Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease (original) (raw)

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Data deposits

Data have been deposited in the NCBI database of Genotypes and Phenotypes under accession numbers phs000130.v1.p1 and phs000345.v1.p1. Summary statistics for imputed GWAS are available at http://www.broadinstitute.org/mpg/ricopili/. Summary statistics for the meta-analysis markers are available at http://www.ibdgenetics.org/. The 523 causal gene network Cytoscape file is available on request.

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Acknowledgements

We thank all the subjects who contributed samples and the physicians and nursing staff who helped with recruitment globally. UK case collections were supported by the National Association for Colitis and Crohn’s disease; Wellcome Trust grant 098051 (L.J., C.A.A., J.C.B.); Medical Research Council UK; the Catherine McEwan Foundation; an NHS Research Scotland career fellowship (R.K.R.); Peninsula College of Medicine and Dentistry, Exeter; the National Institute for Health Research, through the Comprehensive Local Research Network, and through Biomedical Research Centre awards to Guy’s & Saint Thomas’ National Health Service Trust, King’s College London, Addenbrooke’s Hospital, University of Cambridge School of Clinical Medicine and to the University of Manchester and Central Manchester Foundation Trust. The British 1958 Birth Cohort DNA collection was funded by Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02, and the UK National Blood Service controls by the Wellcome Trust. The Wellcome Trust Case Control Consortium projects were supported by Wellcome Trust grants 083948/Z/07/Z, 085475/B/08/Z and 085475/Z/08/Z. North American collections and data processing were supported by funds to the National Institute of Diabetes, Digestive and Kidney diseases (NIDDK) IBD Genetics Consortium, which is funded by the following grants: DK062431 (S.R.B.), DK062422 (J.H.C.), DK062420 (R.H.D.), DK062432 (J.D.R.), DK062423 (M.S.S.), DK062413 (D.P.M.), DK076984 (M.J.D.), DK084554 (M.J.D. and D.P.M.) and DK062429 (J.H.C.). Additional funds were provided by funding to J.H.C. (DK062429-S1 and Crohn’s & Colitis Foundation of America, Senior Investigator Award (5-2229)) and R.H.D. (CA141743). K.Y.H. is supported by the National Institutes of Health (NIH) MSTP TG T32GM07205 training award. Cedars-Sinai is supported by USPHS grant PO1DK046763 and the Cedars-Sinai F. Widjaja Inflammatory Bowel and Immunobiology Research Institute Research Funds, National Center for Research Resources (NCRR) grant M01-RR00425, UCLA/Cedars-Sinai/Harbor/Drew Clinical and Translational Science Institute (CTSI) Grant (UL1 TR000124-01), the Southern California Diabetes and Endocrinology Research Grant (DERC) (DK063491), The Helmsley Foundation (D.P.M.) and the Crohn's and Colitis Foundation of America (D.P.M.). R.J.X. and A.N.A. are funded by DK83756, AI062773, DK043351 and the Helmsley Foundation. The Netherlands Organization for Scientific Research supported R.K.W. with a clinical fellowship grant (90.700.281) and C.W. (VICI grant 918.66.620). C.W. is also supported by the Celiac Disease Consortium (BSIK03009). This study was also supported by the German Ministry of Education and Research through the National Genome Research Network, the Popgen biobank, through the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence ‘Inflammation at Interfaces’ and DFG grant no. FR 2821/2-1. S.B. was supported by DFG BR 1912/6-1 and the Else Kröner-Fresenius-Stiftung (Else Kröner-Exzellenzstipendium 2010_EKES.32). Italian case collections were supported by the Italian Group for IBD and the Italian Society for Paediatric Gastroenterology, Hepatology and Nutrition and funded by the Italian Ministry of Health GR-2008-1144485. Activities in Sweden were supported by the Swedish Society of Medicine, Ihre Foundation, Örebro University Hospital Research Foundation, Karolinska Institutet, the Swedish National Program for IBD Genetics, the Swedish Organization for IBD, and the Swedish Medical Research Council. D.F. and S.V. are senior clinical investigators for the Funds for Scientific Research (FWO/FNRS) Belgium. We acknowledge a grant from Viborg Regional Hospital, Denmark. V. Andersen was supported by SHS Aabenraa, Denmark. We acknowledge funding provided by the Royal Brisbane and Women’s Hospital Foundation, National Health and Medical Research Council, Australia and by the European Community (5th PCRDT). We acknowledge the following groups that provided biological samples or data for this study: the Inflammatory Bowel in South Eastern Norway (IBSEN) study group, the Norwegian Bone Marrow Donor Registry (NMBDR), the Avon Longitudinal Study of Parents and Children, the Human Biological Data Interchange and Diabetes UK, and Banco Nacional de ADN, Salamanca. This research also uses resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the NIDDK, National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation (JDRF) and supported by U01 DK062418. The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ.

