Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect

Rafik Tadros; Catherine Francis; Xiao Xu; Alexa M C Vermeer; Andrew R Harper; Roy Huurman; Ken Kelu Bisabu; Roddy Walsh; Edgar T Hoorntje; Wouter P Te Rijdt; Rachel J Buchan; Hannah G van Velzen; Marjon A van Slegtenhorst; Jentien M Vermeulen; Joost Allard Offerhaus; Wenjia Bai; Antonio de Marvao; Najim Lahrouchi; Leander Beekman; Jacco C Karper; Jan H Veldink; Elham Kayvanpour; Antonis Pantazis; A John Baksi; Nicola Whiffin; Francesco Mazzarotto; Geraldine Sloane; Hideaki Suzuki; Deborah Schneider-Luftman; Paul Elliott; Pascale Richard; Flavie Ader; Eric Villard; Peter Lichtner; Thomas Meitinger; Michael W T Tanck; J Peter van Tintelen; Andrew Thain; David McCarty; Robert A Hegele; Jason D Roberts; Julie Amyot; Marie-Pierre Dubé; Julia Cadrin-Tourigny; Geneviève Giraldeau; Philippe L L'Allier; Patrick Garceau; Jean-Claude Tardif; S Matthijs Boekholdt; R Thomas Lumbers; Folkert W Asselbergs; Paul J R Barton; Stuart A Cook; Sanjay K Prasad; Declan P O'Regan; Jolanda van der Velden; Karin J H Verweij; Mario Talajic; Guillaume Lettre; Yigal M Pinto; Benjamin Meder; Philippe Charron; Rudolf A de Boer; Imke Christiaans; Michelle Michels; Arthur A M Wilde; Hugh Watkins; Paul M Matthews; James S Ware; Connie R Bezzina

doi:10.1038/s41588-020-00762-2

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect

Nat Genet. 2021 Feb;53(2):128-134. doi: 10.1038/s41588-020-00762-2. Epub 2021 Jan 25.

Authors

Rafik Tadros^#^{1

2}, Catherine Francis^#^{3

4}, Xiao Xu^#⁵, Alexa M C Vermeer^#^{6

7

8}, Andrew R Harper^{9

10}, Roy Huurman¹¹, Ken Kelu Bisabu¹², Roddy Walsh⁶, Edgar T Hoorntje^{13

14}, Wouter P Te Rijdt^{13

14}, Rachel J Buchan^{3

4}, Hannah G van Velzen¹¹, Marjon A van Slegtenhorst¹⁵, Jentien M Vermeulen¹⁶, Joost Allard Offerhaus⁶, Wenjia Bai^{17

18}, Antonio de Marvao⁵, Najim Lahrouchi⁶, Leander Beekman⁶, Jacco C Karper¹⁹, Jan H Veldink²⁰, Elham Kayvanpour^{21

22}, Antonis Pantazis³, A John Baksi^{3

4}, Nicola Whiffin^{3

4

5}, Francesco Mazzarotto^{3

4

23

24}, Geraldine Sloane^{3

4}, Hideaki Suzuki^{18

25

26}, Deborah Schneider-Luftman^{27

28}, Paul Elliott²⁸, Pascale Richard^{29

30}, Flavie Ader^{29

30

31}, Eric Villard³⁰, Peter Lichtner³², Thomas Meitinger^{32

33

34}, Michael W T Tanck³⁵, J Peter van Tintelen^{7

36}, Andrew Thain³⁷, David McCarty³⁷, Robert A Hegele³⁷, Jason D Roberts³⁷, Julie Amyot¹², Marie-Pierre Dubé³⁸, Julia Cadrin-Tourigny¹², Geneviève Giraldeau¹², Philippe L L'Allier¹², Patrick Garceau¹², Jean-Claude Tardif³⁸, S Matthijs Boekholdt³⁹, R Thomas Lumbers^{40

41

42}, Folkert W Asselbergs^{43

44}, Paul J R Barton^{3

4}, Stuart A Cook^{4

5

45

46}, Sanjay K Prasad^{3

4}, Declan P O'Regan⁵, Jolanda van der Velden⁴⁷, Karin J H Verweij¹⁶, Mario Talajic¹², Guillaume Lettre³⁸, Yigal M Pinto^{6

8}, Benjamin Meder²¹, Philippe Charron^{8

30

48}, Rudolf A de Boer¹⁹, Imke Christiaans¹³, Michelle Michels¹¹, Arthur A M Wilde^{6

