Towards precision medicine for stress disorders: diagnostic biomarkers and targeted drugs

Helen Le-Niculescu, K. Roseberry, D. F. Levey, J. Rogers, K. Kosary, S. Prabha, T. Jones, S. Judd, M. A. McCormick, A. R. Wessel, A. Williams, P. L. Phalen, F. Mamdani, A. Sequeira, S. M. Kurian, Alexander Niculescu

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The biological fingerprint of environmental adversity may be key to understanding health and disease, as it encompasses the damage induced as well as the compensatory reactions of the organism. Metabolic and hormonal changes may be an informative but incomplete window into the underlying biology. We endeavored to identify objective blood gene expression biomarkers for psychological stress, a subjective sensation with biological roots. To quantify the stress perception at a particular moment in time, we used a simple visual analog scale for life stress in psychiatric patients, a high-risk group. Then, using a stepwise discovery, prioritization, validation, and testing in independent cohort design, we were successful in identifying gene expression biomarkers that were predictive of high-stress states and of future psychiatric hospitalizations related to stress, more so when personalized by gender and diagnosis. One of the top biomarkers that survived discovery, prioritization, validation, and testing was FKBP5, a well-known gene involved in stress response, which serves as a de facto reassuring positive control. We also compared our biomarker findings with telomere length (TL), another well-established biological marker of psychological stress and show that newly identified predictive biomarkers such as NUB1, APOL3, MAD1L1, or NKTR are comparable or better state or trait predictors of stress than TL or FKBP5. Over half of the top predictive biomarkers for stress also had prior evidence of involvement in suicide, and the majority of them had evidence in other psychiatric disorders, providing a molecular underpinning for the effects of stress in those disorders. Some of the biomarkers are targets of existing drugs, of potential utility in patient stratification, and pharmacogenomics approaches. Based on our studies and analyses, the biomarkers with the best overall convergent functional evidence (CFE) for involvement in stress were FKBP5, DDX6, B2M, LAIR1, RTN4, and NUB1. Moreover, the biomarker gene expression signatures yielded leads for possible new drug candidates and natural compounds upon bioinformatics drug repurposing analyses, such as calcium folinate and betulin. Our work may lead to improved diagnosis and treatment for stress disorders such as PTSD, that result in decreased quality of life and adverse outcomes, including addictions, violence, and suicide.

Original languageEnglish (US)
JournalMolecular Psychiatry
DOIs
StatePublished - Jan 1 2019

Fingerprint

Precision Medicine
Biomarkers
Pharmaceutical Preparations
Psychological Stress
Psychiatry
Telomere
Suicide
Drug Repositioning
Gene Expression
Leucovorin
Pharmacogenetics
Dermatoglyphics
Post-Traumatic Stress Disorders
Computational Biology
Visual Analog Scale
Transcriptome
Violence
Hospitalization
Quality of Life

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Towards precision medicine for stress disorders : diagnostic biomarkers and targeted drugs. / Le-Niculescu, Helen; Roseberry, K.; Levey, D. F.; Rogers, J.; Kosary, K.; Prabha, S.; Jones, T.; Judd, S.; McCormick, M. A.; Wessel, A. R.; Williams, A.; Phalen, P. L.; Mamdani, F.; Sequeira, A.; Kurian, S. M.; Niculescu, Alexander.

In: Molecular Psychiatry, 01.01.2019.

Research output: Contribution to journalArticle

Le-Niculescu, H, Roseberry, K, Levey, DF, Rogers, J, Kosary, K, Prabha, S, Jones, T, Judd, S, McCormick, MA, Wessel, AR, Williams, A, Phalen, PL, Mamdani, F, Sequeira, A, Kurian, SM & Niculescu, A 2019, 'Towards precision medicine for stress disorders: diagnostic biomarkers and targeted drugs', Molecular Psychiatry. https://doi.org/10.1038/s41380-019-0370-z
Le-Niculescu, Helen ; Roseberry, K. ; Levey, D. F. ; Rogers, J. ; Kosary, K. ; Prabha, S. ; Jones, T. ; Judd, S. ; McCormick, M. A. ; Wessel, A. R. ; Williams, A. ; Phalen, P. L. ; Mamdani, F. ; Sequeira, A. ; Kurian, S. M. ; Niculescu, Alexander. / Towards precision medicine for stress disorders : diagnostic biomarkers and targeted drugs. In: Molecular Psychiatry. 2019.
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