Parental origin of sequence variants associated with complex diseases - Nature

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Acknowledgements This project was funded in part by FP7-MC-IAPP Grant agreement no. 218071 (CancerGene) to deCODE genetics.

Author Contributions A.K. and K.S. planned and directed the research. A.K. wrote the first draft of the paper and, together with K.S., V.S., G.M., G.T. and U.T., wrote most of the final version. A.K. and G.M. designed the method to determine parental origin. G.M., with assistance from P.I.O., implemented the algorithm. D.F.G. wrote the code for association analysis taking parental origin into account and performed some initial analyses. P.S., S.B. and S.S. tabulated the established disease-associated variants and the regions known to harbour imprinted genes. V.S. and G.T. contributed to the analysis of the diabetes data and, together with A.K. and U.T., planned the follow-up association and functional studies. A.G., A.K. and M.L.F. imputed the untyped SNPs. S.N.S. and P.S. were responsible for the breast cancer and basal-cell carcinoma data. A.B.H., G.S. and R.B. provided clinical data for T2D, O.Th.J., T.J. and H.S. provided clinical data for breast cancer, and J.H.O., B.S. and K.R.B. provided clinical data for basal-cell carcinoma. The DIAGRAM Consortium provided the novel T2D-associated variants that are close to imprinted genes. Aslaug J., A.S., Adalbjorg J., K.Th.K. and S.A.G. performed the methylation and expression studies. A.C.F.-S. assisted in the interpretation of the results from the association and functional studies.

Author notes

1. Valgerdur Steinthorsdottir, Gisli Masson and Gudmar Thorleifsson: These authors contributed equally to this work.

Authors and Affiliations

1. deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland ,

   Augustine Kong, Valgerdur Steinthorsdottir, Gisli Masson, Gudmar Thorleifsson, Patrick Sulem, Soren Besenbacher, Aslaug Jonasdottir, Asgeir Sigurdsson, Kari Th. Kristinsson, Adalbjorg Jonasdottir, Michael L. Frigge, Arnaldur Gylfason, Pall I. Olason, Sigurjon A. Gudjonsson, Sverrir Sverrisson, Simon N. Stacey, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir & Kari Stefansson

2. Department of Dermatology,,

   Bardur Sigurgeirsson & Jon H. Olafsson

3. Department of Pathology,,

   Kristrun R. Benediktsdottir

4. Department of Oncology,,

   Helgi Sigurdsson & Oskar Th. Johannsson

5. Department of Surgery,,

   Thorvaldur Jonsson

6. Department of Endocrinology and Metabolism, Landspitali-University Hospital, 101 Reykjavik, Iceland,

   Rafn Benediktsson, Astradur B. Hreidarsson & Gunnar Sigurdsson

7. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK

   Anne C. Ferguson-Smith

8. Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland

   Unnur Thorsteinsdottir & Kari Stefansson

9. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.,

   Benjamin F. Voight, Soumya Raychaudhuri, Shaun Purcell, Steve A. McCarroll, Ayellet V. Segrè, Kristin Ardlie, Noël P. Burtt, Gabe Crawford, Amanda L. Elliott, Todd Green, Candace Guiducci, Richa Saxena, Mark J. Daly, Jose C. Florez & David Altshuler

10. Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.,

    Benjamin F. Voight, Soumya Raychaudhuri, Shaun Purcell, Todd Green, Richa Saxena, Mark J. Daly, Jose C. Florez & David Altshuler

11. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.,

    Benjamin F. Voight, Jose C. Florez, James B. Meigs & David Altshuler

12. Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109-2029, USA.,

    Laura J. Scott, Ryan P. Welch, Cristen J. Willer, Martha Ganser, Anne U. Jackson, Heather M. Stringham, Goncalo R. Abecasis & Michael Boehnke

13. deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.,

    Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Augustine Kong, G. Bragi Walters, Unnur Thorsteinsdottir & Kari Stefansson

14. CNRS-UMR-8090, Institute of Biology and Lille 2 University, Pasteur Institute, F-59019 Lille, France.,

    Christian Dina, Christine Proença, Stephane Cauchi & Philippe Froguel

15. INSERM, UMR915, CNRS, ERL3147, 44007 Nantes, France.,

    Christian Dina

16. Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK.,

    Eleftheria Zeggini, Suzannah Bumpstead, Felicity Payne, Nicholas Smith & Inês Barroso

17. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.,

    Eleftheria Zeggini, Teresa Ferreira, Katherine S. Elliott, Cecilia M. Lindgren, Inga Prokopenko, N. William Rayner, Neil R. Robertson, Andrew P. Morris & Mark I. McCarthy.

18. Institute of Epidemiology, Helmholtz Zentrum Muenchen, 85764 Neuherberg, Germany.,

    Cornelia Huth, Harald Grallert, Christian Gieger, Norman Klopp, Thomas Meitinger, Ann-Kristin Petersen, Barbara Thorand, H.-Erich Wichmann & Thomas Illig

19. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, 81377 Munich, Germany.,

    Cornelia Huth, Harald Grallert & H.-Erich Wichmann

20. Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.,

    Yurii S. Aulchenko, Najaf Amin, Jacqueline Witteman, Albert Hofman & Cornelia M. van Duijn

21. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK.,

    Laura J. McCulloch, Amanda J. Bennett, Christopher J. Groves, Neelam Hassanali, Katharine R. Owen, Inga Prokopenko, N. William Rayner, Neil R. Robertson, Anna L. Gloyn & Mark I. McCarthy.

22. Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario M5G 0A3, Canada.,

    Guanming Wu & Lincoln D. Stein

23. Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.,

    Soumya Raychaudhuri

24. Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.,

    Shaun Purcell

25. Department of Molecular Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.,

    Steve A. McCarroll, Ayellet V. Segrè, Amanda L. Elliott & David Altshuler

26. MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK.,

    Claudia Langenberg, Simon Griffin & Nicholas J. Wareham

27. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA.,

    Oliver M. Hoffmann & Winston A. Hide

28. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.,

    Josée Dupuis

29. Departments of Nutrition and Epidemiology, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA.,

    Lu Qi, Peter Kraft, Qi Sun, David Hunter & Frank B. Hu

30. Department of Medicine, Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, Massachusetts 02115, USA.,

    Lu Qi, Marilyn Cornelis, Rob van Dam & Frank B. Hu

31. Department of Internal Medicine, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands.,

    Mandy van Hoek, Thijs van Herpt, Eric Sijbrands & Andre Uitterlinden

32. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh EH4 2XU, UK.,

    Pau Navarro

33. INSERM U780, F-94807 Villejuif, France.,

    Beverley Balkau

34. University Paris-Sud, F-91405 Orsay, France.,

    Beverley Balkau

35. Landspitali University Hospital, 101 Reykjavik, Iceland.,

    Rafn Benediktsson & Gunnar Sigurdsson

36. Icelandic Heart Association, 201 Kopavogur, Iceland.,

    Rafn Benediktsson & Gunnar Sigurdsson

37. Division of Endocrinology, Diabetes and Metabolism, Ulm University, 89081 Ulm, Germany.,

    Roza Blagieva & Bernhard O. Boehm

38. The Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas 77030, USA.,

    Eric Boerwinkle

39. National Human Genome Research Institute, National Institute of Health, Bethesda, Maryland 20892, USA.,

    Lori L. Bonnycastle, Peter S. Chines, Michael R. Erdos, Mario A Morken, Narisu Narisu & Amy J. Swift

40. R&D Centre, Skaraborg Institute, 541 30 Skövde, Sweden.,

    Kristina Bengtsson Boström

41. Department of Internal Medicine, Catharina Hospital, PO Box 1350, 5602 ZA Eindhoven, The Netherlands.,

    Bert Bravenboer

42. Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, F-91100 Corbeil-Essonnes, France.,

    Guillaume Charpentier

43. Department of Biostatistics and Collaborative Studies Coordinating Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.,

    David J. Couper

44. Diabetes Research Centre,,

    Alex S. F. Doney, Andrew D. Morris & Colin N. A. Palmer

45. Pharmacogenomics Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK.,

    Alex S. F. Doney, Andrew D. Morris & Colin N. A. Palmer

46. National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts 01702, USA.,

    Caroline S. Fox

47. Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.,

    Caroline S. Fox

48. Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK.,

    Christopher S. Franklin, Igor Rudan, Harry Campbell & James F. Wilson

49. Hagedorn Research Institute, DK-2820 Gentofte, Denmark.,

    Niels Grarup, Thomas Sparsø, Torben Hansen & Oluf Pedersen

50. CHU de Poitiers, Endocrinologie Diabetologie, CIC INSERM 0801, INSERM U927, Université de Poitiers, UFR, Médecine Pharmacie, 86021 Poitiers Cedex, France.,

    Samy Hadjadj

51. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.,

    Christian Herder & Michael Roden

52. Folkhälsan Research Center, FIN-00014 Helsinki, Finland.,

    Bo Isomaa & Tiinamaija Tuomi

53. Malmska Municipal Health Center and Hospital, 68601 Jakobstad, Finland.,

    Bo Isomaa

54. DRWF Human Islet Isolation Facility and Oxford Islet Transplant Programme, University of Oxford, Old Road, Headington, Oxford OX3 7LJ, UK.,

    Paul R. V. Johnson

55. Research Centre for Prevention and Health, Glostrup University Hospital, DK-2600 Glostrup, Denmark.,

    Torben Jørgensen

56. Department of Epidemiology, Department of Medicine, and Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland 21287, USA.,

    Wen H. L. Kao

57. Department of Medicine, University of Kuopio and Kuopio University Hospital, FIN-70211 Kuopio, Finland.,

    Johanna Kuusisto & Markku Laakso

58. Department of General Medical Practice, University of Aarhus, DK-8000 Aarhus, Denmark.,

    Torsten Lauritzen

59. Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland 21287, USA.,

    Man Li

60. Department of Internal Medicine, Maxima MC, PO-Box 90052, 5600 PD Eindhoven, The Netherlands.,

    Alouisius Lieverse & Thijs van Herpt

61. Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, University Hospital Malmö, Lund University, 205 02 Malmö, Sweden.,