8}, Hugh Watkins^#^{9

10}, Paul M Matthews^#¹⁸, James S Ware^#^{49

50

51}, Connie R Bezzina^#^{52

53}

Affiliations

¹ Cardiovascular Genetics Center, Montreal Heart Institute, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada. rafik.tadros@umontreal.ca.
² Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands. rafik.tadros@umontreal.ca.
³ Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK.
⁴ National Heart and Lung Institute, Imperial College London, London, UK.
⁵ MRC London Institute of Medical Sciences, Imperial College London, London, UK.
⁶ Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
⁷ Department of Clinical Genetics, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
⁸ European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART).
⁹ Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹⁰ Wellcome Centre for Human Genetics, Oxford, UK.
¹¹ Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands.
¹² Cardiovascular Genetics Center, Montreal Heart Institute, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada.
¹³ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹⁴ Netherlands Heart Institute, Utrecht, the Netherlands.
¹⁵ Department of Clinical Genetics, Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands.
¹⁶ Department of Psychiatry, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
¹⁷ Data Science Institute, Imperial College London, London, UK.
¹⁸ Department of Brain Sciences and UK Dementia Research Institute at Imperial College London, Hammersmith Hospital, Imperial College London, London, UK.
¹⁹ Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
²⁰ Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
²¹ Institute for Cardiomyopathies, Heidelberg Heart Center, University of Heidelberg, Heidelberg, Germany.
²² DZHK (German Center for Cardiovascular Research), Berlin, Germany.
²³ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
²⁴ Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy.
²⁵ Department of Cardiovascular Medicine, Tohoku University Hospital, Seiryo, Aoba, Sendai, Japan.
²⁶ Tohoku Medical Megabank Organization, Tohoku University, Seiryo, Aoba, Sendai, Japan.
²⁷ The Francis Crick Institute, London, UK.
²⁸ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
²⁹ Service de biochimie métabolique, UF de cardiogénétique et myogénétique moléculaire et cellulaire, APHP, Hôpital Pitié-Salpêtrière, Paris, France.
³⁰ INSERM, UMR_S 1166 and ICAN Institute for Cardiometabolism and Nutrition, Faculté de Médecine, Sorbonne Université, Paris, France.
³¹ Faculté de Pharmacie, Université de Paris, Paris, France.
³² Institute of Human Genetics, Helmholtz Zentrum Muenchen, Neuherberg, Germany.
³³ Klinikum rechts der Isar der TU Muenchen School of Medicine, Institute of Human Genetics, Munich, Germany.
³⁴ DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
³⁵ Department of Clinical Epidemiology, Biostatistics and Bioinformatics, University of Amsterdam, Amsterdam Public Health (APH), Amsterdam UMC, Amsterdam, the Netherlands.
³⁶ Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
³⁷ Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
³⁸ Montreal Heart Institute Research Center, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada.
³⁹ Department of Cardiology, University of Amsterdam, Heartcenter, Amsterdam UMC, Amsterdam, the Netherlands.
⁴⁰ Institute of Health Informatics, University College London, London, UK.
⁴¹ Health Data Research UK, Gibbs Building, London, UK.
⁴² Barts Heart Centre, Saint Bartholomew's Hospital, London, UK.
⁴³ Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
⁴⁴ Institute of Cardiovascular Science and Institute of Health Informatics, Faculty of Population Health Sciences, University College London, London, UK.
⁴⁵ National Heart Research Institute Singapore, National Heart Center Singapore, Singapore, Singapore.
⁴⁶ Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.
⁴⁷ Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Amsterdam, the Netherlands.
⁴⁸ Département de Génétique, Centre de référence des maladies cardiaques héréditaires ou rares, APHP, Hôpital Pitié-Salpêtrière, Paris, France.
⁴⁹ Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK. j.ware@imperial.ac.uk.
⁵⁰ National Heart and Lung Institute, Imperial College London, London, UK. j.ware@imperial.ac.uk.
⁵¹ MRC London Institute of Medical Sciences, Imperial College London, London, UK. j.ware@imperial.ac.uk.
⁵² Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands. c.r.bezzina@amsterdamumc.nl.
⁵³ European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART), . c.r.bezzina@amsterdamumc.nl.

^# Contributed equally.

Abstract

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cardiomyopathy, Dilated / genetics*
Cardiomyopathy, Dilated / mortality
Cardiomyopathy, Dilated / physiopathology
Cardiomyopathy, Hypertrophic / genetics*
Cardiomyopathy, Hypertrophic / mortality
Cardiomyopathy, Hypertrophic / physiopathology
Case-Control Studies
Gene Frequency
Genetic Predisposition to Disease
Genome-Wide Association Study
Heart Ventricles / physiopathology
Humans
Kaplan-Meier Estimate
Linkage Disequilibrium
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Ventricular Function, Left / genetics

Abstract

Publication types

MeSH terms

Grants and funding