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Author Notes:

Email: kressler@mclean@harvard.edu

A.P.W. formulated the research question, performed the data analysis and wrote the initial version of the paper. K.J.R. obtained funding, oversees the GTP study, contacted collaborators and revised the paper. All authors edited and commented on the manuscript.

G.G. provided consultant on the data analysis. B.B. contributed to conducting the GTP study. E.B.B. contributed to generating gene expression data. L.M.A. contributed to the genetic data analysis.

A.L. performed the genetic replication analysis in the Drakenstein cohort. A.C.B. and M.U. performed the gene expression replication analysis. J.J.S. performed and wrote the fMRI data analysis.

A.K.S. contributed to performing cell count estimate. T.K. performed the validation assays for DICER1 and miRNA expression and contributed to the design of the miRNA study.

D.J.S. and N.K. obtained funding, conducted the study, and obtained genetic data for the South African cohort.

A.E.A., K.C.K., D.E.W., M.U. and S.G. contributed to obtain funding and carrying out the DNHS. P.J. and Y.L. contributed to designing and conducting the miRNA study.

We appreciate the technical support of all of the staff and volunteers of the Grady Trauma Project, particularly Kimberly Kerley, BA, Jennifer Leveille, BA, Kristina Mercer, MS, Jordan Laird, BS, Allen W. Graham, BA, Angelo Brown and Claudia Klengel, MD.

We thank Charles Gillespie, MD/PhD, Ann Schwartz, MD and Tamara Weiss, MD for medical support, Divya Mehta, PhD for contributing to generation of gene expression data, Abigail Lott, PhD for maintaining the database.

Additionally, we thank Nirav Patel, MS, and Gregory Tharp, MS at the Emory Yerkes Genomics Core for technical support with the small RNA sequencing and data analysis.

We thank the participants of the Grady Trauma Project for their time and effort.

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Research Funding:

This study was supported in part by the Department of Veterans Affairs Career Development Award IK2CX000601 and the NARSAD Young Investigator Award (to A.P.W.). This work was primarily supported by the National Institutes of Mental Health (MH096764 and MH071537 to K.J.R.).

Support was also received from Emory and Grady Memorial Hospital General Clinical Research Center, National Institutes of Health (NIH). The Drakenstein study was funded by the Bill and Melinda Gates Foundation (1017641), the NIH (R21 MH098662) and the Medical Research Council (MRC) of South Africa. The DNHS was funded by DA022720 and RC1MH088283 (to A.E.A.).

T.K. is supported by a NARSAD YI Grant and an EMBO Long-Term Fellowship. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • GENOME-WIDE ASSOCIATION
  • DNA-DAMAGE
  • CHILDHOOD MALTREATMENT
  • PSYCHIATRIC-DISORDERS
  • GENE-EXPRESSION
  • SEQUENCING DATA
  • IMMUNE-SYSTEM
  • HEART-DISEASE
  • UP-REGULATION
  • BRAIN

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

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Journal Title:

Nature Communications

Volume:

Volume 6

Publisher:

, Pages 10106-10106

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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