DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression

Aliza P. Wingo; Lynn M. Almli; Jennifer J. Stevens; Torsten Klengel; Monica Uddin; Yujing Li; Angela C. Bustamante; Adriana Lori; Nastassja Koen; Dan J. Stein; Alicia K. Smith; Allison E. Aiello; Karestan C. Koenen; Derek E. Wildman; Sandro Galea; Bekh Bradley; Elisabeth B. Binder; Peng Jin; Greg Gibson; Kerry J. Ressler

doi:10.1038/ncomms10106

DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression

Aliza P. Wingo, Lynn M. Almli, Jennifer J. Stevens, Torsten Klengel, Monica Uddin, Yujing Li, Angela C. Bustamante, Adriana Lori, Nastassja Koen, Dan J. Stein, Alicia K. Smith, Allison E. Aiello, Karestan C. Koenen, Derek E. Wildman, Sandro Galea, Bekh Bradley, Elisabeth B. Binder, Peng Jin, Greg Gibson, Kerry J. Ressler^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

78 Scopus citations

Abstract

DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity. Here, through genome-wide differential gene expression survey of post-traumatic stress disorder (PTSD) with comorbid depression (PTSD&Dep), we find that blood DICER1 expression is significantly reduced in cases versus controls, and replicate this in two independent cohorts. Our follow-up studies find that lower blood DICER1 expression is significantly associated with increased amygdala activation to fearful stimuli, a neural correlate for PTSD. Additionally, a genetic variant in the 3′ un-translated region of DICER1, rs10144436, is significantly associated with DICER1 expression and with PTSD&Dep, and the latter is replicated in an independent cohort. Furthermore, genome-wide differential expression survey of miRNAs in blood in PTSD&Dep reveals miRNAs to be significantly downregulated in cases versus controls. Together, our novel data suggest DICER1 plays a role in molecular mechanisms of PTSD&Dep through the DICER1 and the miRNA regulation pathway.

Original language	English
Article number	10106
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms10106
State	Published - 3 Dec 2015
Externally published	Yes

Funding

Funders	Funder number
National Institute of Child Health and Human Development
Long-Term Fellowship
National Institutes of Health
European Molecular Biology Organization
National Alliance for Research on Schizophrenia and Depression
Young Investigator Award
National Institute of General Medical Sciences	P01GM099568
National Institute of Mental Health	R01MH094757, R01MH096764, F32MH101976, R01MH071537, R21MH098662, RC1MH088283
U.S. Department of Veterans Affairs	IK2CX000601
Medical Research Council	DA022720, RC1MH088283
National Institute on Drug Abuse	R01DA022720
Bill and Melinda Gates Foundation	1017641
Eunice Kennedy Shriver National Institute of Child Health and Human Development	P2CHD050924

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10.1038/ncomms10106

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Wingo, A. P., Almli, L. M., Stevens, J. J., Klengel, T., Uddin, M., Li, Y., Bustamante, A. C., Lori, A., Koen, N., Stein, D. J., Smith, A. K., Aiello, A. E., Koenen, K. C., Wildman, D. E., Galea, S., Bradley, B., Binder, E. B., Jin, P., Gibson, G., & Ressler, K. J. (2015). DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression. Nature Communications, 6, Article 10106. https://doi.org/10.1038/ncomms10106

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title = "DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression",

abstract = "DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity. Here, through genome-wide differential gene expression survey of post-traumatic stress disorder (PTSD) with comorbid depression (PTSD&Dep), we find that blood DICER1 expression is significantly reduced in cases versus controls, and replicate this in two independent cohorts. Our follow-up studies find that lower blood DICER1 expression is significantly associated with increased amygdala activation to fearful stimuli, a neural correlate for PTSD. Additionally, a genetic variant in the 3′ un-translated region of DICER1, rs10144436, is significantly associated with DICER1 expression and with PTSD&Dep, and the latter is replicated in an independent cohort. Furthermore, genome-wide differential expression survey of miRNAs in blood in PTSD&Dep reveals miRNAs to be significantly downregulated in cases versus controls. Together, our novel data suggest DICER1 plays a role in molecular mechanisms of PTSD&Dep through the DICER1 and the miRNA regulation pathway.",

