Through unbiased transcriptomics and multiple molecular tools, transient downregulation of the Orthodenticle homeobox 2 (OTX2) gene was recently causatively associated with the development of depressive-like behaviors in a mouse model of early life stress. The analyses presented in this manuscript test the translational applicability of these findings by examining peripheral markers of methylation of OTX2 and OTX2-regulated genes in relation to measures of depression and resting-state functional connectivity data collected as part of a larger study examining risk and resilience in maltreated children. The sample included 157 children between the ages of 8 and 15 years (χ = 11.4, SD = 1.9). DNA specimens were derived from saliva samples and processed using the Illumina 450 K beadchip. A subset of children (N = 47) with DNA specimens also had resting-state functional MRI data. After controlling for demographic factors, cell heterogeneity, and three principal components, maltreatment history and methylation in OTX2 significantly predicted depression in the children. In terms of the imaging data, increased OTX2 methylation was found to be associated with increased functional connectivity between the right vmPFC and bilateral regions of the medial frontal cortex and the cingulate, including the subcallosal gyrus, frontal pole, and paracingulate gyrus—key structures implicated in depression. Mouse models of early stress hold significant promise in helping to unravel the mechanisms by which child adversity confers risk for psychopathology, with data presented in this manuscript supporting a potential role for OTX2 and OTX2-related (e.g., WNT1, PAX6) genes in the pathophysiology of stress-related depressive disorders in children.

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We thank the children and families who participated in this research and the administration of the Vermont Department of Children and Families for their collaboration on this effort. This work was supported by the Zanvyl and Isabelle Krieger Fund (JK), the NIH R01MH098073 (JK, JH), R01 MD011746-01 (JK); the National Center for Posttraumatic Stress Disorder—Veterans Affairs, Connecticut (JG, JK); the VA Cooperative Study #575B, Genomics of Posttraumatic Stress Disorder in Veterans (JG, JK); and the Biological Sciences Training Program through 5T32 MH14276 (JLM-O).

Author information


  1. Center for Child and Family Traumatic Stress, Kennedy Krieger Institute, Baltimore, MD, USA

    • Joan Kaufman
    •  & Catherine Kearney
  2. Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    • Joan Kaufman
    •  & Richard S. Lee
  3. Department of Psychiatry, Yale University, New Haven, CT, USA

    • Joan Kaufman
    • , Janitza L. Montalvo-Ortiz
    • , Bao-Zhu Yang
    •  & Joel Gelernter
  4. Center for Neurodevelopmental and Imaging Research, Kennedy Krieger Institute, Baltimore, MD, USA

    • Nicholas F. Wymbs
    •  & Stewart Mostofsky
  5. Department of Psychiatry, Vermont Center for Children, Youth, and Families, University of Vermont, Burlington, VT, USA

    • Catherine Orr
    • , Matthew D. Albaugh
    • , Robert Althoff
    • , Kerry O’Loughlin
    • , Hannah Holbrook
    • , Hugh Garavan
    •  & James Hudziak
  6. Department of Biostatistics, Yale University, New Haven, CT, USA

    • Hongyu Zhao
    •  & Joel Gelernter
  7. Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Catherine Peña
    •  & Eric J. Nestler
  8. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    • Stewart Mostofsky
  9. Veterans Administration, West Haven, CT, USA

    • Joel Gelernter


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Correspondence to Joan Kaufman.

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