A mega-analysis of genome-wide association studies for major depressive disorder (original) (raw)

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Acknowledgements

We thank the thousands of people with MDD who donated time and effort to make this research possible. The PGC was funded by NIMH Grants MH085520 (lead PI PFS) and MH080403. We thank our colleagues in the PGC Bipolar Disorder Working Group who allowed pre-publication access to their GWAS mega-analysis results for the MDD-BIP cross-disorder analyses. The Bonn/Mannheim (BoMa) GWAS was supported by the German Federal Ministry of Education and Research, within the context of the National Genome Research Network 2 (NGFN-2), the National Genome Research Network plus (NGFNplus) and the Integrated Genome Research Network (IG) MooDS (Grant 01GS08144 to S Cichon and MM Nöethen, and Grant 01GS08147 to M Rietschel). The work at deCODE was funded by European Union Grants LSHM-CT-2006-037761 (Project SGENE), PIAP-GA-2008-218251 (Project PsychGene) and HEALTH-F2-2009-223423 (Project PsychCNVs). GenPod was funded by the Medical Research Council (UK) and supported by the Mental Health Research Network. Genotyping of the GenPod sample was funded by the Innovative Medicines Initiative Joint Undertaking under Grant Agreement number 115008 (NEWMEDS). The GenRED GWAS project was supported by NIMH R01 Grants MH061686 (DF Levinson), MH059542 (WH Coryell), MH075131 (WB Lawson), MH059552 (JB Potash), MH059541 (WA Scheftner) and MH060912 (MM Weissman). We acknowledge the contributions of Dr George S Zubenko and Dr Wendy N Zubenko, Department of Psychiatry, University of Pittsburgh School of Medicine, to the GenRED I project. The NIMH Cell Repository at Rutgers University and the NIMH Center for Collaborative Genetic Studies on Mental Disorders made essential contributions to this project. Genotyping was carried out by the Broad Institute Center for Genotyping and Analysis with support from Grant U54 RR020278 (which partially subsidized the genotyping of the GenRED cases). Collection and quality control analyses of the control data set were supported by grants from NIMH and the National Alliance for Research on Schizophrenia and Depression. We are grateful to Knowledge Networks (Menlo Park, CA, USA) for assistance in collecting the control data set. We express our profound appreciation to the families who participated in this project, and to the many clinicians who facilitated the referral of participants to the study. The Depression Genes and Networks ARRA grant was funded by RC2MH089916. Funding for the Harvard i2b2 sample was provided by a subcontract to RH Perlis and JW Smoller as part of the i2b2 Center (Informatics for Integrating Biology and the Bedside), an NIH-funded National Center for Biomedical Computing based at Partners HealthCare System (U54LM008748, PI: IS Kohane), and by an NIMH Grant to RH Perlis (MH086026). Max Planck Institute of Psychiatry MARS study was supported by the BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression (01ES0811). Genotyping was supported by the Bavarian Ministry of Commerce, and the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN2 and NGFN-Plus, FKZ 01GS0481 and 01GS08145). The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) contributed to GAIN-MDD and to MDD2000. Funding was from: the Netherlands Organization for Scientific Research (MagW/ZonMW Grants 904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192; Geestkracht program Grant 10-000-1002); the Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, VU University's Institutes for Health and Care Research and Neuroscience Campus Amsterdam, NBIC/BioAssist/RK (2008.024); the European Science Foundation (EU/QLRT-2001-01254); the European Community's Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Science Council (ERC, 230374). Genotyping was funded in part by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (MH081802). CM Middeldorp was supported by the Netherlands Organization for Scientific Research (NOW-VENI grant 916-76-125). The PsyCoLaus study was supported by grants from the Swiss National Science Foundation (#3200B0–105993, #3200B0-118′308, 33CSC0-122661) and from GlaxoSmithKline (Psychiatry Center of Excellence for Drug Discovery and Genetics Division, Drug Discovery - Verona, R&D). We express our gratitude to the Lausanne inhabitants who volunteered to participate in the PsyCoLaus study. We also thank V Mooser, G Weaber and P Vollenweider who initiated the CoLaus project. Funding for the QIMR samples was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, 619667), the Australian Research Council (FT0991360, FT0991022), the FP-5 GenomEUtwin Project (QLG2-CT- 2002-01254) and the US National Institutes of Health (AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951), and the Center for Inherited Disease Research (Baltimore, MD, USA). We thank the twins and their families registered at the Australian Twin Registry for their participation in the many studies that have contributed to this research. RADIANT was funded by: a joint grant from the UK Medical Research Council and GlaxoSmithKline (G0701420); the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King's College London; and the UK Medical Research Council (G0000647). The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (Grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the ‘Center of Knowledge Interchange’ program of the Siemens AG. SHIP-LEGEND is funded by the German Research Foundation (DFG: GR 1912/5-1). Genotyping of STAR*D was supported by an NIMH Grant to SP Hamilton (MH072802). STAR*D was funded by the National Institute of Mental Health (contract N01MH90003) to the University of Texas Southwestern Medical Center at Dallas (AJ Rush, principal investigator). The TwinGene study was supported by the Swedish Ministry for Higher Education, the Swedish Research Council (M-2005-1112), GenomEUtwin (EU/QLRT-2001-01254; QLG2-CT-2002-01254), the Swedish Foundation for Strategic Research and the US National Institutes of Health (U01 DK066134). This study makes use of data generated by the Wellcome Trust Case–Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under awards 076113 and 085475.

