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Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity

Nature Genetics volume 53, pages 135–142 (2021)Cite this article

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Abstract

Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart disorder. Rare pathogenic variants in sarcomere genes cause HCM, but with unexplained phenotypic heterogeneity. Moreover, most patients do not carry such variants. We report a genome-wide association study of 2,780 cases and 47,486 controls that identified 12 genome-wide-significant susceptibility loci for HCM. Single-nucleotide polymorphism heritability indicated a strong polygenic influence, especially for sarcomere-negative HCM (64% of cases; h2g = 0.34 ± 0.02). A genetic risk score showed substantial influence on the odds of HCM in a validation study, halving the odds in the lowest quintile and doubling them in the highest quintile, and also influenced phenotypic severity in sarcomere variant carriers. Mendelian randomization identified diastolic blood pressure (DBP) as a key modifiable risk factor for sarcomere-negative HCM, with a one standard deviation increase in DBP increasing the HCM risk fourfold. Common variants and modifiable risk factors have important roles in HCM that we suggest will be clinically actionable.

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Fig. 1: Study design for the HCM genome-wide association analysis.
Fig. 2: Validation of an HCM GRS.
Fig. 3: Relationship between standardized GRS and maximum left ventricular wall thickness.
Fig. 4: Two-sample inverse-variance-weighted Mendelian randomization identifies modifiable risk factors for HCM.

Data availability

All of the relevant data are included within the paper and/or its Supplementary Information files. The datasets generated during this study are available from the corresponding author upon reasonable request. The institutional domain www.well.ox.ac.uk/hcm will provide summary-level statistics.

Code availability

Publicly available software tools were used to analyze these data. These include: SAIGE (https://github.com/weizhouUMICH/SAIGE), SNPTEST (https://mathgen.stats.ox.ac.uk/genetics_software/snptest/snptest.html), GCTA (https://cnsgenomics.com/software/gcta/), PLINK (https://www.cog-genomics.org/plink/1.9/data), BGENIX (https://bitbucket.org/gavinband/bgen/wiki/bgenix), QCTOOL (https://www.well.ox.ac.uk/~gav/qctool_v2/), GWAMA (https://genomics.ut.ee/en/tools/gwama) and MR-Base (http://www.mrbase.org/).

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Acknowledgements

This work was supported by funding from the British Heart Foundation (BHF), the Medical Research Council (MRC), the National Heart, Lung, and Blood Institute (NIH grant U01HL117006-01A1), the Wellcome Trust (201543/B/16/Z), Wellcome Trust core awards (090532/Z/09/Z and 203141/Z/16/Z) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. A.R.H. has received support from the MRC Doctoral Training Partnership. A.G. has received support from the BHF, European Commission (LSHM-CT-2007-037273 and HEALTH-F2-2013-601456) and Tripartite Immunometabolism Consortium (TrIC)-NovoNordisk Foundation (NNF15CC0018486). S.E.P. acknowledges support from the NIHR Barts Biomedical Research Centre. A.W. has received support from the Wellcome Trust. S.N., M.F. and H.W. are members of the Oxford BHF Centre of Research Excellence (RE/13/1/30181). We are grateful for access to the high-performance Oxford Biomedical Research Computing (BMRC) facility, a joint development between the Wellcome Centre for Human Genetics and the Big Data Institute that is supported by Health Data Research UK and the NIHR Oxford Biomedical Research Centre. The views expressed are those of the author(s) and do not necessarily reflect those of the NHS, NIHR, Department of Health or Department of Health and Social Care. We thank the NIHR BioResource volunteers for their participation and gratefully acknowledge the NIHR BioResource centers, NHS Trusts and staff for their contribution. We thank the NIHR and NHS Blood and Transplant. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project, which is managed by Genomics England (a wholly owned company of the Department of Health and Social Care) and funded by the NIHR and NHS England with research infrastructure funding from the Wellcome Trust, Cancer Research UK and the MRC. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. We acknowledge the contribution of the Oxford Medical Genetics Laboratories.

