Elevated systemic expression of ER stress related genes is associated with stress-related mental disorders in the Detroit Neighborhood Health Study.
BACKGROUND
The role of endoplasmic reticulum (ER) stress response in mental illness is not well understood. Human studies and animal models of depression show elevated brain ER stress response. In addition, some ER stress associated disorders (e.g. cardiovascular disease) show higher rates of depression compared to the general population, raising the possibility that ER stress response contributes to depression risk. It remains unknown, however, if ER stress response is present among individuals suffering from other stress-related mental illness, and whether such a response would be evident in a non-clinical sample. This study tests for systemic changes in ER stress response associated with Major Depressive Disorder (MDD) or post-traumatic stress disorder (PTSD) among community-dwelling individuals.


METHODS
We analyzed expression of BiP, EDEM1, CHOP, and XBP1, the major indicators of ER stress response, with real-time PCR in leukocyte-derived RNA samples from 86 participants of the Detroit Neighborhood Health Study. Participants were selected based on the presence of either past year MDD or past year PTSD; controls were age and sex matched.


RESULTS
Relative to controls, MDD is associated with a 1.34-fold increase in BiP (P=0.004), 1.35-fold increase in EDEM1 (P=0.001), 1.68-fold increase in CHOP (P=0.002), and 1.60-fold increase in XBP1 (P=0.004). These results remained significant after correction for multiple testing. In contrast, PTSD is associated with a 1.27-fold increase in EDEM1 expression only (P=0.027), a result that is attenuated to non-significance following adjustment for multiple testing; however, a subsample of participants with past month PTSD showed elevated expression of BiP and EDEM1 (uncorrected P value 0.049 and 0.017, respectively).


CONCLUSIONS
These data indicate systemic and persistent activation of the ER stress response pathway in MDD among community-dwelling individuals. Systemic activation of the ER stress response may also occur in PTSD among persons with more recent symptoms.
Wayne State University School of Medicine, Center for Molecular Medicine and Genetics, Detroit, MI 48201, USA.
Lisa
L
Nevell
Wayne State University School of Medicine, Center for Molecular Medicine and Genetics, Detroit, MI 48201, USA; Wayne State University School of Medicine, Department of Immunology and Microbiology, Detroit, MI 48201, USA.
Kezhong
K
Zhang
University of North Carolina at Chapel Hill, Gillings School of Global Public Health, Department of Epidemiology, Chapel Hill NC 27599 USA.
Allison E
AE
Aiello
Columbia University Mailman School of Public Health, Department of Epidemiology, New York, NY 10032, USA.
Karestan
K
Koenen
Columbia University Mailman School of Public Health, Department of Epidemiology, New York, NY 10032, USA.
Sandro
S
Galea
Wayne State University School of Medicine, Center for Molecular Medicine and Genetics, Detroit, MI 48201, USA.
Richelo
R
Soliven
Wayne State University School of Medicine, Center for Molecular Medicine and Genetics, Detroit, MI 48201, USA.
Chao
C
Zhang
Wayne State University School of Medicine, Center for Molecular Medicine and Genetics, Detroit, MI 48201, USA; Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, MI 48201, USA.
Derek E
DE
Wildman
Wayne State University School of Medicine, Center for Molecular Medicine and Genetics, Detroit, MI 48201, USA; Wayne State University School of Medicine, Department of Psychiatry and Behavioral Neurosciences, Detroit, MI 48201, USA. Electronic address: monica.uddin@wayne.edu.
Monica
M
Uddin
D000328:Adult; D002318:Cardiovascular Diseases / Q000453:epidemiology; D003865:Major Depressive Disorder / Q000453:epidemiology / Q000523:psychology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000453:epidemiology / Q000235:genetics* / Q000523:psychology*; D008824:Michigan / Q000453:epidemiology; D008875:Middle Aged; D015995:Prevalence; D012111:Residence Characteristics; D013313:Stress Disorders, Post-Traumatic / Q000453:epidemiology / Q000523:psychology; D013315:Stress, Psychological / Q000235:genetics* / Q000523:psychology*
Cardiovascular diseases; Case–control studies; Endoplasmic reticulum stress; Epidemiology; Gene expression pattern analysis; Matched-pair analysis; Metabolic diseases; Unfolded protein response