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  1. Stephan Ripke, Naomi R Wray, Cathryn M Lewis, Steven P Hamilton, Myrna M Weissman, Gerome Breen, Enda M Byrne, Douglas H R Blackwood, Dorret I Boomsma, Sven Cichon, Andrew C Heath, Florian Holsboer, Susanne Lucae, Pamela A F Madden, Nicholas G Martin, Peter McGuffin, Pierandrea Muglia, Markus M Noethen, Brenda P Penninx, Michele L Pergadia, James B Potash, Marcella Rietschel, Danyu Lin, Bertram Müller-Myhsok, Jianxin Shi, Stacy Steinberg, Hans J Grabe, Paul Lichtenstein, Patrik Magnusson, Roy H Perlis, Martin Preisig, Jordan W Smoller, Kari Stefansson, Rudolf Uher, Zoltan Kutalik, Katherine E Tansey, Alexander Teumer, Alexander Viktorin, Michael R Barnes, Thomas Bettecken, Elisabeth B Binder, René Breuer, Victor M Castro, Susanne E Churchill, William H Coryell, Nick Craddock, Ian W Craig, Darina Czamara, Eco J De Geus, Franziska Degenhardt, Anne E Farmer, Maurizio Fava, Josef Frank, Vivian S Gainer, Patience J Gallagher, Scott D Gordon, Sergey Goryachev, Magdalena Gross, Michel Guipponi, Anjali K Henders, Stefan Herms, Ian B Hickie, Susanne Hoefels, Witte Hoogendijk, Jouke Jan Hottenga, Dan V Iosifescu, Marcus Ising, Ian Jones, Lisa Jones, Tzeng Jung-Ying, James A Knowles, Isaac S Kohane, Martin A Kohli, Ania Korszun, Mikael Landen, William B Lawson, Glyn Lewis, Donald MacIntyre, Wolfgang Maier, Manuel Mattheisen, Patrick J McGrath, Andrew McIntosh, Alan McLean, Christel M Middeldorp, Lefkos Middleton, Grant M Montgomery, Shawn N Murphy, Matthias Nauck, Willem A Nolen, Dale R Nyholt, Michael O'Donovan, Högni Oskarsson, Nancy Pedersen, William A Scheftner, Andrea Schulz, Thomas G Schulze, Stanley I Shyn, Engilbert Sigurdsson, Susan L Slager, Johannes H Smit, Hreinn Stefansson, Michael Steffens, Thorgeir Thorgeirsson, Federica Tozzi, Jens Treutlein, Manfred Uhr, Edwin J C G van den Oord, Gerard Van Grootheest, Henry Völzke, Jeffrey B Weilburg, Gonneke Willemsen, Frans G Zitman, Benjamin Neale, Mark Daly, Douglas F Levinson and Patrick F Sullivan: See Appendix for list of collaborators.