Author information

Author notes

  1. These authors contributed equally: James S. Ware, Connie R. Bezzina, Martin Farrall, Hugh Watkins.

Authors and Affiliations

  1. Radcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford, Oxford, UK

    Andrew R. Harper, Anuj Goel, Christopher Grace, Kate L. Thomson, Elizabeth Ormondroyd, Stefan Neubauer, Martin Farrall & Hugh Watkins

  2. Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK

    Andrew R. Harper, Anuj Goel, Christopher Grace, Kate L. Thomson, Adam Waring, Elizabeth Ormondroyd, Martin Farrall & Hugh Watkins

  3. Oxford Medical Genetics Laboratories, Churchill Hospital, Oxford, UK

    Kate L. Thomson

  4. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    Steffen E. Petersen

  5. National Heart and Lung Institute, Imperial College London, London, UK

    Xiao Xu & James S. Ware

  6. University of Virginia Health System, Charlottesville, VA, USA

    Christopher M. Kramer

  7. Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA

    Carolyn Y. Ho

  8. Cardiovascular Genetics Centre, Montréal Heart Institute, Montréal, Québec, Canada

    Rafik Tadros

  9. Amsterdam UMC, AMC Heart Center, Amsterdam, the Netherlands

    Connie R. Bezzina

  10. NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK

    Hugh Watkins

  11. MedStar Heart and Vascular Institute, Washington, DC, USA

    Paul Kolm, Sarahfaye F. Dolman, Cheng Zhang & William Weintraub

  12. Cardiovascular Division, Departments of Medicine and Radiology, Brigham and Women’s Hospital, Boston, MA, USA

    Raymond Kwong

  13. National Heart, Lung, and Blood Institute, Bethesda, MD, USA

    Patrice Desvigne-Nickens, Nancy Geller & Dong-Yun Kim

  14. Cardiovascular Division, University of Virginia Health System, Charlottesville, VA, USA

    John P. Dimarco

  15. Hypertrophic Cardiomyopathy Center of Excellence, Johns Hopkins University, Baltimore, MD, USA

    Theodore Abraham

  16. St George’s University Hospitals NHS Foundation Trust, London, UK

    Lisa Anderson

  17. Departments of Medicine (Cardiovascular Division) and Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Evan Appelbaum

  18. Division of Cardiology, Department of Clinical and Molecular Medicine, St. Andrea Hospital, Sapienza University, Rome, Italy

    Camillo Autore

  19. British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK

    Colin Berry

  20. Cardio-Thoraco-Vascular Department, University Hospital of Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy

    Elena Biagini

  21. Department of Cardiology, New Queen Elizabeth Hospital Birmingham, Birmingham, UK

    William Bradlow

  22. Bristol Heart Institute, NIHR Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK

    Chiara Bucciarelli-Ducci

  23. Cardiovascular Division, King’s College London British Heart Foundation Centre of Research Excellence, The Rayne Institute, St. Thomas’ Hospital, London, UK

    Amedeo Chiribiri

  24. Division of Cardiology, Department of Medicine, Bluhm Cardiovascular Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Lubna Choudhury

  25. Division of Cardiology, Peter Munk Cardiac Center, University Health Network, University of Toronto, Toronto, Ontario, Canada

    Andrew Crean

  26. Aberdeen Cardiovascular and Diabetes Centre, University of Aberdeen, Aberdeen, UK

    Dana Dawson

  27. Department of Cardiovascular Medicine, Center for Radiation Heart Disease, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA

    Milind Y. Desai

  28. Division of Cardiology, Department of Medicine, Royal Victoria Hospital, McGill University Health Centre, Montréal, Québec, Canada

    Eleanor Elstein

  29. Department of Cardiology, University Hospital Southampton NHS Foundation Trust, Southampton, UK

    Andrew Flett

  30. Department of Medicine, Heidelberg University, Heidelberg, Germany

    Matthias Friedrich

  31. Division of Cardiovascular Medicine, Knight Cardiovascular Institute, Oregon Health and Sciences University (OHSU), Portland, OR, USA

    Stephen Heitner

  32. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Adam Helms

  33. Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA

    Daniel L. Jacoby

  34. Duke Cardiovascular Magnetic Resonance Center and Division of Cardiology, Duke University Medical Center, Durham, NC, USA