    Valeriya Lyssenko, Peter Nilsson & Leif Groop

62. Department of Endocrinology, Diabetology, Nutrition, Bichat-Claude Bernard University Hospital, Assistance Publique des Hôpitaux de Paris, 75877 Paris Cedex 18, France.,

    Michel Marre

63. INSERM U695, Université Paris 7, 75870 Paris Cedex 18, France.,

    Michel Marre

64. Department of Community Medicine and General Practice, HUNT Research Center, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway.,

    Kristian Midthjell, Carl Platou & Kristian Hveem

65. Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Magdalen Road, Exeter EX1 2LU, UK.,

    John R. B. Perry, Beverley M. Shields, Michael N. Weedon, Timothy M. Frayling & Andrew T. Hattersley

66. Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Barrack Road, Exeter EX2 5DW, UK.,

    John R. B. Perry, Beverley M. Shields, Michael N. Weedon, Timothy M. Frayling & Andrew T. Hattersley

67. Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.,

    Wolfgang Rathmann & Klaus Strassburger

68. Department of Human Genetics, McGill University, Montreal H3H 1P3, Canada.,

    Ghislain Rocheleau & Rob Sladek

69. Department of Medicine, Faculty of Medicine, McGill University, Montreal H3A 1A4, Canada.,

    Ghislain Rocheleau & Rob Sladek

70. McGill University and Genome Quebec Innovation Centre, Montreal H3A 1A4, Canada.,

    Ghislain Rocheleau & Rob Sladek

71. Department of Medicine/Metabolic Diseases, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.,

    Michael Roden

72. Department of Endocrinology and Diabetes, Norfolk and Norwich University Hospital NHS Trust, Norwich NR1 7UY, UK.,

    Michael J. Sampson

73. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.,

    Richa Saxena & David Altshuler

74. General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA.,

    Peter Shrader & James B. Meigs

75. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.,

    Peter Shrader

76. Institut Interrégional pour la Santé, F-37521 La Riche, France.,

    Jean Tichet

77. Department of Medicine, Helsinki University Hospital, University of Helsinki, FIN-00290 Helsinki, Finland.,

    Tiinamaija Tuomi & Leif Groop

78. Department of Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles, California 90033, USA.,

    Richard N. Bergman

79. National Institutes of Health, Bethesda, Maryland 20892, USA.,

    Francis S. Collins

80. Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, S-751 85 Uppsala, Sweden.,

    Ulf Gyllensten

81. University of Southern Denmark, DK-5230 Odense, Denmark.,

    Torben Hansen

82. Centre for Diabetes and Metabolic Medicine, Barts and The London, Royal London Hospital, Whitechapel, London E1 1BB, UK.,

    Graham A. Hitman

83. Department of Medicine, The Hospital of Levanger, N-7600 Levanger, Norway.,

    Kristian Hveem

84. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA.,

    Karen L. Mohlke

85. Institute of Genetic Medicine, European Academy Bozen/Bolzano, Viale Druso 1, 39100 Bolzano, Italy.,

    Peter P. Pramstaller

86. Croatian Centre for Global Health, Faculty of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia.,

    Igor Rudan

87. Institute for Clinical Medical Research, University Hospital “Sestre Milosrdnice”, Vinogradska 29, 10000 Zagreb, Croatia.,

    Igor Rudan

88. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki FIN-00300, Finland.,

    Jaakko Tuomilehto

89. Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.,

    Mark Walker

90. Department of Preventive Medicine, Keck Medical School, University of Southern California, Los Angeles, California 90089-9001, USA.,

    Richard M. Watanabe

91. Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota 55454, USA.,

    James S. Pankow

92. Department of Biomedical Science, Panum, Faculty of Health Science, University of Copenhagen, 2200 Copenhagen, Denmark.,

    Oluf Pedersen

93. Faculty of Health Science, University of Aarhus, DK-8000 Aarhus, Denmark.,

    Oluf Pedersen

94. Faculty of Medicine, University of Iceland, 101 Reykjavík, Iceland.,

    Unnur Thorsteinsdottir & Kari Stefansson

95. Genomic Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.,

    Philippe Froguel

96. Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts 02144, USA.,

    David Altshuler

97. Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK.,

    Mark I. McCarthy.

Consortia

Corresponding authors

Correspondence to Augustine Kong, Augustine Kong, Kari Stefansson or Kari Stefansson.

Competing interests

The authors from Decode Genetics Inc. own stocks and stock options in the company.

Supplementary Information

This file contains Supplementary Notes, Supplementary Tables 1-9, Supplementary Figures 1-4 with Legends and Supplementary References. (PDF 355 kb)

Cite this article

Kong, A., Steinthorsdottir, V., Masson, G. et al. Parental origin of sequence variants associated with complex diseases. Nature 462, 868–874 (2009). https://doi.org/10.1038/nature08625

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• Received: 14 August 2009

• Accepted: 29 October 2009

• Issue Date: 17 December 2009

• DOI: https://doi.org/10.1038/nature08625