Author information

Author notes

1. Luke Jostins, Stephan Ripke, Jeffrey C. Barrett and Judy H Cho: These authors contributed equally to this work.

Authors and Affiliations

1. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.,
   Luke Jostins, Carl A. Anderson & Jeffrey C. Barrett
2. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, Massachusetts, USA
   Stephan Ripke & Mark J. Daly
3. Broad Institute of MIT and Harvard, Cambridge, 02142, Massachusetts, USA
   Stephan Ripke & Mark J. Daly
4. Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen 9700 RB, The Netherlands.,
   Rinse K. Weersma & Dirk De Jong
5. Division of Gastroenterology, Department of Medicine, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, 15261, Pennsylvania, USA
   Richard H. Duerr, Leonard Baidoo, Karin Fransen & Miguel Regueiro
6. Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, 15261, Pennsylvania, USA
   Richard H. Duerr
7. F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, 90048, California, USA
   Dermot P. McGovern, Stephan R. Targan & Kent D. Taylor
8. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, California, USA
   Dermot P. McGovern, Talin Haritunians, Jerome I. Rotter & Kent D. Taylor
9. Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06520, USA.,
   Ken Y. Hui & Judy H Cho
10. Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, UK.,
    James C. Lee & Miles Parkes
11. Department of Health Studies, University of Chicago, Chicago, 60637, Illinois, USA
    L. Philip Schumm
12. Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut 06520, USA.,
    Yashoda Sharma, Kaida Ning, Clara Abraham, Matija Hedl & Judy H Cho
13. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, Massachusetts, USA
    Jonah Essers
14. University of Maribor, Faculty of Medicine, Center for Human Molecular Genetics and Pharmacogenomics, Maribor 2000, Slovenia.,
    Mitja Mitrovic & Uros Potocnik
15. Department of Genetics, University Medical Center Groningen, Groningen 9700 RB, The Netherlands.,
    Mitja Mitrovic
16. Department of Clinical and Experimental Medicine, Gastroenterology section, KU Leuven, Leuven 3000, Belgium.,
    Isabelle Cleynen & Severine Vermeire
17. Unit of Animal Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) and Faculty of Veterinary Medicine, University of Liège, Liège 4000, Belgium.,
    Emilie Theatre & Michel Georges
18. Division of Gastroenterology, Centre Hospitalier Universitaire, Université de Liège, Liège 4000, Belgium.,
    Emilie Theatre & Edouard Louis
19. Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King’s College London School of Medicine, Guy’s Hospital, London SE1 9RT, UK.,
    Sarah L. Spain, Natalie J. Prescott & Christopher G. Mathew
20. Division of Rheumatology Immunology and Allergy, Brigham and Women’s Hospital, Boston, 02115, Massachusetts, USA
    Soumya Raychaudhuri & Xinli Hu
21. Program in Medical and Population Genetics, Broad Institute, Cambridge, 02142, Massachusetts, USA
    Soumya Raychaudhuri
22. Division of Genetics, Brigham and Women’s Hospital, Boston, 02115, Massachusetts, USA
    Soumya Raychaudhuri
23. Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec H1T 1C8, Canada.,
    Philippe Goyette, Gabrielle Boucher & John D. Rioux
24. Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey 07102, USA.,
    Zhi Wei
25. Department of Gastroenterology & Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.,
    Jean-Paul Achkar
26. Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, 44195, Ohio, USA
    Jean-Paul Achkar
27. Peninsula College of Medicine and Dentistry, Exeter EX1 2LU, UK.,
    Tariq Ahmad
28. Department of Gastroenterology, Erasmus Hospital, Free University of Brussels, Brussels, 1070 Belgium.,
    Leila Amininejad & Denis Franchimont
29. Massachusetts General Hospital, Harvard Medical School, Gastroenterology Unit, Boston, 02114, Massachusetts, USA
    Ashwin N. Ananthakrishnan, Kathy L. Devaney & Ramnik J. Xavier
30. Medical Department, Viborg Regional Hospital, Viborg 8800, Denmark.,
    Vibeke Andersen
31. Department of Gastroenterology and Hepatology, Inflammatory Bowel Disease Service, Royal Adelaide Hospital, and School of Medicine, University of Adelaide, Adelaide 5000, Australia.,
    Jane M. Andrews
32. Institute of Clinical Chemistry, Christian-Albrechts-University, Kiel 24105, Germany.,
    Tobias Balschun, David Ellinghaus, Stefan Schreiber & Andre Franke
33. Department of Gastroenterology and Hepatology, Flinders Medical Centre and School of Medicine, Flinders University, Adelaide 5000, Australia.,
    Peter A. Bampton
34. Division of Gastroenterology, McGill University Health Centre, Royal Victoria Hospital, Montréal, Québec H3A 1A1, Canada.,
    Alain Bitton & Jürgen Glas
35. Department of Medicine II, University Hospital Munich-Grosshadern, Ludwig-Maximilians-University, Munich 80336, Germany.,
    Stephan Brand
36. Department of Gastroenterology, Charité, Campus Mitte, Universitätsmedizin Berlin, Berlin 10117, Germany.,
    Carsten Büning
37. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York City, 10029, New York, USA
    Ariella Cohain, Bin Zhang & Eric E. Schadt
