Original Article

Molecular Psychiatry (2013) 18, 497–511; doi:10.1038/mp.2012.21; published online 3 April 2012

A mega-analysis of genome-wide association studies for major depressive disorder

Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium 117

  1. 1Harvard University/Broad Institute, USA
  2. 2Queensland Institute of Medical Research/University of Queensland, Australia
  3. 3Institute of Psychiatry, King's College London, UK
  4. 4University of California, San Francisco, USA
  5. 5Columbia University, USA
  6. 6Institute of Psychiatry, King's College London, UK
  7. 7Queensland Institute of Medical Research, Australia
  8. 8University of Edinburgh, UK
  9. 9VU University, Amsterdam, The Netherlands
  10. 10University of Bonn, Germany
  11. 11Washington University, St Louis, USA
  12. 12Max Planck Institute of Psychiatry, Germany
  13. 13Max Planck Institute of Psychiatry, Germany
  14. 14Washington University, St Louis, USA
  15. 15Queensland Institute of Medical Research, Australia
  16. 16Institute of Psychiatry, King's College London, UK
  17. 17GlaxoSmithKline, Italy
  18. 18University of Bonn, Germany
  19. 19VU University Medical Center, Amsterdam, The Netherlands
  20. 20Washington University, St Louis, USA
  21. 21University of Iowa, USA
  22. 22Central Inst Mental Health, University of Heidelberg, Germany
  23. 23University of North Carolina, USA
  24. 24Max Planck Institute of Psychiatry, Germany
  25. 25National Cancer Institute, USA
  26. 26deCODE Genetics, Iceland
  27. 27University of Greifswald, Germany
  28. 28Karolinska Institutet, Sweden
  29. 29Karolinska Institutet, Sweden
  30. 30Massachusetts General Hospital, USA
  31. 31University of Lausanne, Switzerland
  32. 32Massachusetts General Hospital, USA
  33. 33deCODE Genetics, Iceland
  34. 34Institute of Psychiatry, King's College London, UK
  35. 35University of Lausanne, Switzerland
  36. 36Institute of Psychiatry, King's College London, UK
  37. 37University of Greifswald, Germany
  38. 38Karolinska Institutet, Sweden
  39. 39GlaxoSmithKline, UK
  40. 40Max Planck Institute of Psychiatry, Germany
  41. 41Max Planck Institute of Psychiatry, Germany
  42. 42Central Inst Mental Health, University of Heidelberg, Germany
  43. 43Partners HealthCare System, USA
  44. 44Partners HealthCare System, USA
  45. 45University of Iowa, USA
  46. 46Cardiff University, UK
  47. 47Institute of Psychiatry, King's College London, UK
  48. 48Max Planck Institute of Psychiatry, Germany
  49. 49VU University, Amsterdam, The Netherlands
  50. 50University of Bonn, Germany
  51. 51Institute of Psychiatry, King's College London, UK
  52. 52Massachusetts General Hospital, USA
  53. 53Central Inst Mental Health, University of Heidelberg, Germany
  54. 54Partners HealthCare System, USA
  55. 55Massachusetts General Hospital, USA
  56. 56Queensland Institute of Medical Research, Australia
  57. 57Partners HealthCare System, USA
  58. 58University of Bonn, Germany
  59. 59University of Geneva, Switzerland
  60. 60Queensland Institute of Medical Research, Australia
  61. 61University of Bonn, Germany
  62. 62University of Sydney, Sydney, Australia
  63. 63University of Bonn, Germany
  64. 64Erasmus Medical Center, The Netherlands
  65. 65VU University, Amsterdam, The Netherlands
  66. 66Massachusetts General Hospital, USA
  67. 67Max Planck Institute of Psychiatry, Germany
  68. 68Cardiff University, UK
  69. 69University of Birmingham, UK
  70. 70North Carolina State University, USA
  71. 71University of Southern California, USA
  72. 72Brigham and Women's Hospital, USA
  73. 73Max Planck Institute of Psychiatry, Germany
  74. 74Queen Mary University of London, UK
  75. 75Karolinska Institutet, Sweden
  76. 76Howard University, USA
  77. 77University of Bristol, UK
  78. 78University of Edinburgh, UK
  79. 79University of Bonn, Germany
  80. 80University of Bonn, Germany
  81. 81Columbia University, USA
  82. 82University of Edinburgh, UK
  83. 83University of Edinburgh, UK
  84. 84VU University, Amsterdam, The Netherlands
  85. 85Imperial College, UK
  86. 86Queensland Institute of Medical Research, Australia
  87. 87Massachusetts General Hospital, USA
  88. 88University of Greifswald, Germany
  89. 89Groningen University Medical Center, The Netherlands
  90. 90Queensland Institute of Medical Research, Australia
  91. 91Cardiff University, UK
  92. 92Therapeia, University Hospital, Iceland
  93. 93Karolinska Institutet, Sweden
  94. 94Rush University Medical Center, USA
  95. 95University of Greifswald, Germany
  96. 96University of Goettingen, USA
  97. 97University of Washington, USA
  98. 98Landspitali University Hospital, Iceland
  99. 99Mayo Clinic, USA
  100. 100VU University Medical Center, Amsterdam, The Netherlands
  101. 101deCODE Genetics, Iceland
  102. 102University of Bonn, Germany
  103. 103deCODE Genetics, Iceland
  104. 104GlaxoSmithKline, Italy
  105. 105Central Inst Mental Health, University of Heidelberg, Germany
  106. 106Max Planck Institute of Psychiatry, Germany
  107. 107Virginia Commonwealth University, USA
  108. 108VU University Medical Center, Amsterdam, The Netherlands
  109. 109University of Greifswald, Germany
  110. 110Massachusetts General Hospital, USA
  111. 111VU University, Amsterdam, The Netherlands
  112. 112Leiden University Medical Center, Leiden, The Netherlands
  113. 113Harvard University/Broad Institute, USA
  114. 114Harvard University/Broad Institute, USA
  115. 115Stanford University, USA
  116. 116University of North Carolina, USA

Correspondence: Dr PF Sullivan, Department of Genetics, CB #7264, 5097 Genomic Medicine, University of North Carolina, Chapel Hill, NC 27599-7264, USA. E-mail: pfsulliv@med.unc.edu

117See Appendix for list of collaborators.

Received 6 December 2011; Revised 19 January 2012; Accepted 13 February 2012
Advance online publication 3 April 2012

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Abstract

Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 × 10−8), and all were in a 248kb interval of high LD on 3p21.1 (chr3:52425083–53822102, minimum P=5.9 × 10−9 at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.

Keywords:

genetics; genome-wide association study; major depressive disorder; mega-analysis; meta-analysis