Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.pdf (2.69 MB)
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Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.

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posted on 24.06.2019, 15:11 by BP Prins, TJ Mead, JA Brody, G Sveinbjornsson, I Ntalla, NA Bihlmeyer, M van den Berg, J Bork-Jensen, S Cappellani, S Van Duijvenboden, NT Klena, GC Gabriel, X Liu, C Gulec, N Grarup, J Haessler, LM Hall, A Iorio, A Isaacs, R Li-Gao, H Lin, C-T Liu, L-P Lyytikäinen, J Marten, H Mei, M Müller-Nurasyid, M Orini, S Padmanabhan, F Radmanesh, J Ramirez, A Robino, M Schwartz, J van Setten, AV Smith, N Verweij, HR Warren, S Weiss, A Alonso, DO Arnar, ML Bots, RA de Boer, AF Dominiczak, M Eijgelsheim, PT Ellinor, X Guo, SB Felix, TB Harris, C Hayward, SR Heckbert, PL Huang, JW Jukema, M Kähönen, JA Kors, PD Lambiase, LJ Launer, M Li, A Linneberg, CP Nelson, O Pedersen, M Perez, A Peters, O Polasek, BM Psaty, OT Raitakari, KM Rice, JI Rotter, MF Sinner, EZ Soliman, TD Spector, K Strauch, U Thorsteinsdottir, A Tinker, S Trompet, A Uitterlinden, I Vaartjes, P van der Meer, U Völker, H Völzke, M Waldenberger, JG Wilson, Z Xie, FW Asselbergs, M Dörr, CM van Duijn, P Gasparini, DF Gudbjartsson, V Gudnason, T Hansen, S Kääb, JK Kanters, C Kooperberg, T Lehtimäki, HJ Lin, SA Lubitz, DO Mook-Kanamori, FJ Conti, CH Newton-Cheh, J Rosand, I Rudan, NJ Samani, G Sinagra, BH Smith, H Holm, BH Stricker, S Ulivi, N Sotoodehnia, SS Apte, P van der Harst, K Stefansson, PB Munroe, DE Arking, CW Lo, Y Jamshidi
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.


This work was funded by a grant to YJ from the British Heart Foundation (PG/12/38/29615). AGES: This study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00–063. The researchers are indebted to the participants for their willingness to participate in the study. ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium” was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). BRIGHT: The Exome Chip genotyping was funded by Wellcome Trust Strategic Awards (083948 and 085475). This work was also supported by the Medical Research Council of Great Britain (Grant no. G9521010D); and by the British Heart Foundation (Grant no. PG/02/128). AFD was supported by the British Heart Foundation (Grant nos. RG/07/005/23633 and SP/08/005/25115); and by the European Union Ingenious HyperCare Consortium: Integrated Genomics, Clinical Research, and Care in Hypertension (grant no. LSHM-C7–2006-037093). The BRIGHT study is extremely grateful to all the patients who p



Genome Biology, 2018, 19:87

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/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences


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Summary statistics: The discovery summary statistics for both European and African-American ancestry meta-analyses are available at https://doi.org/10.17632/7jgbckpdr4.1 (DOI:https://doi.org/10.17632/7jgbckpdr4.1) and PhenoScanner [65] http://www.phenoscanner.medschl.cam.ac.uk/phenoscanner. Individual cohort data: Cardiovascular Health Study (CHS) Cohort: an NHLBI-funded observational study of risk factors for cardiovascular disease in adults aged 65 years or older. dbGaP. https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000287.v6.p1 [66].



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