Authors and Affiliations

  1. Harvard University/Broad Institute, USA
    Stephan Ripke
  2. Queensland Institute of Medical Research/University of Queensland, Australia
    Naomi R Wray
  3. Institute of Psychiatry, King's College London, UK
    Cathryn M Lewis
  4. University of California, San Francisco, USA
    Steven P Hamilton
  5. Columbia University, USA
    Myrna M Weissman
  6. Institute of Psychiatry, King's College London, UK
    Gerome Breen
  7. Queensland Institute of Medical Research, Australia
    Enda M Byrne
  8. University of Edinburgh, UK
    Douglas H R Blackwood
  9. VU University, Amsterdam, The Netherlands
    Dorret I Boomsma
  10. University of Bonn, Germany
    Sven Cichon
  11. Washington University, St Louis, USA
    Andrew C Heath
  12. Max Planck Institute of Psychiatry, Germany
    Florian Holsboer
  13. Max Planck Institute of Psychiatry, Germany
    Susanne Lucae
  14. Washington University, St Louis, USA
    Pamela A F Madden
  15. Queensland Institute of Medical Research, Australia
    Nicholas G Martin
  16. Institute of Psychiatry, King's College London, UK
    Peter McGuffin
  17. GlaxoSmithKline, Italy
    Pierandrea Muglia
  18. University of Bonn, Germany
    Markus M Noethen
  19. VU University Medical Center, Amsterdam, The Netherlands
    Brenda P Penninx
  20. Washington University, St Louis, USA
    Michele L Pergadia
  21. University of Iowa, USA
    James B Potash
  22. Central Inst Mental Health, University of Heidelberg, Germany
    Marcella Rietschel
  23. University of North Carolina, USA
    Danyu Lin
  24. Max Planck Institute of Psychiatry, Germany
    Bertram Müller-Myhsok
  25. National Cancer Institute, USA
    Jianxin Shi
  26. deCODE Genetics, Iceland
    Stacy Steinberg
  27. University of Greifswald, Germany
    Hans J Grabe
  28. Karolinska Institutet, Sweden
    Paul Lichtenstein
  29. Karolinska Institutet, Sweden
    Patrik Magnusson
  30. Massachusetts General Hospital, USA
    Roy H Perlis
  31. University of Lausanne, Switzerland
    Martin Preisig
  32. Massachusetts General Hospital, USA
    Jordan W Smoller
  33. deCODE Genetics, Iceland
    Kari Stefansson
  34. Institute of Psychiatry, King's College London, UK
    Rudolf Uher
  35. University of Lausanne, Switzerland
    Zoltan Kutalik
  36. Institute of Psychiatry, King's College London, UK
    Katherine E Tansey
  37. University of Greifswald, Germany
    Alexander Teumer
  38. Karolinska Institutet, Sweden
    Alexander Viktorin
  39. GlaxoSmithKline, UK
    Michael R Barnes
  40. Max Planck Institute of Psychiatry, Germany
    Thomas Bettecken
  41. Max Planck Institute of Psychiatry, Germany
    Elisabeth B Binder
  42. Central Inst Mental Health, University of Heidelberg, Germany
    René Breuer
  43. Partners HealthCare System, USA
    Victor M Castro
  44. Partners HealthCare System, USA
    Susanne E Churchill
  45. University of Iowa, USA
    William H Coryell
  46. Cardiff University, UK
    Nick Craddock
  47. Institute of Psychiatry, King's College London, UK
    Ian W Craig
  48. Max Planck Institute of Psychiatry, Germany
    Darina Czamara
  49. VU University, Amsterdam, The Netherlands
    Eco J De Geus
  50. University of Bonn, Germany
    Franziska Degenhardt
  51. Institute of Psychiatry, King's College London, UK
    Anne E Farmer
  52. Massachusetts General Hospital, USA
    Maurizio Fava
  53. Central Inst Mental Health, University of Heidelberg, Germany
    Josef Frank
  54. Partners HealthCare System, USA
    Vivian S Gainer
  55. Massachusetts General Hospital, USA
    Patience J Gallagher
  56. Queensland Institute of Medical Research, Australia
    Scott D Gordon
