051Genomics and proteomics of hypertension and its vascular complications: the pathwayomic strategies.Anna DominiczakBritish Heart Foundation (BHF)RG/07/005/23633RI CARDIOVASCULAR & MEDICAL SCIENCES
483571Collaborative strategy for a definitive genome scan in essential hypertension: high fidelity phenotyping and "hypercontrols"Anna DominiczakBritish Heart Foundation (BHF)SP/08/005/25115RI CARDIOVASCULAR & MEDICAL SCIENCES
381721Generation ScotlandAnna DominiczakChief Scientist office (CSO)CZD/16/6RI CARDIOVASCULAR & MEDICAL SCIENCES