Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure · SciRah

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Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Sonia H Shah^{a b c}, Albert Henry^{a c d}, Carolina Roselli^{e f}, Honghuang Lin^{g h}, Garðar Sveinbjörnssonⁱ, Ghazaleh Fatemifar^{a d j}, Åsa K. Hedman^k, Jemma B. Wilk^l, Michael P. Morley^m, Mark D. Chaffin^f, Anna Helgadóttirⁱ, Niek Verweij

Nature Communications Nature Portfolio2020-01-09 839 citations91 references

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Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies. Heart failure is a complex syndrome that is associated with many different underlying risk factors. Here, to increase power, the authors jointly analyse cases of heart failure of different aetiologies in a genome-wide association study and identify 11 loci of which ten had not been previously reported.

TL;DRMendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. (Semantic Scholar)

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Discussion

^aBritish Heart Foundation Research Accelerator, University College London, London, UK
^bInstitute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia
^cInstitute of Cardiovascular Science, University College London, London, UK
^dInstitute of Health Informatics, University College London, London, UK
^eDepartment of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
^fProgram in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
^gNational Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA
^hSection of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
ⁱdeCODE genetics/Amgen Inc., Sturlugata 8, 101, Reykjavik, Iceland
^jHealth Data Research UK London, University College London, London, UK
^kCardiovascular Medicine unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden
^lPfizer Worldwide Research & Development, 1 Portland St, Cambridge, MA, USA
^mPenn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
ⁿDepartment of Epidemiology and Biostatistics, Imperial College London, St Mary's Campus, London, W2 1PG, UK
^oMRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, Imperial College London, St Mary's Campus, London, W2 1PG, UK
^pDepartment of Clinical Sciences, Lund University, Malmö, Sweden
^qDepartment of Cardiology, Herlev Gentofte Hospital, Herlev Ringvej 57, 2650, Herlev, Denmark
^rCardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
^sCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
^tDepartment of Neurobiology, Care Sciences and Society/ Section of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden
^uSchool of Health and Social Sciences, Dalarna University, Falun, Sweden
^vRegeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA
^wDepartment of Biostatistics, University of Washington, Seattle, WA, USA
^xDepartment of Medicine, University of Washington, Seattle, WA, USA
^yDivision of Cardiology, Department of Medicine, Emory University Medical Center, Atlanta, GA, USA
^zDepartment of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas School of Public Health, Houston, Texas, USA
^aaDepartment of Molecular and Functional Genomics, Geisinger, Danville, PA, USA
^abDivision of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA
^acHarvard Medical School, Boston, MA, 02115, USA
^adDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
^aeNovartis Institutes for Biomedical Research, Cambridge, MA, USA
^afDepartment of Biostatistics, University of Liverpool, Liverpool, UK