  57. Partners HealthCare System, USA
    Sergey Goryachev
  58. University of Bonn, Germany
    Magdalena Gross
  59. University of Geneva, Switzerland
    Michel Guipponi
  60. Queensland Institute of Medical Research, Australia
    Anjali K Henders
  61. University of Bonn, Germany
    Stefan Herms
  62. University of Sydney, Sydney, Australia
    Ian B Hickie
  63. University of Bonn, Germany
    Susanne Hoefels
  64. Erasmus Medical Center, The Netherlands
    Witte Hoogendijk
  65. VU University, Amsterdam, The Netherlands
    Jouke Jan Hottenga
  66. Massachusetts General Hospital, USA
    Dan V Iosifescu
  67. Max Planck Institute of Psychiatry, Germany
    Marcus Ising
  68. Cardiff University, UK
    Ian Jones
  69. University of Birmingham, UK
    Lisa Jones
  70. North Carolina State University, USA
    Tzeng Jung-Ying
  71. University of Southern California, USA
    James A Knowles
  72. Brigham and Women's Hospital, USA
    Isaac S Kohane
  73. Max Planck Institute of Psychiatry, Germany
    Martin A Kohli
  74. Queen Mary University of London, UK
    Ania Korszun
  75. Karolinska Institutet, Sweden
    Mikael Landen
  76. Howard University, USA
    William B Lawson
  77. University of Bristol, UK
    Glyn Lewis
  78. University of Edinburgh, UK
    Donald MacIntyre
  79. University of Bonn, Germany
    Wolfgang Maier
  80. University of Bonn, Germany
    Manuel Mattheisen
  81. Columbia University, USA
    Patrick J McGrath
  82. University of Edinburgh, UK
    Andrew McIntosh
  83. University of Edinburgh, UK
    Alan McLean
  84. VU University, Amsterdam, The Netherlands
    Christel M Middeldorp
  85. Imperial College, UK
    Lefkos Middleton
  86. Queensland Institute of Medical Research, Australia
    Grant M Montgomery
  87. Massachusetts General Hospital, USA
    Shawn N Murphy
  88. University of Greifswald, Germany
    Matthias Nauck
  89. Groningen University Medical Center, The Netherlands
    Willem A Nolen
  90. Queensland Institute of Medical Research, Australia
    Dale R Nyholt
  91. Cardiff University, UK
    Michael O'Donovan
  92. Therapeia, University Hospital, Iceland
    Högni Oskarsson
  93. Karolinska Institutet, Sweden
    Nancy Pedersen
  94. Rush University Medical Center, USA
    William A Scheftner
  95. University of Greifswald, Germany
    Andrea Schulz
  96. University of Goettingen, USA
    Thomas G Schulze
  97. University of Washington, USA
    Stanley I Shyn
  98. Landspitali University Hospital, Iceland
    Engilbert Sigurdsson
  99. Mayo Clinic, USA
    Susan L Slager
  100. VU University Medical Center, Amsterdam, The Netherlands
    Johannes H Smit
  101. deCODE Genetics, Iceland
    Hreinn Stefansson
  102. University of Bonn, Germany
    Michael Steffens
  103. deCODE Genetics, Iceland
    Thorgeir Thorgeirsson
  104. GlaxoSmithKline, Italy
    Federica Tozzi
  105. Central Inst Mental Health, University of Heidelberg, Germany
    Jens Treutlein
  106. Max Planck Institute of Psychiatry, Germany
    Manfred Uhr
  107. Virginia Commonwealth University, USA
    Edwin J C G van den Oord
  108. VU University Medical Center, Amsterdam, The Netherlands
    Gerard Van Grootheest
  109. University of Greifswald, Germany
    Henry Völzke
  110. Massachusetts General Hospital, USA
    Jeffrey B Weilburg
  111. VU University, Amsterdam, The Netherlands
    Gonneke Willemsen
  112. Leiden University Medical Center, Leiden, The Netherlands
    Frans G Zitman
  113. Harvard University/Broad Institute, USA
    Benjamin Neale
  114. Harvard University/Broad Institute, USA
    Mark Daly
  115. Stanford University, USA
    Douglas F Levinson
  116. University of North Carolina, USA
    Patrick F Sullivan

