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

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

Publication date: Mar 12, 2019

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.

Le-Niculescu, H., 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., and Niculescu, A.B. Towards precision medicine for stress disorders: diagnostic biomarkers and targeted drugs. 04211. 2019 Mol Psychiatry.

Concepts Keywords
Analog Imaging biomarker
B2M Pharmacogenomics
Biological Marker Posttraumatic stress disorder
Biomarker Mental disorder
Biomarkers Cell biology
Blood Genomics
Calcium Folinate Psychiatric diagnosis
Cohort Design Abnormal psychology
Fingerprint Biomarkers
Gender Branches of biology
Organism Clinical medicine
Pharmacogenomics Medicine
Psychiatric Disorders Precision stress disorders
Psychological Stress
PTSD
Stratification
Stress
Stress Response
Suicide
Telomere
TL

Semantics

Type Source Name
disease MESH violence
disease MESH PTSD
gene UNIPROT RTN4
gene UNIPROT LAIR1
gene UNIPROT B2M
gene UNIPROT DDX6
gene UNIPROT BEST1
disease MESH suicide
drug DRUGBANK Tropicamide
gene UNIPROT NKTR
gene UNIPROT MAD1L1
gene UNIPROT APOL3
gene UNIPROT APOL2
gene UNIPROT NUB1
pathway BSID Stress response
gene UNIPROT FKBP5
gene UNIPROT THOP1
disease MESH diagnosis
disease MESH visual
gene UNIPROT LITAF
disease MESH psychological stress
pathway BSID Gene Expression
gene UNIPROT MAGEE1

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