Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

Philipp S Wild; Janine F Felix; Arne Schillert; Alexander Teumer; Ming-Huei Chen; Maarten J.G Leening; Uwe Völker; Vera Großmann; Jennifer A Brody; Marguerite R Irvin; Sanjiv J Shah; Setia Pramana; Wolfgang Lieb; Reinhold Schmidt; Alice V Stanton; Dörthe Malzahn; Albert Vernon Smith; Johan Sundström; Cosetta Minelli; Daniela Ruggiero; Leo-Pekka Lyytikäinen; Daniel Tiller; J. Gustav Smith; Claire Monnereau; Marco R Di Tullio; Solomon K Musani; Alanna C Morrison; Tune H Pers; Michael Morley; Marcus E Kleber; Jayashri Aragam; Emelia J Benjamin; Joshua C Bis; Egbert Bisping; Ulrich Broeckel; Susan Cheng; Jaap W Deckers; Fabiola Del Greco M; Frank Edelmann; Myriam Fornage; Lude Franke; Nele Friedrich; Tamara B Harris; Edith Hofer; Albert Hofman; Jie Huang; Alun D Hughes; Mika Kähönen; KNHI investigators; Jochen Kruppa; Karl J Lackner; Lars Lannfelt; Rafael Laskowski; Lenore J Launer; Margrét Leosdottir; Honghuang Lin; Cecilia M Lindgren; Christina Loley; Calum A MacRae; Deborah Mascalzoni; Jamil Mayet; Daniel Medenwald; Andrew P Morris; Christian Müller; Martina Müller-Nurasyid; Stefania Nappo; Peter M Nilsson; Sebastian Nuding; Teresa Nutile; Annette Peters; Arne Pfeufer; Diana Pietzner; Peter P Pramstaller; Olli T Raitakari; Kenneth M Rice; Fernando Rivadeneira; Jerome I Rotter; Saku T Ruohonen; Ralph L Sacco; Tandaw E Samdarshi; Helena Schmidt; Andrew S.P Sharp; Denis C Shields; Rossella Sorice; Nona Sotoodehnia; Bruno H Stricker; Praveen Surendran; Simon Thom; Anna M Töglhofer; André G Uitterlinden; Rolf Wachter; Henry Völzke; Andreas Ziegler; Thomas Münzel; Winfried März; Thomas P Cappola; Joel N Hirschhorn; Gary F Mitchell; Nicholas L Smith; Ervin R Fox; Nicole D Dueker; Vincent W.V Jaddoe; Olle Melander; Martin Russ; Terho Lehtimäki; Marina Ciullo; Andrew A Hicks; Lars Lind; Vilmundur Gudnason; Burkert Pieske; Anthony J Barron; Robert Zweiker; Heribert Schunkert; Erik Ingelsson; Kiang Liu; Donna K Arnett; Bruce M Psaty; Stefan Blankenberg; Martin G Larson; Stephan B Felix; Oscar H Franco; Tanja Zeller; Ramachandran S Vasan; Marcus Dörr

doi:10.1172/JCI84840

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Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

Journal article

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Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

Philipp S Wild, Janine F Felix, Arne Schillert, Alexander Teumer, Ming-Huei Chen, Maarten J.G Leening, Uwe Völker, Vera Großmann, Jennifer A Brody, Marguerite R Irvin, …

The Journal of clinical investigation, Vol.127(5), pp.1798-1812

2017-05-01

DOI: https://doi.org/10.1172/JCI84840

PMCID: PMC5409098

PMID: 28394258

Abstract

Clinical Medicine

BACKGROUND. Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS. A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS. The discovery analysis included 21 cohorts for structural and systolic function traits ( n = 32,212) and 17 cohorts for diastolic function traits ( n = 21,852). Replication was performed in 5 cohorts ( n = 14,321) and 6 cohorts ( n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG , rs4765663 in CACNA1C , rs6702619 near PALMD , rs7127129 in TMEM16A , rs11207426 near FGGY , rs17608766 in GOSR2 , and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION. The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies. FUNDING. For detailed information per study, see Acknowledgments.