author = "Wingo, {Aliza P.} and Almli, {Lynn M.} and Stevens, {Jennifer J.} and Torsten Klengel and Monica Uddin and Yujing Li and Bustamante, {Angela C.} and Adriana Lori and Nastassja Koen and Stein, {Dan J.} and Smith, {Alicia K.} and Aiello, {Allison E.} and Koenen, {Karestan C.} and Wildman, {Derek E.} and Sandro Galea and Bekh Bradley and Binder, {Elisabeth B.} and Peng Jin and Greg Gibson and Ressler, {Kerry J.}",

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Wingo, AP, Almli, LM, Stevens, JJ, Klengel, T, Uddin, M, Li, Y, Bustamante, AC, Lori, A, Koen, N, Stein, DJ, Smith, AK, Aiello, AE, Koenen, KC, Wildman, DE, Galea, S, Bradley, B, Binder, EB, Jin, P, Gibson, G & Ressler, KJ 2015, 'DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression', Nature Communications, vol. 6, 10106. https://doi.org/10.1038/ncomms10106

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T1 - DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression

AU - Wingo, Aliza P.

AU - Almli, Lynn M.

AU - Stevens, Jennifer J.

AU - Klengel, Torsten

AU - Uddin, Monica

AU - Li, Yujing

AU - Bustamante, Angela C.

AU - Lori, Adriana

AU - Koen, Nastassja

AU - Stein, Dan J.

AU - Smith, Alicia K.

AU - Aiello, Allison E.

AU - Koenen, Karestan C.

AU - Wildman, Derek E.

AU - Galea, Sandro

AU - Bradley, Bekh

AU - Binder, Elisabeth B.

AU - Jin, Peng

AU - Gibson, Greg

AU - Ressler, Kerry J.

PY - 2015/12/3

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N2 - DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity. Here, through genome-wide differential gene expression survey of post-traumatic stress disorder (PTSD) with comorbid depression (PTSD&Dep), we find that blood DICER1 expression is significantly reduced in cases versus controls, and replicate this in two independent cohorts. Our follow-up studies find that lower blood DICER1 expression is significantly associated with increased amygdala activation to fearful stimuli, a neural correlate for PTSD. Additionally, a genetic variant in the 3′ un-translated region of DICER1, rs10144436, is significantly associated with DICER1 expression and with PTSD&Dep, and the latter is replicated in an independent cohort. Furthermore, genome-wide differential expression survey of miRNAs in blood in PTSD&Dep reveals miRNAs to be significantly downregulated in cases versus controls. Together, our novel data suggest DICER1 plays a role in molecular mechanisms of PTSD&Dep through the DICER1 and the miRNA regulation pathway.

AB - DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity. Here, through genome-wide differential gene expression survey of post-traumatic stress disorder (PTSD) with comorbid depression (PTSD&Dep), we find that blood DICER1 expression is significantly reduced in cases versus controls, and replicate this in two independent cohorts. Our follow-up studies find that lower blood DICER1 expression is significantly associated with increased amygdala activation to fearful stimuli, a neural correlate for PTSD. Additionally, a genetic variant in the 3′ un-translated region of DICER1, rs10144436, is significantly associated with DICER1 expression and with PTSD&Dep, and the latter is replicated in an independent cohort. Furthermore, genome-wide differential expression survey of miRNAs in blood in PTSD&Dep reveals miRNAs to be significantly downregulated in cases versus controls. Together, our novel data suggest DICER1 plays a role in molecular mechanisms of PTSD&Dep through the DICER1 and the miRNA regulation pathway.

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DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression

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