Original Article

Molecular Psychiatry (2014) 19, 1267–1274; doi:10.1038/mp.2013.161; published online 3 December 2013

Type I interferon signaling genes in recurrent major depression: increased expression detected by whole-blood RNA sequencing

S Mostafavi1, A Battle1, X Zhu2, J B Potash3, M M Weissman4, J Shi5, K Beckman6, C Haudenschild7, C McCormick8, R Mei9, M J Gameroff4, H Gindes3, P Adams4, F S Goes10, F M Mondimore10, D F MacKinnon10, L Notes11, B Schweizer10, D Furman12, S B Montgomery13,14, A E Urban2, D Koller1 and D F Levinson2

  1. 1Department of Computer Science, Stanford University, Stanford, CA, USA
  2. 2Department of Psychiatry and Behavioral Science, Stanford University School of Medicine, Stanford, CA, USA
  3. 3Department of Psychiatry, University of Iowa Hospitals & Clinics, Iowa City, IA, USA
  4. 4Department of Psychiatry, Columbia University and New York State Psychiatric Institute, New York, NY, USA
  5. 5Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
  6. 6Biomedical Genomics Center, University of Minnesota, Minneapolis, MN, USA
  7. 7Personalis, Inc., Menlo Park, CA, USA
  8. 8Illumina, Inc., La Jolla, CA, USA
  9. 9Centrillion Biosciences, Inc., Palo Alto, CA, USA
  10. 10Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA
  11. 11Depatment of Clinical Psychology, American University, Washington DC, DC, USA
  12. 12Department of Microbiology & Immunology, School of Medicine, Stanford University, Stanford, CA, USA
  13. 13Department of Genetics, Stanford University, Stanford, CA, USA
  14. 14Department of Pathology, Stanford University, Stanford, CA, USA

Correspondence: Professor Dr DF Levinson, Department of Psychiatry and Behavioral Science, Stanford University School of Medicine, 401 Quarry Rd, Room 3322, 94305-5797, Stanford, CA, USA. E-mail: dflev@stanford.edu

Received 24 May 2013; Revised 27 August 2013; Accepted 24 September 2013
Advance online publication 3 December 2013



A study of genome-wide gene expression in major depressive disorder (MDD) was undertaken in a large population-based sample to determine whether altered expression levels of genes and pathways could provide insights into biological mechanisms that are relevant to this disorder. Gene expression studies have the potential to detect changes that may be because of differences in common or rare genomic sequence variation, environmental factors or their interaction. We recruited a European ancestry sample of 463 individuals with recurrent MDD and 459 controls, obtained self-report and semi-structured interview data about psychiatric and medical history and other environmental variables, sequenced RNA from whole blood and genotyped a genome-wide panel of common single-nucleotide polymorphisms. We used analytical methods to identify MDD-related genes and pathways using all of these sources of information. In analyses of association between MDD and expression levels of 13857 single autosomal genes, accounting for multiple technical, physiological and environmental covariates, a significant excess of low P-values was observed, but there was no significant single-gene association after genome-wide correction. Pathway-based analyses of expression data detected significant association of MDD with increased expression of genes in the interferon α/β signaling pathway. This finding could not be explained by potentially confounding diseases and medications (including antidepressants) or by computationally estimated proportions of white blood cell types. Although cause–effect relationships cannot be determined from these data, the results support the hypothesis that altered immune signaling has a role in the pathogenesis, manifestation, and/or the persistence and progression of MDD.


interferon-I signaling; major depressive disorder; MDD; pathway expression signature; RNA-sequencing; transcriptomic