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Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure

Author

Listed:
  • Danielle Rasooly

    (Harvard Medical School
    VA Boston Healthcare System)

  • Gina M. Peloso

    (VA Boston Healthcare System
    Boston University School of Public Health)

  • Alexandre C. Pereira

    (University of São Paulo
    Harvard University)

  • Hesam Dashti

    (Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Claudia Giambartolomei

    (Health Data Science Centre, Human Technopole
    Istituto Italiano di Tecnologia)

  • Eleanor Wheeler

    (University of Cambridge, Addenbrookes Hospital)

  • Nay Aung

    (Queen Mary University of London
    St Bartholomew’s Hospital, Barts Health NHS Trust, West Smithfield)

  • Brian R. Ferolito

    (VA Boston Healthcare System)

  • Maik Pietzner

    (University of Cambridge, Addenbrookes Hospital
    Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin
    Precision Healthcare University Research Institute, Queen Mary University of London)

  • Eric H. Farber-Eger

    (Vanderbilt University Medical Center)

  • Quinn Stanton Wells

    (Biomedical Informatics, and Pharmacology)

  • Nicole M. Kosik

    (VA Boston Healthcare System)

  • Liam Gaziano

    (VA Boston Healthcare System
    University of Cambridge, Worts Causeway)

  • Daniel C. Posner

    (VA Boston Healthcare System)

  • A. Patrícia Bento

    (European Bioinformatics Institute, Wellcome Genome Campus)

  • Qin Hui

    (Emory University Rollins School of Public Health
    Atlanta VA Health Care System)

  • Chang Liu

    (Emory University Rollins School of Public Health)

  • Krishna Aragam

    (VA Boston Healthcare System
    Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Zeyuan Wang

    (Emory University Rollins School of Public Health)

  • Brian Charest

    (VA Boston Healthcare System)

  • Jennifer E. Huffman

    (VA Boston Healthcare System)

  • Peter W. F. Wilson

    (Atlanta VA Health Care System
    Emory University School of Medicine)

  • Lawrence S. Phillips

    (Atlanta VA Health Care System
    Emory University)

  • John Whittaker

    (University of Cambridge)

  • Patricia B. Munroe

    (Queen Mary University of London, Charterhouse Square
    Queen Mary University of London)

  • Steffen E. Petersen

    (St Bartholomew’s Hospital, Barts Health NHS Trust, West Smithfield
    Queen Mary University of London, Charterhouse Square)

  • Kelly Cho

    (Harvard Medical School
    VA Boston Healthcare System)

  • Andrew R. Leach

    (European Bioinformatics Institute, Wellcome Genome Campus)

  • María Paula Magariños

    (European Bioinformatics Institute, Wellcome Genome Campus)

  • John Michael Gaziano

    (Harvard Medical School
    VA Boston Healthcare System)

  • Claudia Langenberg

    (University of Cambridge, Addenbrookes Hospital
    Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin
    Precision Healthcare University Research Institute, Queen Mary University of London)

  • Yan V. Sun

    (Emory University Rollins School of Public Health
    Atlanta VA Health Care System
    Emory University School of Medicine, 1639 Pierce Dr NE)

  • Jacob Joseph

    (VA Providence Healthcare System
    Warren Alpert Medical School of Brown University)

  • Juan P. Casas

    (Harvard Medical School
    VA Boston Healthcare System)

Abstract

We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian randomization and colocalization analyses on human proteins to provide putative causal evidence for the role of druggable proteins in the genesis of heart failure. We identify 39 genome-wide significant heart failure risk variants, of which 18 are previously unreported. Using a combination of Mendelian randomization proteomics and genetic cis-only colocalization analyses, we identify 10 additional putatively causal genes for heart failure. Findings from GWAS and Mendelian randomization-proteomics identify seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of heart failure.

Suggested Citation

  • Danielle Rasooly & Gina M. Peloso & Alexandre C. Pereira & Hesam Dashti & Claudia Giambartolomei & Eleanor Wheeler & Nay Aung & Brian R. Ferolito & Maik Pietzner & Eric H. Farber-Eger & Quinn Stanton , 2023. "Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39253-3
    DOI: 10.1038/s41467-023-39253-3
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    References listed on IDEAS

    as
    1. Claudia Giambartolomei & Damjan Vukcevic & Eric E Schadt & Lude Franke & Aroon D Hingorani & Chris Wallace & Vincent Plagnol, 2014. "Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics," PLOS Genetics, Public Library of Science, vol. 10(5), pages 1-15, May.
    2. Tian Ge & Chia-Yen Chen & Yang Ni & Yen-Chen Anne Feng & Jordan W. Smoller, 2019. "Polygenic prediction via Bayesian regression and continuous shrinkage priors," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    3. Angli Xue & Yang Wu & Zhihong Zhu & Futao Zhang & Kathryn E. Kemper & Zhili Zheng & Loic Yengo & Luke R. Lloyd-Jones & Julia Sidorenko & Yeda Wu & Allan F. McRae & Peter M. Visscher & Jian Zeng & Jian, 2018. "Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    4. Hélène Choquet & Seyyedhassan Paylakhi & Stephen C. Kneeland & Khanh K. Thai & Thomas J. Hoffmann & Jie Yin & Mark N. Kvale & Yambazi Banda & Nicholas G. Tolman & Pete A. Williams & Catherine Schaefer, 2018. "A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    5. Kyoko Watanabe & Erdogan Taskesen & Arjen Bochoven & Danielle Posthuma, 2017. "Functional mapping and annotation of genetic associations with FUMA," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    6. James P. Pirruccello & Alexander Bick & Minxian Wang & Mark Chaffin & Samuel Friedman & Jie Yao & Xiuqing Guo & Bharath Ambale Venkatesh & Kent D. Taylor & Wendy S. Post & Stephen Rich & Joao A. C. Li, 2020. "Analysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    7. Jacob Joseph & Chang Liu & Qin Hui & Krishna Aragam & Zeyuan Wang & Brian Charest & Jennifer E. Huffman & Jacob M. Keaton & Todd L. Edwards & Serkalem Demissie & Luc Djousse & Juan P. Casas & J. Micha, 2022. "Genetic architecture of heart failure with preserved versus reduced ejection fraction," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    8. Sarah E. Graham & Shoa L. Clarke & Kuan-Han H. Wu & Stavroula Kanoni & Greg J. M. Zajac & Shweta Ramdas & Ida Surakka & Ioanna Ntalla & Sailaja Vedantam & Thomas W. Winkler & Adam E. Locke & Eirini Ma, 2021. "The power of genetic diversity in genome-wide association studies of lipids," Nature, Nature, vol. 600(7890), pages 675-679, December.
    9. Gibran Hemani & Kate Tilling & George Davey Smith, 2017. "Orienting the causal relationship between imprecisely measured traits using GWAS summary data," PLOS Genetics, Public Library of Science, vol. 13(11), pages 1-22, November.
    10. Kira J. Stanzick & Yong Li & Pascal Schlosser & Mathias Gorski & Matthias Wuttke & Laurent F. Thomas & Humaira Rasheed & Bryce X. Rowan & Sarah E. Graham & Brett R. Vanderweff & Snehal B. Patil & Cass, 2021. "Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    11. Sonia Shah & Albert Henry & Carolina Roselli & Honghuang Lin & Garðar Sveinbjörnsson & Ghazaleh Fatemifar & Åsa K. Hedman & Jemma B. Wilk & Michael P. Morley & Mark D. Chaffin & Anna Helgadottir & Nie, 2020. "Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
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