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

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

doi:10.1038/ncomms10106

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.

Highlights

DICER1 is an enzyme that generates mature microRNAs, which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity
In a subset of these participants (n 1⁄4 145–150), we had information on current alcohol and drug use disorders, bipolar disorder and current psychotic disorder assessed by the Mini International Neuropsychiatric Interview (MINI)[10] and Structure Clinical Interview for DSM-IV (SCID)[11]
We found that DICER1 mRNA level was significantly reduced in the cases relative to the controls after we adjusted simultaneously for sex, age, population substructure, current alcohol and drug use disorders, current psychotic disorder, bipolar disorder and estimated blood cell counts

Summary

Introduction

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. 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. We survey genome-wide differential gene expression profiles in blood in cases of PTSD&Dep and traumatized controls with no PTSD and no depression. We find that expression of DICER1 is significantly reduced in the cases relative to the controls, and this finding is replicated in two independent cohorts This is quite intriguing given prior possible association of DICER1 to depression-related phenotypes in humans and mice[7,8]. Given DICER1 functions, we survey genome-wide differential miRNA expression profiles in blood in a smaller discovery sample of PTSD&Dep and find two miRNAs significantly reduced in abundance in the cases. This stress-related DICER1 and miRNA regulation in blood is paralleled by recent findings of stress-related DICER1 and miRNA regulation in brain in a mouse model[8]

Objectives

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Results

Conclusion