38. Department of Genomics, Life & Brain Center, University Hospital Bonn, Bonn 53012, Germany.,
    Sven Cichon
39. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm 14 183, Sweden.,
    Mauro D’Amato
40. Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, 90048, California, USA
    Marla Dubinsky
41. Department of Gastroenterology, Torbay Hospital, Torbay, Devon TQ2 7AA, UK.,
    Cathryn Edwards
42. School of Medical Sciences, Faculty of Medical & Health Sciences, The University of Auckland, Auckland 1142, New Zealand.,
    Lynnette R. Ferguson & Angharad R. Morgan
43. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen T9700 RB, The Netherlands.,
    Karin Fransen & Cisca Wijmenga
44. Department of Medicine, University of Otago, Christchurch 8140, New Zealand.,
    Richard Gearry
45. Department of Gastroenterology, Christchurch Hospital, Christchurch 8011, New Zealand.,
    Richard Gearry
46. Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg 85764, Germany.,
    Christian Gieger
47. St Mark’s Hospital, Watford Road, Harrow, Middlesex HA1 3UJ, UK.,
    Ailsa Hart
48. Nottingham Digestive Diseases Centre, Queens Medical Centre, Nottingham NG7 1AW, UK.,
    Chris Hawkey
49. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo 0424, Norway.,
    Tom H. Karlsen
50. Department of Gastroenterology, Kaunas University of Medicine, Kaunas 44307, Lithuania.,
    Limas Kupcinskas & Jurgita Sventoraityte
51. Department of Pediatrics, Emory University School of Medicine, Atlanta, 30322, Georgia, USA
    Subra Kugathasan
52. Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, San Giovanni Rotondo 71013, Italy.,
    Anna Latiano, Orazio Palmieri & Vito Annese
53. Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent 9000, Belgium.,
    Debby Laukens & Martine De Vos
54. School of Medicine and Pharmacology, The University of Western Australia, Fremantle, Western Australia 6009, Australia.,
    Ian C. Lawrance
55. Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.,
    Charlie W. Lees & Jack Satsangi
56. Department of Gastroenterology, The Townsville Hospital, Townsville, 4810, Queensland, Australia
    Gillian Mahy
57. Institute of Human Genetics, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.,
    John Mansfield
58. Department of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.,
    Craig Mowat
59. Genetic Medicine, MAHSC, University of Manchester, Manchester M13 9PL, UK.,
    William Newman
60. Department of Gastroenterology, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.,
    Cyriel Y. Ponsioen
61. University of Maribor, Faculty for Chemistry and Chemical Engineering, Maribor 2000, Slovenia.,
    Uros Potocnik
62. Royal Hospital for Sick Children, Paediatric Gastroenterology and Nutrition, Glasgow G3 8SJ, UK.,
    Richard K. Russell & David C. Wilson
63. Department of Gastroenterology, Guy’s & St Thomas’ NHS Foundation Trust, St Thomas’ Hospital, London SE1 7EH, UK.,
    Jeremy D. Sanderson
64. Department of Gastroenterology, Hospital Clinic/Institut d’Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
    Miquel Sans
65. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-EHD), Barcelona 08036, Spain.,
    Miquel Sans
66. Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Kiel 24118, Germany.,
    Stefan Schreiber & Sebastian Zeissig
67. Inflammatory Bowel Diseases, Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane 4029, Australia.,
    Lisa A. Simms & Graham Radford-Smith
68. Norfolk and Norwich University Hospital, Norwich NR4 7UY, UK.,
    Mark Tremelling
69. Department of Gastroenterology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands.,
    Hein W. Verspaget
70. Child Life and Health, University of Edinburgh, Edinburgh, Scotland EH9 1UW, UK.,
    David C. Wilson
71. Institute of Human Genetics and Department of Neurology, Technische Universität München, Munich 80336, Germany.,
    Juliane Winkelmann
72. Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA
    Ramnik J. Xavier
73. Department of Biostatistics, School of Public Health, Yale University, New Haven, Connecticut 06520, USA.,
    Clarence K. Zhang & Hongyu Zhao
74. Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Ontario M5G 1X5, Canada.,
    Mark S. Silverberg
75. Azienda Ospedaliero Universitaria (AOU) Careggi, Unit of Gastroenterology SOD2, Florence 50134, Italy.,
    Vito Annese
76. Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, 19104, Pennsylvania, USA
    Hakon Hakonarson
77. Department of Pediatrics, Center for Pediatric Inflammatory Bowel Disease, The Children’s Hospital of Philadelphia, Philadelphia, 19104, Pennsylvania, USA
    Hakon Hakonarson
78. Department of Medicine, and Department of Epidemiology, Meyerhoff Inflammatory Bowel Disease Center, School of Medicine, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, 21205, Maryland, USA
    Steven R. Brant
79. Department of Gastroenterology, Royal Brisbane and Women’s Hospital, and School of Medicine, University of Queensland, Brisbane 4029, Australia
    Graham Radford-Smith
80. Department of Gastroenterology, University Hospital Leuven, Leuven 3000, Belgium,
    Severine Vermeire

