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Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

  • Published:2020-07-28 Issue:4 Volume:142 Page:324-338
  • ISSN:0009-7322
  • Container-title:Circulation
  • language:en
  • Short-container-title:Circulation

Author:

Lahrouchi Najim12,Tadros Rafik13,Crotti Lia24567,Mizusawa Yuka12,Postema Pieter G.12,Beekman Leander12,Walsh Roddy12,Hasegawa Kanae89,Barc Julien210,Ernsting Marko211,Turkowski Kari L.12,Mazzanti Andrea213,Beckmann Britt M.14,Shimamoto Keiko15,Diamant Ulla-Britt216,Wijeyeratne Yanushi D.217,Kucho Yu18,Robyns Tomas21920,Ishikawa Taisuke21,Arbelo Elena22,Christiansen Michael232425,Winbo Annika26,Jabbari Reza227,Lubitz Steven A.2829,Steinfurt Johannes30,Rudic Boris31,Loeys Bart32,Shoemaker M. Ben33,Weeke Peter E.2733,Pfeiffer Ryan34,Davies Brianna35,Andorin Antoine1736,Hofman Nynke12,Dagradi Federica24,Pedrazzini Matteo5,Tester David J.12,Bos J. Martijn12,Sarquella-Brugada Georgia2373839,Campuzano Óscar394041,Platonov Pyotr G.42,Stallmeyer Birgit11,Zumhagen Sven11,Nannenberg Eline A.43,Veldink Jan H.44,van den Berg Leonard H.44,Al-Chalabi Ammar4546,Shaw Christopher E.4647,Shaw Pamela J.4548,Morrison Karen E.49,Andersen Peter M.5051,Müller-Nurasyid Martina145253,Cusi Daniele5455,Barlassina Cristina5455,Galan Pilar56,Lathrop Mark57,Munter Markus57,Werge Thomas585960,Ribasés Marta61,Aung Tin62,Khor Chiea C.63,Ozaki Mineo64,Lichtner Peter65,Meitinger Thomas65,van Tintelen J. Peter436667,Hoedemaekers Yvonne66,Denjoy Isabelle268,Leenhardt Antoine268,Napolitano Carlo213,Shimizu Wataru1569,Schott Jean-Jacques21036,Gourraud Jean-Baptiste21036,Makiyama Takeru70,Ohno Seiko87172,Itoh Hideki871,Krahn Andrew D.35,Antzelevitch Charles7374,Roden Dan M.753376,Saenen Johan77,Borggrefe Martin31,Odening Katja E.30,Ellinor Patrick T.2829,Tfelt-Hansen Jacob22778,Skinner Jonathan R.79,van den Berg Maarten P.80,Olesen Morten Salling8182,Brugada Josep283,Brugada Ramón408485,Makita Naomasa86,Breckpot Jeroen87,Yoshinaga Masao18,Behr Elijah R.217,Rydberg Annika216,Aiba Takeshi15,Kääb Stefan14,Priori Silvia G.213,Guicheney Pascale88,Tan Hanno L.1289,Newton-Cheh Christopher90,Ackerman Michael J.12,Schwartz Peter J.2,Schulze-Bahr Eric211,Probst Vincent21069,Horie Minoru871,Wilde Arthur A.12,Tanck Michael W.T.91,Bezzina Connie R.12ORCID

Affiliation:

1. Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.).

2. Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.).

3. Cardiovascular Genetics Center, Montreal Heart Institute and Faculty of Medicine, Université de Montréal, Canada (R.T.).

4. Center for Cardiac Arrhythmias of Genetic Origin (L.C., F.D., P.J.S.), Istituto Auxologico Italiano, IRCCS, Milan, Italy.

5. Laboratory of Cardiovascular Genetics (L.C., M.P., P.J.S.), Istituto Auxologico Italiano, IRCCS, Milan, Italy.

6. Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital (L.C.), Istituto Auxologico Italiano, IRCCS, Milan, Italy.

7. Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy (L.C.).

8. Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan (K.H., S.O., H.I., M.H.).

9. Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Japan (K.H.).

10. L’Institut du Thorax, INSERM, CNRS, UNIV Nantes, France (J.B., J.-J.S., J.-B.G., V.P.).

11. Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Muenster, Germany (M.E., B.S., S.Z., E.S.-B.).