    Han Kim

  35. Mount Sinai West, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Bette Kim

  36. Quebec Heart and Lung Institute, Laval University, Québec City, Québec, Canada

    Eric Larose

  37. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    Masliza Mahmod

  38. Department of Cardiology, Robert Bosch Hospital, Stuttgart, Germany

    Heiko Mahrholdt

  39. Hypertrophic Cardiomyopathy Center and Research Institute, Tufts Medical Center, Boston, MA, USA

    Martin Maron

  40. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK

    Gerry McCann

  41. Erasmus University, Rotterdam, the Netherlands

    Michelle Michels

  42. Barts Heart Centre, The Cardiovascular Magnetic Resonance Imaging Unit, St Bartholomew’s Hospital, London, UK

    Saidi Mohiddin

  43. Methodist DeBakey Heart and Vascular Center, Houston, TX, USA

    Sherif Nagueh

  44. Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK

    David Newby

  45. Cardiomyopathy Unit and Genetic Unit, Careggi University Hospital, Florence, Italy

    Iacopo Olivotto

  46. Centre for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Anjali Owens

  47. Montréal Heart Institute, Montréal, Québec, Canada

    F. Pierre-Mongeon

  48. National Heart and Lung Institute, Imperial College London and Royal Brompton Hospital, London, UK

    Sanjay Prasad

  49. Vita Salute University and San Raffaele Hospital, Milan, Italy

    Ornella Rimoldi

  50. Department of Medicine, University of Virginia, Charlottesville, VA, USA

    Michael Salerno

  51. Charité, Medical Faculty of the Humboldt University, Experimental and Clinical Research Center and Helios Clinics Cardiology Department, Berlin, Germany

    Jeanette Schulz-Menger

  52. Hypertrophic Cardiomyopathy Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA

    Mark Sherrid

  53. Department of Cardiovascular Imaging Science, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK

    Peter Swoboda

  54. Department of Cardiology, Amsterdam UMC, Amsterdam, the Netherlands

    Albert van Rossum

  55. Departments of Medicine and Radiology, Weill Cornell Medical College, New York, NY, USA

    Jonathan Weinsaft

  56. Calgary Foothills Medical Centre, University of Calgary, Calgary, Alberta, Canada

    James White

  57. Department of Radiology, Mayo Clinic, Rochester, MN, USA

    Eric Williamson

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  1. Andrew R. Harper
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  2. Anuj Goel
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  7. Adam Waring
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  16. Hugh Watkins
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Consortia

HCMR Investigators

  • Paul Kolm
  • , Raymond Kwong
  • , Sarahfaye F. Dolman
  • , Patrice Desvigne-Nickens
  • , John P. Dimarco
  • , Nancy Geller
  • , Dong-Yun Kim
  • , Cheng Zhang
  • , William Weintraub
  • , Theodore Abraham
  • , Lisa Anderson
  • , Evan Appelbaum
  • , Camillo Autore
  • , Colin Berry
  • , Elena Biagini
  • , William Bradlow
  • , Chiara Bucciarelli-Ducci
  • , Amedeo Chiribiri
  • , Lubna Choudhury
  • , Andrew Crean
  • , Dana Dawson
  • , Milind Y. Desai
  • , Eleanor Elstein
  • , Andrew Flett
  • , Matthias Friedrich
  • , Stephen Heitner
  • , Adam Helms
  • , Daniel L. Jacoby
  • , Han Kim
  • , Bette Kim
  • , Eric Larose
  • , Masliza Mahmod
  • , Heiko Mahrholdt
  • , Martin Maron
  • , Gerry McCann
  • , Michelle Michels
  • , Saidi Mohiddin
  • , Sherif Nagueh
  • , David Newby
  • , Iacopo Olivotto
  • , Anjali Owens
  • , F. Pierre-Mongeon
  • , Sanjay Prasad
  • , Ornella Rimoldi
  • , Michael Salerno
  • , Jeanette Schulz-Menger
  • , Mark Sherrid
  • , Peter Swoboda
  • , Albert van Rossum
  • , Jonathan Weinsaft
  • , James White
  •  & Eric Williamson

Contributions

A.R.H., M.F. and H.W. conceived of and designed the study. A.R.H., A.G., C.G., K.L.T., S.E.P., A.W., E.O., C.M.K., S.N. and C.Y.H. acquired, analyzed and interpreted the data. X.X. and R.T. provided assistance with replication. A.R.H., M.F. and H.W. wrote the manuscript. J.S.W., C.R.B. and R.T. critically revised the manuscript for important intellectual content.

Corresponding author

Correspondence to Hugh Watkins.

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Competing interests

As of April 2020, A.R.H. is an employee of AstraZeneca.

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Peer review information Nature Genetics thanks the anonymous reviewers for their contribution to the peer review of this work.

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Supplementary Tables 1–25

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Harper, A.R., Goel, A., Grace, C. et al. Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. Nat Genet 53, 135–142 (2021). https://doi.org/10.1038/s41588-020-00764-0

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