Authors

1. Luke Jostins
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2. Stephan Ripke
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3. Rinse K. Weersma
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4. Richard H. Duerr
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5. Dermot P. McGovern
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6. Ken Y. Hui
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7. James C. Lee
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8. L. Philip Schumm
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9. Yashoda Sharma
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10. Carl A. Anderson
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11. Jonah Essers
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12. Mitja Mitrovic
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13. Kaida Ning
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14. Isabelle Cleynen
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15. Emilie Theatre
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16. Sarah L. Spain
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17. Soumya Raychaudhuri
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18. Philippe Goyette
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19. Zhi Wei
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20. Clara Abraham
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21. Jean-Paul Achkar
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22. Tariq Ahmad
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23. Leila Amininejad
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24. Ashwin N. Ananthakrishnan
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25. Vibeke Andersen
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26. Jane M. Andrews
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27. Leonard Baidoo
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28. Tobias Balschun
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29. Peter A. Bampton
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30. Alain Bitton
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31. Gabrielle Boucher
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32. Stephan Brand
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33. Carsten Büning
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34. Ariella Cohain
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35. Sven Cichon
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36. Mauro D’Amato
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37. Dirk De Jong
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38. Kathy L. Devaney
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39. Marla Dubinsky
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40. Cathryn Edwards
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41. David Ellinghaus
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42. Lynnette R. Ferguson
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43. Denis Franchimont
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44. Karin Fransen
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45. Richard Gearry
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46. Michel Georges
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47. Christian Gieger
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48. Jürgen Glas
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49. Talin Haritunians
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50. Ailsa Hart
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51. Chris Hawkey
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52. Matija Hedl
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53. Xinli Hu
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54. Tom H. Karlsen
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55. Limas Kupcinskas
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56. Subra Kugathasan
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57. Anna Latiano
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58. Debby Laukens
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59. Ian C. Lawrance
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60. Charlie W. Lees
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61. Edouard Louis
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62. Gillian Mahy
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63. John Mansfield
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64. Angharad R. Morgan
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65. Craig Mowat
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66. William Newman
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67. Orazio Palmieri
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68. Cyriel Y. Ponsioen
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69. Uros Potocnik
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70. Natalie J. Prescott
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71. Miguel Regueiro
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72. Jerome I. Rotter
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73. Richard K. Russell
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74. Jeremy D. Sanderson
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75. Miquel Sans
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Consortia