12. Departments of Cardiovascular Medicine (Division of Heart Rhythm Services and the Windland Smith Rice Genetic Heart Rhythm Clinic), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (K.L.T., D.J.T., J.M.B., M.J.A.).

13. Molecular Cardiology, ICS Maugeri, IRCCS and Department of Molecular Medicine, University of Pavia, Italy (A.M., C.N., S.G.P.).

14. Department of Internal Medicine I, University Hospital of the Ludwig Maximilians University, Munich, Germany (B.M.B., M.M.-N., S.K.).

15. Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan (K.S., W.S., T.A.).

16. Department of Clinical Sciences, Unit of Paediatrics, Umeå University, Sweden (U.-B.D., A.R.).

17. Molecular and Clinical Sciences Research Institute, St George’s University of London and Cardiology Clinical Academic Group, St George’s University Hospitals NHS Foundation Trust, United Kingdom (Y.D.W., A.A., E.R.B.).

18. National Hospital Organization Kagoshima Medical Center, Japan (Y.K., M.Y.).

19. Department of Cardiovascular Diseases, University Hospitals Leuven, Belgium (T.R.).

20. Department of Cardiovascular Sciences, KU Leuven, Belgium (T.R.).

21. Omics Research Center, National Cerebral and Cardiovascular Center, Osaka, Japan (T.I.).

22. Cardiovascular Institute, Hospital Clinic de Barcelona, Universitat de Barcelona, Institut d’Investigació August Pi i Sunyer (IDIBAPS), and Centro de Investigacion Biomedica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain (E.A.).

23. Department of Congenital Disorders, Statens Serum Institute, Copenhagen, Denmark (M.C.).

24. The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark (M.C.).

25. Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Denmark (M.C.).

26. Department of Physiology, The University of Auckland, New Zealand (A.W.).

27. The Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Denmark (R.J., P.E.W., J.T.-H.).

28. Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston (S.A.L., P.T.E.).

29. Cardiovascular Disease Initiative and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (S.A.L., P.T.E.).

30. Department of Cardiology and Angiology I, Heart Center University of Freiburg, Medical Faculty, Germany (J.S., K.E.O.).

31. Department of Medicine, University Medical Center Mannheim, and German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Germany (B.R., M.B.).

32. Department of Clinical Genetics, Antwerp University Hospital, Belgium (B.L.).

33. Department of Medicine (M.B.S., P.E.W., D.M.R.), Vanderbilt University Medical Center, Nashville, TN.

34. Masonic Medical Research Institute, Utica, NY (R.P.).

35. Heart Rhythm Services, Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, Canada (B.D., A.D.K.).

36. L’Institut du Thorax, CHU Nantes, Service de Cardiologie, France (A.A., J.-J.S., J.-B.G.).

37. Arrhythmia, Inherited Heart Disease and Sudden Death Unit, Hospital Sant Joan de Déu, European Reference Center at the ERN GUARD-Heart Reference Network for Rare Cardiac Diseases, Barcelona, Spain (G.S.-B.).

38. Medical Science Department, School of Medicine, University of Girona, Spain (G.S.-B.).

39. Cardiovascular Program, Research Institute of Sant Joan de Déu (IRSJD), Barcelona, Spain (G.S.-B., O.C.).

40. Center for Biomedical Diagnosis, Hospital Clinic de Barcelona, Universitat de Barcelona; Institut d’Investigació August Pi i Sunyer (IDIBAPS); Cardiovascular Genetics Center, University of Girona-IDIBGI; and Medical Science Department, School of Medicine, University of Girona, Spain (O.C., R.B.).

41. Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain (O.C.).

42. Center for Integrative Electrocardiology (CIEL), Department of Cardiology, Clinical Sciences, Lund University, Sweden (P.G.P.).

43. Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, The Netherlands (E.A.N., J.P.v.T.).

44. Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, The Netherlands (J.H.V., L.H.v.d.B.).

45. King’s College Hospital, Bessemer Road, London, United Kingdom (A.A.-C.).

46. Department of Basic and Clinical Neuroscience, King’s College London, Maurice Wohl Clinical Neuroscience Institute, United Kingdom (A.A.-C., C.E.S.).