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.189 Genome Studies; 1.189.455 Genome-Wide Association Studies
Web Of Science research areas: Medicine, Research & Experimental
ESI research areas: Clinical Medicine

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Title: Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function
Creators: Philipp S Wild - Preventive Cardiology and Preventive Medicine, Department of Medicine 2, and
Janine F Felix - Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
Arne Schillert - Institute for Medical Biometry and Statistics, University Lübeck, University Medical Center Schleswig-Holstein, Lübeck, Germany
Alexander Teumer - Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
Ming-Huei Chen - Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA
Maarten J.G Leening - Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
Uwe Völker - DZHK, partner site Greifswald, Greifswald, Germany
Vera Großmann - Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
Jennifer A Brody - Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA
Marguerite R Irvin - Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA
Sanjiv J Shah - Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Setia Pramana - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Wolfgang Lieb - Institute of Epidemiology and Popgen Biobank, Christian-Albrechts University of Kiel, Kiel, Germany
Reinhold Schmidt - Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz, Austria
Alice V Stanton - Blood Pressure Unit, Beaumont Hospital, Dublin, Ireland
Dörthe Malzahn - Department of Genetic Epidemiology, University Medical Center, Georg-August University, Göttingen, Germany
Albert Vernon Smith - Icelandic Heart Association, Kopavogur, Iceland
Johan Sundström - Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden
Cosetta Minelli - Population Health and Occupational Disease, National Heart and Lung Institute (NHLI), Imperial College London, London, United Kingdom
Daniela Ruggiero - Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, Naples, Italy
Leo-Pekka Lyytikäinen - Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
Daniel Tiller - Institute of Medical Epidemiology, Biostatistics, and Informatics, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
J. Gustav Smith - Department of Cardiology, Lund University and Skåne University Hospital, Lund, Sweden
Claire Monnereau - Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
Marco R Di Tullio - Department of Medicine, Columbia University Medical Center, New York, New York, USA
Solomon K Musani - Jackson Heart Study, University of Mississippi Medical Center, Jackson, Mississippi, USA
Alanna C Morrison - Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health Science Center at Houston, Houston, Texas, USA
Tune H Pers - Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Michael Morley - Penn Cardiovascular Institute and Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Marcus E Kleber - Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Jayashri Aragam - Harvard Medical School, Boston, Massachusetts, USA
Emelia J Benjamin - National Heart, Lung, and Blood Institute’s and Boston University’s Framingham Heart Study, Framingham, Massachusetts, USA
Joshua C Bis - Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA
Egbert Bisping - Department of Cardiology, Medical University Graz, Graz, Austria
Ulrich Broeckel - Medical College of Wisconsin, Milwaukee, Wisconsin, USA
Susan Cheng - National Heart, Lung, and Blood Institute’s and Boston University’s Framingham Heart Study, Framingham, Massachusetts, USA
Jaap W Deckers - Department of Cardiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
Fabiola Del Greco M - Center for Biomedicine, European Academy of Bolzano/Bozen, Bolzano, Italy – Affiliated institute of the University of Lübeck, Lübeck, Germany
Frank Edelmann - Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
Myriam Fornage - University of Texas Health Science Center, Houston, Texas, USA
Lude Franke - Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands
Nele Friedrich - DZHK, partner site Greifswald, Greifswald, Germany
Tamara B Harris - Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, NIH, Bethesda, Maryland, USA
Edith Hofer - Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz, Austria
Albert Hofman - Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
Jie Huang - Boston VA Research Institute, Boston, Massachusetts, USA
Alun D Hughes - Institute of Cardiovascular Science, University College London, London, United Kingdom
Mika Kähönen - Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland
KNHI investigators - KNHI investigators and their affiliations are detailed in the Supplemental Acknowledgments
Jochen Kruppa - Institute for Medical Biometry and Statistics, University Lübeck, University Medical Center Schleswig-Holstein, Lübeck, Germany
Karl J Lackner - Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany
Lars Lannfelt - Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden
Rafael Laskowski - Department of Medicine 2, University Medical Center Mainz, Mainz, Germany
Lenore J Launer - Neuroepidemiology Section, National Institute on Aging, NIH, Bethesda, Maryland, USA
Margrét Leosdottir - Department of Cardiology, Lund University, and Skåne University Hospital, Malmö, Sweden
Honghuang Lin - National Heart, Lung, and Blood Institute’s and Boston University’s Framingham Heart Study, Framingham, Massachusetts, USA
Cecilia M Lindgren - Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Christina Loley - Institute for Medical Biometry and Statistics, University Lübeck, University Medical Center Schleswig-Holstein, Lübeck, Germany
Calum A MacRae - Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA
Deborah Mascalzoni - Center for Biomedicine, European Academy of Bolzano/Bozen, Bolzano, Italy – Affiliated institute of the University of Lübeck, Lübeck, Germany
