Abstract
The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2093-2103 |
| Number of pages | 11 |
| Journal | Human molecular genetics |
| Volume | 25 |
| Issue number | 10 |
| DOIs | |
| State | Published - May 15 2016 |
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Genetics(clinical)
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In: Human molecular genetics, Vol. 25, No. 10, 15.05.2016, p. 2093-2103.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram
AU - Lifelines Cohort Study
AU - LifeLines GWAS Working Group
AU - Verweij, Niek
AU - Leach, Irene Mateo
AU - Isaacs, Aaron
AU - Arking, Dan E.
AU - Bis, Joshua C.
AU - Pers, Tune H.
AU - Van Den Berg, Marten E.
AU - Lyytikäinen, Leo Pekka
AU - Barnett, Phil
AU - Wang, Xinchen
AU - Soliman, Elsayed Z.
AU - Van Duijn, Cornelia M.
AU - Kähönen, Mika
AU - Van Veldhuisen, Dirk J.
AU - Kors, Jan A.
AU - Raitakari, Olli T.
AU - Silva, Claudia T.
AU - Lehtimäki, Terho
AU - Hillege, Hans L.
AU - Hirschhorn, Joel N.
AU - Boyer, Laurie A.
AU - Van Gilst, Wiek H.
AU - Alonso, Alvaro
AU - Sotoodehnia, Nona
AU - Eijgelsheim, Mark
AU - De Boer, Rudolf A.
AU - De Bakker, Paul I.W.
AU - Franke, Lude
AU - Van Der Harst, Pim
AU - Klauw, Melanie van der
AU - Navis, Gerjan
AU - Ormel, Hans
AU - Postma, Dirkje
AU - Rosmalen, Judith
AU - Slaets, Joris
AU - Stolk, Ronald
AU - Wolffenbuttel, Bruce
AU - Alizadeh, Behrooz
AU - Boezen, Marike
AU - Bruinenberg, Marcel
AU - Festen, Noortje
AU - Snieder, Harold
AU - Wijmenga, Cisca
N1 - Funding Information: We thank Behrooz Alizadeh, Annemieke Boesjes, Marcel Bruinenberg, Noortje Festen, Ilja Nolte, Lude Franke, Mitra Valimohammadi for their help in creating the GWAS database, and Rob Bieringa, Joost Keers, René Oostergo, Rosalie Visser, Judith Vonk for their work related to data-collection and validation. The authors are grateful to the study participants, the staff from the LifeLines Cohort Study and Medical Biobank Northern Netherlands, and the participating general practitioners and pharmacists. LifeLines Scientific Protocol Preparation: Rudolf de Boer, Hans Hillege, Melanie van der Klauw, GerjanNavis, Hans Ormel, Dirkje Postma, Judith Rosmalen, Joris Slaets, Ronald Stolk, Bruce Wolffenbuttel; LifeLines GWAS Working Group: Behrooz Alizadeh, Marike Boezen, Marcel Bruinenberg, Noortje Festen, Lude Franke, Pim van der Harst, Gerjan Navis, Dirkje Postma, Harold Snieder, Cisca Wijmenga and Bruce Wolffenbuttel. The authors acknowledge the services of the Life-Lines Cohort Study, the contributing research centres delivering data to LifeLines and all the study participants.PREVEND: PREVEND genetics is supported by the Dutch Kidney Foundation (grant E033), the EU Project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (grant 2R01LM010098), The Netherlands Organization for Health Research and Development (NWO-Groot grant 175.010.2007.006, NWO VENI grant 916.761.70, ZonMw grant 90.700.441) and the Dutch Inter University Cardiology Institute Netherlands (ICIN). N.V. is supported by the Netherlands Heart Foundation (grant NHS2010B280). LifeLines: The LifeLines Cohort Study, and generation and management of GWAS genotype data for the LifeLines Cohort Study is supported by the Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation. L.F. is supported by the Netherlands Organization for Scientific Research (NWO VENI grant 916.10.135) and a Horizon Breakthrough grant from the Netherlands Genomics Initiative (grant 92519031. The research leading to these results has received funding from the European Community's Health Seventh Framework Programme (FP7/2007-2013) under grant agreement 259867. RS I, II and III: Akzo Nobel, Alzheimer's Association, Astra Pharmaceutial N.V., Astra-Zeneca, Bayer