47. UK Dementia Research Institute, King’s College London, United Kingdom (C.E.S.).

48. Sheffield Institute for Translational Neuroscience, University of Sheffield, United Kingdom (P.J.S.).

49. Faculty of Medicine, University of Southampton, University Hospital Southampton, United Kingdom (K.E.M.).

50. Department of Neurology, Ulm University, Germany (P.M.A.).

51. Department of Pharmacology and Clinical Neuroscience, Umeå University, Sweden (P.M.A.).

52. Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany (M.M.-N.).

53. Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Germany (M.M.-N.).

54. Department of Health Sciences, University of Milan, Italy (D.C., C.B.).

55. Bio4Dreams - Business Nursery for Life Sciences, Milan, Italy (D.C., C.B.).

56. Equipe de Recherche en Epidémiologie Nutritionnelle, Centre d’Epidémiologie et Statistiques Paris Cité, Université Paris 13, Inserm (U1153), Inra (U1125), COMUE Sorbonne-Paris-Cité, Bobigny, France (P.G.).

57. McGill University and Génome Québec Innovation Centre, Montréal, Canada (M.L., M.M.).

58. The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark (T.W.).

59. Institute of Biological Psychiatry, Mental Health Centre Sct Hans, Copenhagen University Hospital, Roskilde, Denmark (T.W.).

60. Department of Clinical Medicine, University of Copenhagen, Denmark (T.W.).

61. Psychiatric Genetics Unit, Institute Vall d’Hebron Research (VHIR), Universitat Autònoma de Barcelona, Spain (M.R.).

62. Singapore Eye Research Institute (T.A.).

63. Genome Institute of Singapore (C.C.K.).

64. Ozaki Eye Hospital, Miyazaki, Japan (M.O.).

65. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (P.L., T.M.).

66. Department of Clinical Genetics, University Medical Centre Groningen, The Netherlands (J.P.v.T., Y.H.).

67. Department of Clinical Genetics, University Medical Centre Utrecht, University of Utrecht, The Netherlands (J.P.v.T.).

68. AP-HP, Hôpital Bichat, Département de Cardiologie et Centre de Référence des Maladies Cardiaques Héréditaires, F-75018 Paris, France, Université de Paris INSERM U1166, F-75013 France (I.D., A.L.).

69. Department of Cardiovascular Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan (W.S., V.P.).

70. Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan (T.M.).

71. Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan (S.O., H.I., M.H.).

72. Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Suita, Japan (S.O.).

73. Lankenau Institute for Medical Research and Lankenau Heart Institute, Wynnewood, PA (C.A.).

74. Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA (C.A.).

75. Department of Biomedical Informatics (D.M.R.), Vanderbilt University Medical Center, Nashville, TN.

76. Department of Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, TN.

77. Department of Cardiology, Antwerp University Hospital, Belgium (J.S.).

78. Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Denmark (J.T.-H.).

79. Cardiac Inherited Disease Group, Starship Children’s Hospital, Auckland, New Zealand (J.R.S.).

80. Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (M.P.v.d.B.).

81. Laboratory for Molecular Cardiology, Department of Cardiology, The Heart Centre, Rigshospitalet (Copenhagen University Hospital), Denmark (M.S.O.).

82. Department of Biomedical Sciences, University of Copenhagen, Denmark (M.S.O.).

83. Arrhythmia Unit, Hospital Sant Joan de Déu, Institut d’Investigació August Pi i Sunyer (IDIBAPS), Cardiovascular Institute, and Hospital Clinic de Barcelona, Universitat de Barcelona, Spain (J.B.).

84. Cardiovascular Genetics Center, University of Girona-IDIBGI, and Medical Science Department, School of Medicine, University of Girona, Spain (R.B.).

85. Cardiology Service, Hospital Josep Trueta, Girona, Spain (R.B.).

86. National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan (N.M.).

87. Centre for Human Genetics, University Hospitals Leuven, Belgium (J.B.).

88. INSERM, Sorbonne University, UMRS 1166, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France (P.G.).

89. Netherlands Heart Institute, Utrecht (H.L.T.).

90. Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston (C.N.-C.).

91. Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, University of Amsterdam, The Netherlands (M.W.T.T.).

Abstract

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance ( P <5×10 −8 ) near NOS1AP , KCNQ1 , and KLF12 , and 1 missense variant in KCNE1 (p.Asp85Asn) at the suggestive threshold ( P <10 −6 ). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r g =0.40; P =3.2×10 −3 ). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls ( P <10−13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive ( P <0.005). Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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