Meta-analysis of genome-wide association data of bipolar disorder and major depressive disorder (original) (raw)

Substantial indirect evidence suggests overlap between bipolar disorder (BIP) and major depressive disorder (MDD). BIP and MDD have in common major depressive episodes with BIP being distinguished by the additional presence of manic (bipolar 1) or hypomanic episodes (bipolar 2). Genetic epidemiological1 and genome-wide linkage studies2 are also consistent with overlap between genetic risk factors for both disorders. In an attempt to identify common genetic risk factors, we conducted a meta-analysis combining data from genome-wide association studies of BIP (4387 cases and 6209 controls)3 and MDD (1695 cases and 1761 controls).4

Ascertainment, diagnostic assessment, genotyping, quality control and analysis are detailed elsewhere.3, 4 Both studies were conducted under the appropriate ethical approvals, and all subjects provided written informed consent. Briefly, BIP results are obtained from a combined analysis of samples from the UK, the US and Ireland5, 6 with all subjects genotyped using Affymetrix 500K chips (Santa Clara, CA, USA). Most cases met criteria for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-IV) bipolar 1 (81%) with smaller numbers meeting criteria for bipolar 2 (16%), schizoaffective disorder/manic type (2%), or bipolar NOS (not otherwise specified) (1%). After quality control, 1 769 948 single nucleotide polymorphisms (SNPs) were analyzed (18.7% were directly genotyped and the remainder were imputed using HapMap2 CEU).7, 8 Cases meeting DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-IV) criteria for MDD were ascertained from clinical and community sources, and controls at low liability for MDD were selected from a community sample.9 Genotyping was conducted by Perlegen using a 600K platform. After quality control (with slightly stricter thresholds to maximize comparability), 1 893 617 SNPs were available (20.4% directly genotyped with the rest imputed using HapMap2 CEU).10 In both studies, SNPs were dropped for excessive missingness, low minor allele frequencies and marked deviations from Hardy–Weinberg equilibrium. Subjects were removed for excessive missingness, unusual genome-wide heterozygosity, first- or second-degree relation to any other subject, and if empirical ancestry deviated markedly from other subjects. There was no known subject overlap across studies (BIP subjects were from the US, the UK and Ireland, and MDD subjects were from The Netherlands).

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Authors and Affiliations

1. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
   Y Liu & P F Sullivan
2. Department of Psychological Medicine, University of Edinburgh, Edinburgh, UK
   D H Blackwood
3. Department of Psychological Medicine, Birmingham University, Birmingham, UK
   S Caesar, K Gordon-Smith & L Jones
4. Department of Psychology, VU University Amsterdam, Amsterdam, The Netherlands
   E J C de Geus, J J Hottenga, G Willemsen & D I Boomsma
5. Department of Psychological Medicine, Institute of Psychiatry, London, UK
   A Farmer & P McGuffin
6. Department of Genetics, Queensland Institute of Medical Research, Brisbane, Queensland, Australia
   M A R Ferreira
7. Department of Psychological Medicine, Newcastle University, Newcastle, UK
   I N Ferrier
8. Department of Psychological Medicine, Cardiff University, Cardiff, UK
   C Fraser, E K Green, D Grozeva, M L Hamshere, P A Holmans, I R Jones, G Kirov, V Moskvina, N Craddock, M C O'Donovan & M J Owen
9. Department of Psychological Medicine, University College London, London, UK
   H M Gurling
10. Department of Psychiatry, VU University Medical Center Amsterdam, Amsterdam, The Netherlands
    P Heutink & W J Hoogendijk
11. Department of Biostatics, University of North Carolina, Chapel Hill, NC, USA
    D Lin
12. Department of Psychological Medicine, University Medical Center, Groningen, The Netherlands
    W A Nolen
13. Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
    R H Perlis, J W Smoller, S Purcell & P Sklar
14. Department of Genetics, VU University Amsterdam, Amsterdam, The Netherlands
    D Posthuma, A B Smit & M Verhage
15. Department of Genetics, Broad Institute, Cambridge, MA, USA
    E M Scolnick
16. Department of Psychiatry, VU University Medical Center Amsterdam, Amsterdam, The Netherlands
    J H Smit, R van Dyck & B W J H Penninx
17. Department of Psychological Medicine, Aberdeen University, Aberdeen, UK
    D St Clair
18. Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada
    A H Young
19. Department of Psychology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands
    T Zandbelt

Authors

1. Y Liu
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2. D H Blackwood
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3. S Caesar
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4. E J C de Geus
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5. A Farmer
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6. M A R Ferreira
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7. I N Ferrier
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8. C Fraser
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9. K Gordon-Smith
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10. E K Green
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11. D Grozeva
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12. H M Gurling
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13. M L Hamshere
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14. P Heutink
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15. P A Holmans
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16. W J Hoogendijk
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17. J J Hottenga
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18. L Jones
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19. I R Jones
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20. G Kirov
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21. D Lin
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22. P McGuffin
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23. V Moskvina
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24. W A Nolen
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25. R H Perlis
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26. D Posthuma
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27. E M Scolnick
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28. A B Smit
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29. J H Smit
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30. J W Smoller
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31. D St Clair
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32. R van Dyck
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33. M Verhage
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34. G Willemsen
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35. A H Young
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36. T Zandbelt
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37. D I Boomsma
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38. N Craddock
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39. M C O'Donovan
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40. M J Owen
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41. B W J H Penninx
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42. S Purcell
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43. P Sklar
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44. P F Sullivan
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Wellcome Trust Case-Control Consortium

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Correspondence toP F Sullivan.

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Competing interests

In the interests of full disclosure, Dr Sullivan reports receiving unrestricted research funding from Eli Lilly for genetic research in schizophrenia. Dr Perlis has received speaking or consulting fees from Astra Zeneca, Eli Lilly, GlaxoSmithKline, Pfizer, and Proteus, LLC. Dr Nolen reports receiving unrestricted research funding and Speaker's fee from Astra Zeneca, Eli Lilly, GlaxoSmithKline, Pfizer, Servier and Wyeth. The other authors report no conflicts.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website

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Liu, Y., Blackwood, D., Caesar, S. et al. Meta-analysis of genome-wide association data of bipolar disorder and major depressive disorder.Mol Psychiatry 16, 2–4 (2011). https://doi.org/10.1038/mp.2009.107

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• Published: 30 March 2010
• Issue Date: January 2011
• DOI: https://doi.org/10.1038/mp.2009.107