Jamil Mayet - International Centre for Circulatory Health, Hammersmith Hospital, London, United Kingdom
Daniel Medenwald - Institute of Medical Epidemiology, Biostatistics, and Informatics, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
Andrew P Morris - Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Christian Müller - Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
Martina Müller-Nurasyid - Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany
Stefania Nappo - Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, Naples, Italy
Peter M Nilsson - Department of Clinical Sciences, Lund University, Malmö, Sweden
Sebastian Nuding - Department of Medicine III, University Clinics Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
Teresa Nutile - Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, Naples, Italy
Annette Peters - DZHK, partner site Munich Heart Alliance, Munich, Germany
Arne Pfeufer - Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
Diana Pietzner - Institute of Medical Epidemiology, Biostatistics, and Informatics, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
Peter P Pramstaller - Center for Biomedicine, European Academy of Bolzano/Bozen, Bolzano, Italy – Affiliated institute of the University of Lübeck, Lübeck, Germany
Olli T Raitakari - Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
Kenneth M Rice - Department of Biostatistics, University of Washington, Seattle, Washington, USA
Fernando Rivadeneira - Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
Jerome I Rotter - Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA
Saku T Ruohonen - Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
Ralph L Sacco - Department of Neurology and
Tandaw E Samdarshi - Division of Cardiology, University of Mississippi Medical Center, Jackson, Mississippi, USA
Helena Schmidt - Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria
Andrew S.P Sharp - Department of Cardiology, Royal Devon and Exeter Hospital and University of Exeter, Exeter, United Kingdom
Denis C Shields - UCD Conway Institute of Biomolecular and Biomedical Research and
Rossella Sorice - Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, Naples, Italy
Nona Sotoodehnia - Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA
Bruno H Stricker - Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
Praveen Surendran - Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland
Simon Thom - International Centre for Circulatory Health, Hammersmith Hospital, London, United Kingdom
Anna M Töglhofer - Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria
André G Uitterlinden - Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
Rolf Wachter - Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August University, Göttingen, Germany
Henry Völzke - Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
Andreas Ziegler - Institute for Medical Biometry and Statistics, University Lübeck, University Medical Center Schleswig-Holstein, Lübeck, Germany
Thomas Münzel - DZHK (German Centre for Cardiovascular Research), partner site RhineMain, Mainz, Germany
Winfried März - Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
Thomas P Cappola - Penn Cardiovascular Institute and Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Joel N Hirschhorn - Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Gary F Mitchell - Cardiovascular Engineering Inc., Norwood, Massachusetts, USA
Nicholas L Smith - Department of Epidemiology, University of Washington, Seattle, Washington, USA
Ervin R Fox - Division of Cardiology, University of Mississippi Medical Center, Jackson, Mississippi, USA
Nicole D Dueker - John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, USA
Vincent W.V Jaddoe - Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
Olle Melander - Department of Clinical Sciences, Lund University, Malmö, Sweden
Martin Russ - Department of Medicine III, University Clinics Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
Terho Lehtimäki - Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
Marina Ciullo - Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, Naples, Italy
Andrew A Hicks - Center for Biomedicine, European Academy of Bolzano/Bozen, Bolzano, Italy – Affiliated institute of the University of Lübeck, Lübeck, Germany
Lars Lind - Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden
Vilmundur Gudnason - Icelandic Heart Association, Kopavogur, Iceland
Burkert Pieske - Department of Cardiology, Medical University Graz, Graz, Austria
Anthony J Barron - International Centre for Circulatory Health, Hammersmith Hospital, London, United Kingdom
Robert Zweiker - Department of Cardiology, Medical University Graz, Graz, Austria
Heribert Schunkert - DZHK, partner site Munich Heart Alliance, Munich, Germany
Erik Ingelsson - Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Kiang Liu - Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Donna K Arnett - Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA
Bruce M Psaty - Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA
Stefan Blankenberg - DZHK, partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
Martin G Larson - Biostatistics Department, Boston University School of Public Health, Boston, Massachusetts, USA
Stephan B Felix - DZHK, partner site Greifswald, Greifswald, Germany
Oscar H Franco - Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
Tanja Zeller - DZHK, partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
Ramachandran S Vasan - National Heart, Lung, and Blood Institute’s and Boston University’s Framingham Heart Study, Framingham, Massachusetts, USA
Marcus Dörr - DZHK, partner site Greifswald, Greifswald, Germany
Publication Details: The Journal of clinical investigation, Vol.127(5), pp.1798-1812
Publisher: American Society for Clinical Investigation
Academic Unit: Leadership Department; Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Department of Neurology
Language: English
Resource Type: Journal article
PMID: 28394258
PMCID: PMC5409098
Record Identifier: 991031578055902976