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Gene expression in major depressive disorder

Molecular Psychiatry volume 21, pages 339–347 (2016)Cite this article

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An Erratum to this article was published on 23 June 2015

Abstract

The search for genetic variants underlying major depressive disorder (MDD) has not yet provided firm leads to its underlying molecular biology. A complementary approach is to study gene expression in relation to MDD. We measured gene expression in peripheral blood from 1848 subjects from The Netherlands Study of Depression and Anxiety. Subjects were divided into current MDD (N=882), remitted MDD (N=635) and control (N=331) groups. MDD status and gene expression were measured again 2 years later in 414 subjects. The strongest gene expression differences were between the current MDD and control groups (129 genes at false-discovery rate, FDR<0.1). Gene expression differences across MDD status were largely unrelated to antidepressant use, inflammatory status and blood cell counts. Genes associated with MDD were enriched for interleukin-6 (IL-6)-signaling and natural killer (NK) cell pathways. We identified 13 gene expression clusters with specific clusters enriched for genes involved in NK cell activation (downregulated in current MDD, FDR=5.8 × 10−5) and IL-6 pathways (upregulated in current MDD, FDR=3.2 × 10−3). Longitudinal analyses largely confirmed results observed in the cross-sectional data. Comparisons of gene expression results to the Psychiatric Genomics Consortium (PGC) MDD genome-wide association study results revealed overlap with DVL3. In conclusion, multiple gene expression associations with MDD were identified and suggest a measurable impact of current MDD state on gene expression. Identified genes and gene clusters are enriched with immune pathways previously associated with the etiology of MDD, in line with the immune suppression and immune activation hypothesis of MDD.

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Acknowledgements

Gene expression data were funded by the US National Institute of Mental Health (RC2 MH089951) as a part of the American Recovery and Reinvestment Act of 2009. The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) were funded by 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 (BBMRI-NL), 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). Transport, extraction, cDNA preparation and generation of microarray data for the NTR samples were carried out under a supplement to the NIMH Center for Collaborative Genomics Research on Mental Disorders (U24 MH068457, Principal Investigator JT). RJ was supported by the Biobank-based Integrative Omics Study (BIOS) consortium, which is funded by the Biobanking and Biomolecular Research Infrastructure (BBMRI-NL, NWO project 184.021.007). Gene expression data used for this study are available at dbGaP, accession number phs000486.v1.p1 (http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000486.v1.p1).

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Author notes

  1. R Jansen and B W J H Penninx: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands

    R Jansen, B W J H Penninx, Y Milaneschi, A Beekman, J H Smit & G van Grootheest

  2. Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA

    V Madar, F A Wright & F Zou

  3. Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA

    K Xia

  4. Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands

    J J Hottenga, G Willemsen, E J de Geus & D I Boomsma

  5. Department of Complex Trait Genetics, VU University Amsterdam, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands

    A R Hammerschlag & D Posthuma

  6. Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands

    N van der Wee

  7. Department of Genetics and the Human Genetics Institute, RUCDR Infinite Biologics, Rutgers University, New Brunswick, NJ, USA

    A I Brooks & J Tischfield

  8. Department of Clinical Genetics, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands

    D Posthuma

  9. Department of Psychiatry, University Medical Center Groningen, Groningen, The Netherlands

    R Schoevers

  10. Department of Statistics, North Carolina State University, Raleigh, NC, USA

    F A Wright

  11. Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA

    F A Wright

  12. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    W Sun & P F Sullivan

  13. Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA

    P F Sullivan

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  1. R Jansen
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  2. B W J H Penninx
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Correspondence to R Jansen.

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Jansen, R., Penninx, B., Madar, V. et al. Gene expression in major depressive disorder. Mol Psychiatry 21, 339–347 (2016). https://doi.org/10.1038/mp.2015.57

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