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A hidden menace? Cytomegalovirus infection is associated with reduced cortical gray matter volume in major depressive disorder

Molecular Psychiatry volume 26, pages 4234–4244 (2021)Cite this article

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Abstract

Human cytomegalovirus (HCMV) infection is associated with neuropathology in patients with impaired immunity and/or inflammatory diseases. However, the association between gray matter volume (GMV) and HCMV has never been examined in major depressive disorder (MDD) despite the presence of inflammation and impaired viral immunity in a subset of patients. We tested this relationship in two independent samples consisting of 179 individuals with MDD and 41 healthy controls (HC) (sample 1) and 124 MDD participants and 148 HCs (sample 2). HCMV positive (HCMV+) and HCMV negative (HCMV-) groups within each sample were balanced on up to 11 different clinical/demographic variables using inverse probability of treatment weighting. GMV of 87 regions was measured with FreeSurfer. There was a main effect of HCMV serostatus but not diagnosis that replicated across samples. Relative to HCMV- subjects, HCMV+ subjects in sample 1 showed a significant reduction of volume in six regions (puncorrected < 0.05). The reductions in GMV of the right supramarginal gyrus (standardized beta coefficient (SBC) = −0.26) and left fusiform gyrus (SBC = −0.25) in sample 1 were replicated in sample 2: right supramarginal gyrus (puncorrected < 0.05, SBC = −0.32), left fusiform gyrus (PFDR < 0.01, SBC = −0.51). Posthoc tests revealed that the effect of HCMV was driven by differences between the HCMV+ and HCMV- MDD subgroups. HCMV IgG level, a surrogate marker of viral activity, was correlated with GMV in the left fusiform gyrus (r = −0.19, Puncorrected = 0.049) and right supramarginal gyrus (r = −0.19, puncorrected = 0.043) in the HCMV+ group of sample 1. Conceivably, HCMV infection may be a treatable source of neuropathology in vulnerable MDD patients.

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Fig. 1: Flow diagram of selection of participants.
Fig. 2: Regional Effect of HCMV infection on gray matter volumes.
Fig. 3: Correlations between HCMV IgG level and gray matter volumes.

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Data availability

The full analysis code, datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank all the research participants and wish to acknowledge the contributions of Brenda Davis, Debbie Neal, Chibing Tan, and Ashlee Taylor from the laboratory of TKT toward the transport, processing, and handling of all blood samples. This work was supported by The William K. Warren Foundation, the National Institute of Mental Health (K01MH096077 and R21MH11387 to JS; R01MH098099 to JB), and the National Institute of General Medical Sciences (P20GM121312 to MPP). The funding sources had no role in the design and conduct of the study: collection, management, analysis, and interpretation of the data; preparation, review, or approval of the paper; and decision to submit the paper for publication.

Tulsa 1000 Investigators

Robin Aupperle1, Jerzy Bodurka1, Yoon-Hee Cha1, Justin Feinstein1, Sahib S. Khalsa1, Martin P. Paulus1, Jonathan Savitz1, Teresa A. Victor1

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Authors and Affiliations

  1. Laureate Institute for Brain Research, Tulsa, OK, USA

    Haixia Zheng, Bart N. Ford, Maurizio Bergamino, Rayus Kuplicki, Robin Aupperle, Jerzy Bodurka, Yoon-Hee Cha, Justin Feinstein, Sahib S. Khalsa, Martin P. Paulus, Jonathan Savitz, Teresa A. Victor, Jerzy Bodurka, Martin P. Paulus & Jonathan Savitz

  2. The University of Tulsa Department of Biological Sciences, Tulsa, OK, USA

    Bart N. Ford

  3. Division of Neuroimaging Research, Barrow Neurological Institute, Phoenix, AZ, USA

    Maurizio Bergamino

  4. Department of Medicine, School of Medicine, the University of California, San Francisco, San Francisco, CA, USA

    Peter W. Hunt

  5. Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, OK, USA

    Jerzy Bodurka

  6. Department of Surgery, University of Oklahoma School of Community Medicine, Tulsa, OK, USA

    T. Kent Teague

  7. Department of Psychiatry, University of Oklahoma School of Community Medicine, Tulsa, OK, USA

    T. Kent Teague

  8. Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, USA

    T. Kent Teague

  9. Cousins Center for Psychoneuroimmunology at UCLA, Los Angeles, CA, USA

    Michael R. Irwin

  10. Semel Institute for Neuroscience at UCLA, Los Angeles, CA, USA

    Michael R. Irwin

  11. David Geffen School of Medicine, Los Angeles, CA, USA

    Michael R. Irwin

  12. Stanley Division of Developmental Neurovirology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Robert H. Yolken

  13. Oxley College of Health Sciences, The University of Tulsa, Tulsa, OK, USA

    Martin P. Paulus & Jonathan Savitz

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Tulsa 1000 Investigators

  • Robin Aupperle
  • , Jerzy Bodurka
  • , Yoon-Hee Cha
  • , Justin Feinstein
  • , Sahib S. Khalsa
  • , Rayus Kuplicki
  • , Martin P. Paulus
  • , Jonathan Savitz
  •  & Teresa A. Victor

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Correspondence to Haixia Zheng.

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Dr PWH reported receiving support from Merck (donated drug) for a clinical trial of letermovir. All other authors have no conflicts of interest to report.

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Zheng, H., Ford, B.N., Bergamino, M. et al. A hidden menace? Cytomegalovirus infection is associated with reduced cortical gray matter volume in major depressive disorder. Mol Psychiatry 26, 4234–4244 (2021). https://doi.org/10.1038/s41380-020-00932-y

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  • DOI: https://doi.org/10.1038/s41380-020-00932-y

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