Consortia

Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium

Corresponding author

Correspondence toPatrick F Sullivan.

Ethics declarations

Competing interests

Elisabeth Binder received grant support from Pharmaneuroboost. Hans J Grabe reports receiving funding from: German Research Foundation; Federal Ministry of Education and Research Germany; speakers honoraria from Bristol-Myers Squibb, Eli Lilly, Novartis, Eisai, Wyeth, Pfizer, Boehringer Ingelheim, Servier and travel funds from Janssen-Cilag, Eli Lilly, Novartis, AstraZeneca and SALUS-Institute for Trend-Research and Therapy Evaluation in Mental Health. Florian Holsboer is a shareholder of Affectis Pharmaceuticals and co-founder of HolsboerMaschmeyer-NeuroChemie. James A Knowles is on the Scientific Advisory Committee for Next-Generation Sequencing of Life Technologies and is a technical advisor to SoftGenetics. Pierandrea Muglia was a full-time employee of GSK when the work was performed. Bertram Müller-Myhsok consulted for Affectis Pharmaceuticals. Matthias Nauck reports funding from: the Federal Ministry of Education and Research Germany, Bio-Rad Laboratories, Siemens AG, Zeitschrift für Laboratoriumsmedizin, Bruker Daltronics, Abbott, Jurilab Kuopio, Roche Diagnostics, Dade Behring, DPC Biermann and Becton Dickinson. Rudolf Uher has received funding from a number of pharmaceutical companies as part of the European Union Innovative Medicine Initiative funded NEWMEDS project. Federica Tozzi was a full-time employee of GSK when the work was performed. Henry Völzke reports funding from: Sanofi-Aventis, Biotronik, the Humboldt Foundation, the Federal Ministry of Education and Research (Germany) and the German Research Foundation. No other author reports a conflict of interest.

Additional information

Author contributions

All collaborators reviewed and approved the final version of the manuscript. Overall coordination: Patrick F Sullivan. Statistical analysis: Mark J Daly (lead), Stephan Ripke, Cathryn M Lewis, Dan-Yu Lin, Naomi R Wray, Benjamin Neale, Douglas F Levinson, Gerome Breen, Enda M Byrne. Phenotype analysis: Naomi R Wray (lead), Douglas F Levinson, Marcella Rietschel, Witte Hoogendijk, Stephan Ripke. Writing committee: Patrick F Sullivan (lead), Steven P Hamilton, Douglas F Levinson, Cathryn M Lewis, Stephan Ripke, Myrna M Weissman, Naomi R Wray.