The International IBD Genetics Consortium (IIBDGC)

Contributions

R.K.W., R.H.D., D.P.M., C.G.M., J.D.R., E.E.S., M.J.D., A.F., M.P. and S.V. contributed equally to the manuscript. J.H.C., J.C.B., R.K.W., R.H.D., D.P.M., A.F., M.P., C.G.M., J.D.R., S.V., M.D.A. and V. Annese conceived, designed and managed the study and managed the funding. J.H.C., J.C.B., L.J., S. Ripke, R.K.W., R.H.D., D.P.M., M.J.D., M.P. and C.G.M. were involved in manuscript preparation. J.H.C., J.C.B., L.J., S. Ripke, R.K.W., K.Y.H., C.A.A., J.E., K.N., S.L.S., S. Raychaudhuri, Z.W., C.A., A.C., G.B., M.H., X.H., B.Z., C.K.Z., H.Z., J.D.R., E.E.S. and M.J.D. performed or supervised statistical and computational analyses. R.K.W., R.H.D., D.P.M., J.C.L., L.P.S., Y.S., P.G., J.-P.A., T.A., L.A., A.N.A., V. Andersen, J.M.A., L.B., P.A.B., A.B., S.B., C.B., S.C., M.D.A., D.D.J., K.L.D., M.D., C.E., L.R.F., D.F., M.G., C.G., R.G., J.G., A.H., C.H., T.H.K., L.K., S.K., A.L., D.L., E.L., I.C.L., C.W.L., A.R.M., C.M., G.M., J.M., W.N., O.P., C.Y.P., U.P., N.J.P., M.R., J.I.R., R.K.R., J.D.S., M.S., J. Satsangi, S.S., L.A.S., J. Sventoraityte, S.R.T., M.T., H.W.V., M.D.V., C.W., D.C.W., J.W., R.J.X., S.Z., M.S.S., V. Annese, H.H., IIBDGC, S.R.B., J.D.R., G.R.S., C.G.M., A.F., M.P., S.V. and J.H.C. were involved in study subject recruitment and assembling phenotypic data. R.K.W., R.H.D., D.P.M., L.P.S., Y.S., M.M., I.C., E.T., T.B., D.E., K.F., T.H., K.D.T., C.G.M., A.F., M.P. and J.H.C. established DNA collections, genotyping and data management. All authors read and approved the final manuscript before submission.

Corresponding author

Correspondence toJudy H Cho.

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Competing interests

The authors declare no competing financial interests.

Additional information

Lists of participants and their affiliations appear in the Supplementary Information.

Supplementary information

Supplementary Information

This file contains Supplementary Text, Supplementary Figures 1-12, full legends for Supplementary Tables 1-6, Supplementary References and a list of IBD Genetics Consortium members – see Supplementary Contents for details. (PDF 6835 kb)

Supplementary Tables

This zipped files contains Supplementary Tables 1-6 as follows: 1 shows the GWAS and Immunochip samples used in the study; 2 contains complete details of 163 IBD loci; 3 contains details of disease overlaps with IMD, PID and MSMD described in section 2 of the methods; 4 contains detailed enrichment statistics for all GO terms and canonical pathways; 5 contains the signals of selection at IBD loci; 6 shows enrichment scores for genes in IBD loci within co-expression modules. Supplementary Table 2, which is contained in this zipped file, has been replaced, as there was an error in the original file. In the ‘Detailed assoc stats’ tab, the ‘IC risk’ and ‘IC_nonrisk’ column labels were inadvertently switched. In addition, clarification of the cohort used to determine the odds ratio (OR) shown in the ‘Detailed assoc stats’ and ‘Main Table’ tabs has been included. This file was replaced online on 31 January 2013. (ZIP 356 kb)

Supplementary Data

This zipped file is a Cytoscape file for the macrophage enriched, omental adipose Bayesian network. (ZIP 722 kb)

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Jostins, L., Ripke, S., Weersma, R. et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature 491, 119–124 (2012). https://doi.org/10.1038/nature11582

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• Received: 17 May 2012
• Accepted: 12 September 2012
• Published: 31 October 2012
• Issue Date: 01 November 2012
• DOI: https://doi.org/10.1038/nature11582