AG, Blinden-penning Foundation, Amsterdam, Brain Foundation of the Netherlands, Bristol-Myers Squibb, Center ofMedical SystemsBiology (CMSB), DutchDiabetes Research Foundation, Dutch Kidney Foundation, Dutch Arthritis Association, Elise Mathilde Foundation, Maarn, Erasmus Medical Center, Erasmus University Rotterdam, European Commission, Foundation for Helping the Blind, The Hague, Foundation for the Ophthalmic Diseased, Rotterdam, Foundation G. Ph. Verhagen, General Electric Healthcare, Glaxo Smith Kline, International Foundation Alzheimer's Research, Inspectorate for Healthcare, Janivo Foundation, K.F. Hein Foundation, Merck Sharp and Dohme, Haarlem, Municipality of City of Rotterdam, National Epilepsy Fund, National Health Fundraising Foundation, National Institute on Aging, NIH, Bethesda, MD, USA, National Society for the Blind and Visually Impaired (LSBS), Netherlands Foundation for the Blind and Visually Handicapped, Netherlands Heart Foundation, Netherlands Institute forHealth Sciences (Nihes), NetherlandsOphthalmicResearch Institute, Netherlands Organisation for Health Research and Development (ZonMw), NetherlandsOrganisation for ScientificResearch (NWO), Netherlands Society for the Prevention of Blindness, Netherlands Thrombosis Foundation, Novo Nordisk, Numico Research B.V., OOG Foundation, The Hague, N.V. Organon, Oxagen, Optimix Foundation, Amsterdam, Physicotherapeutic Institute, Prinses Beatrix Foundation, Procter and Gamble, Research Institute for Diseases in the Elderly (RIDE), Rotterdam Foundation for Ophthalmic Research, Rotterdam Foundation for the Interests of the Blind, St Laurens Institute, Rotterdam, Topcon Europe B.V., Trust Fund Erasmus University Rotterdam, Unilever, Van Leeuwen Van Lignac Foundation, Rotterdam. ERF: The ERF study was supported by grants from the Netherlands Organization for Scientific Research (NWO; Pioneer grant), Erasmus Medical Center, the Centre for Medical Systems Biology (CMSB) and the Netherlands Kidney Foundation.We are grateful to all patients and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. 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. CHS: Cardiovascular Health Study: this CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086 and NHLBI grants HL080295, HL087652, HL105756, HL103612 and HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org/. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124 and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Young Finns Study has been financially supported by the Academy of Finland: grants 286284 (T.L.), 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi) and 41071 (Skidi); the Social Insurance Institution of Finland; Kuopio, Tampere and Turku University Hospital Medical Funds (grant X51001 for T.L.); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation of Cardiovascular Research (T.L.); Finnish Cultural Foundation; Tampere Tuberculosis Foundation (T.L.); Emil Aaltonen Foundation (T.L.) and Yrjö Jahnsson Foundation (T.L.). Funding to pay the Open Access publication charges for this article was provided by the Marie Sklodowska-Curie GF grant (661395) from N. Verweij. Publisher Copyright: © The Author 2016. Published by Oxford University Press.
PY - 2016/5/15
Y1 - 2016/5/15
N2 - The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up.
AB - The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up.
UR - http://www.scopus.com/inward/record.url?scp=84992193975&partnerID=8YFLogxK
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U2 - 10.1093/hmg/ddw058
DO - 10.1093/hmg/ddw058
M3 - Article
C2 - 26962151
AN - SCOPUS:84992193975
SN - 0964-6906
VL - 25
SP - 2093
EP - 2103
JO - Human molecular genetics
JF - Human molecular genetics
IS - 10
ER -