MDD discovery sample data contributed by: Bonn/Mannheim study—René Breuer, Sven Cichon, Franziska Degenhardt, Josef Frank, Magdalena Gross, Stefan Herms, Susanne Hoefels, Wolfgang Maier, Manuel Mattheisen, Markus M Nöethen, Marcella Rietschel, Thomas G Schulze, Michael Steffens, Jens Treutlein; GAIN MDD study—Dorret I Boomsma, Eco J De Geus, Witte Hoogendijk, Jouke Jan Hottenga, Tzeng Jung-Ying, Dan-Yu Lin, Christel M Middeldorp, Willem A Nolen, Brenda P Penninx, Johannes H Smit, Patrick F Sullivan, Gerard van Grootheest, Gonneke Willemsen, Frans G Zitman; GenRED study—William H Coryell, James A Knowles, William B Lawson, Douglas F Levinson, James B Potash, William A Scheftner, Jianxin Shi, Myrna M Weissman; GlaxoSmithKline study—Florian Holsboer, Pierandrea Muglia, Federica Tozzi; MDD2000 study—Douglas HR Blackwood, Dorret I Boomsma, Eco J De Geus, Jouke Jan Hottenga, Donald J MacIntyre, Andrew McIntosh, Alan McLean, Christel M Middeldorp, Willem A Nolen, Brenda P Penninx, Stephan Ripke, Johannes H Smit, Patrick F Sullivan, Gerard van Grootheest, Gonneke Willemsen, Frans G Zitman, Edwin JCG van den Oord; Max Planck Institute of Psychiatry Study—Florian Holsboer, Susanne Lucae, Elisabeth Binder, Bertram Müller-Myhsok, Stephan Ripke, Darina Czamara, Martin A Kohli, Marcus Ising, Manfred Uhr, Thomas Bettecken; RADIANT study—Michael R Barnes, Gerome Breen, Ian W Craig, Anne E Farmer, Cathryn M Lewis, Peter McGuffin, Pierandrea Muglia; Queensland Institute for Medical Research study—Enda Byrne, Scott D Gordon, Andrew C Heath, Anjali K Henders, Ian B Hickie, Pamela AF Madden, Nicholas G Martin, Grant M Montgomery, Dale R Nyholt, Michele L Pergadia, Naomi R Wray; and STAR*D study—Steven P Hamilton, Patrick J McGrath, Stanley I Shyn, Susan L Slager.

MDD replication sample data contributed by: deCODE Genetics—Högni Oskarsson, Engilbert Sigurdsson, Hreinn Stefansson, Kari Stefansson, Stacy Steinberg, Thorgeir Thorgeirsson; Depression Genes Networks study—Douglas F Levinson, James B Potash, Jianxin Shi, Myrna M Weissman; GENPOD—Michel Guipponi, Glyn Lewis, Michael O’Donovan, Katherine E Tansey, Rudolf Uher; GenRED2 study—William H Coryell, James A Knowles, William B Lawson, Douglas F Levinson, James B Potash, William A Scheftner, Jianxin Shi, Myrna M Weissman; Harvard i2b2 study—Victor M Castro, Susanne E Churchill, Maurizio Fava, Vivian S Gainer, Patience J Gallagher, Sergey Goryachev, Dan V Iosifescu, Isaac S Kohane, Shawn N Murphy, Roy H Perlis, Jordan W Smoller, Jeffrey B Weilburg; PsyCoLaus study—Zoltan Kutalik, Martin Preisig; SHIP-LEGEND study—Hans J Grabe, Matthias Nauck, Andrea Schulz, Alexander Teumer, Henry Völzke; and TwinGene study—Mikael Landen, Paul Lichtenstein, Patrik Magnusson, Nancy Pedersen, Alexander Viktorin.

Supplementary Information accompanies the paper on the Molecular Psychiatry website

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Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium. A mega-analysis of genome-wide association studies for major depressive disorder.Mol Psychiatry 18, 497–511 (2013). https://doi.org/10.1038/mp.2012.21

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