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Correlation networks of blood proteins in the neuroimmunology of schizophrenia—replication and extension
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  • Published: 11 April 2026

Correlation networks of blood proteins in the neuroimmunology of schizophrenia—replication and extension

  • Clark D. Jeffries  ORCID: orcid.org/0000-0002-3044-26491,
  • Chris A. Bizon2,
  • John R. Ford3,
  • Jean Addington  ORCID: orcid.org/0000-0002-8298-07564,
  • Carrie E. Bearden  ORCID: orcid.org/0000-0002-8516-923X5,
  • Kristin Cadenhead6,
  • Tyrone D. Cannon  ORCID: orcid.org/0000-0002-5632-31547,
  • Barbara Cornblatt na1,
  • Matcheri Keshavan  ORCID: orcid.org/0000-0002-5945-888X8,9,
  • Daniel Mathalon  ORCID: orcid.org/0000-0001-6090-497410,
  • Larry Seidman na2,
  • William S. Stone  ORCID: orcid.org/0000-0003-2932-72888,9,
  • Elaine F. Walker  ORCID: orcid.org/0000-0002-9798-810111,
  • Scott W. Woods  ORCID: orcid.org/0000-0002-3103-522812 &
  • …
  • Diana O. Perkins  ORCID: orcid.org/0000-0001-9396-22061 

Translational Psychiatry , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Learning and memory
  • Molecular neuroscience
  • Predictive markers
  • Schizophrenia

Abstract

The Pearson sample correlation between two biomarkers across a group of individuals can sometimes be much stronger than expected by chance. In the context of psychosis risk, we previously analyzed blood plasma protein data from initial presentations as collected in the North American Prodrome Longitudinal Study 2 (NAPLS2). We found enhanced correlation between proteins SERPINE1 and TIMP1, both promoters of coagulation and inhibitors of remodeling of extracellular matrix (ECM). Participants were unaffected community controls vs. others of clinical high risk. The SERPINE1-TIMP1 correlation was consistently higher in individuals at clinical high risk for psychosis who later converted to a psychotic disorder vs. participants who were nonconverters or unaffected community controls. Here, we extend those findings using data from a larger cohort, the North American Prodrome Longitudinal Study 3 (NAPLS3). Again, the correlation between SERPINE1 and TIMP1 remained higher in psychosis high-risk converters vs. the other groups. In NAPLS3 we added an assay for PLAT (anti-coagulation plasminogen activator strongly inhibited by SERPINE1). Comparing the three NAPLS3 groups we found a decreased correlation between SERPINE1 and PLAT in converters. In summary, the increased correlation of SERPINE1 and TIMP1 in converters is consistent with restricted brain circuit remodeling and increased tendency to coagulation. Rigorous application of permutation testing yielded NAPLS2 vs. NAPLS3 consistency of SERPINE1-TIMP1 correlation patterns with empirical p-value 0.03.

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Data availability

NAPLS2 and NAPLS3 data are in Supplement 12.

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Acknowledgements

This work was supported by National Institutes of Health (NIH) grants U01 MH081902 to Dr. Cannon, P50 MH066286 to Dr. Bearden, U01 MH82022 to Dr. Woods, U01 MH066134 to Dr. Addington, U01 MH081944 to Dr. Cadenhead, U01 MH066069 to Dr. Perkins, R01 MH076989 to Dr. Mathalon, U01 MH081928 to Dr. Stone, and U01 MH081988 to Dr. Walker. Many referee comments greatly improved the focus and precision of the manuscript.

Author information

Author notes

  1. Deceased: Barbara Cornblatt.

  2. Deceased: Larry Seidman.

Authors and Affiliations

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

    Clark D. Jeffries & Diana O. Perkins

  2. Renaissance Computing Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Chris A. Bizon

  3. Perspectrix, Pittsboro, NC, USA

    John R. Ford

  4. Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada

    Jean Addington

  5. Semel Institute for Neuroscience and Human Behavior, Departments of Psychiatry and Behavioral Sciences and Psychology, University of California, Los Angeles, Los Angeles, CA, USA

    Carrie E. Bearden

  6. Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA

    Kristin Cadenhead

  7. Departments of Psychology and Psychiatry, Yale University, New Haven, CT, USA

    Tyrone D. Cannon

  8. Harvard Medical School, Boston, MA, USA

    Matcheri Keshavan & William S. Stone

  9. Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Matcheri Keshavan & William S. Stone

  10. Department of Psychiatry, University of California San Francisco, San Francisco, USA

    Daniel Mathalon

  11. Department of Psychology, Emory University, Atlanta, GA, USA

    Elaine F. Walker

  12. Department of Psychiatry, Yale University, New Haven, CT, USA

    Scott W. Woods

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Contributions

CJ, DP, and JF designed algorithms and statistical checks and helped write the manuscript; CAB discussed the project a various stages; JA, CEB, KC, TC, BC, MK, DM, LS, WS, EW, SW, and DP had executive roles in clinic management and in writing the manuscript.

Corresponding author

Correspondence to Clark D. Jeffries.

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Competing interests

The authors declair no competing interest.

Ethics approval and consent to participate

Approval for the NAPLS2 and NAPLS3 projects was obtained by each site by their respective named ethics committees listed below. All methods were performed in accordance with the relevant guidelines and regulations, including obtaining informed consent from all study participants. For IRB details at each site, please see the table in the Supplement 11.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Protein labels are Official Gene Symbols (https://www.ncbi.nlm.nih.gov/gene/) in plaintext while genes themselves are in italics. For example, the gene SERPINE1 encodes the protein serpin family E member 1, that is, SERPINE1. Other notable proteins herein are plasminogen activator, tissue type (PLAT); plasminogen activator, urokinase (PLAU); and TIMP metallopeptidase inhibitor 1 (TIMP1). A complete list of symbols and acronyms is in Supplement.

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Jeffries, C.D., Bizon, C.A., Ford, J.R. et al. Correlation networks of blood proteins in the neuroimmunology of schizophrenia—replication and extension. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-03934-6

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  • Received: 27 July 2023

  • Revised: 26 January 2026

  • Accepted: 06 March 2026

  • Published: 11 April 2026

  • DOI: https://doi.org/10.1038/s41398-026-03934-6

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