Date of Award

Fall 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Computational Biology and Bioinformatics

First Advisor

Zhao, Hongyu

Abstract

Posttraumatic stress disorder (PTSD) affects approximately 8% of the general population, with higher rates in those exposed to extreme stress, including combat veterans or victims of sexual assault. Despite extensive study of the neurobiological correlates of PTSD, little is known about its molecular substrates. In Chapter 1, differential gene expression and network analyses of 4 prefrontal cortex (PFC) postmortem subregions of male and female PTSD subjects demonstrates extensive remodeling of the transcriptomic landscape. The data revealed a highly connected down-regulated set of interneuron transcripts in the most significant gene network associated with PTSD and integration of this data with genotype data from the largest PTSD GWAS identified the interneuron synaptic gene ELFN1 as conferring significant genetic liability for PTSD. Marked sexual dimorphism was also identified in the transcriptomic signatures that could contribute to the higher rates of PTSD in women. Comparison with a matched major depressive disorder (MDD) cohort revealed significant divergence between the molecular profiles of subjects with PTSD and MDD despite their high comorbidity. This analysis provides convergent systems-level evidence of genomic networks within the PFC that contribute to the pathophysiology of PTSD in humans. In Chapter 2, I bring the focus to the sex specificity of PTSD. While a definitive understanding of the molecular pathology of PTSD is far from current reality, it has become increasingly clear that many of the molecular effects of PTSD are sex-specific. Woman are twice as likely as men to develop PTSD after a traumatic event and neurobiological evidence suggest structural differences between the brains of males versus females with PTSD. In Chapter 2, the current state of the field of PTSD genomics focusing on the effect of sex was presented. The review provides an overview of sex-different heritability of PTSD, how sex-different gene regulation impacts the PTSD brain and what is known about genomic regulation that is dysregulated in specific cell types in PTSD. Recent advances in genomic technologies have begun to shed light on the sex-specific molecular determinants of PTSD which seem to be governed predominantly by dysfunction of GABAergic signaling and immune function. In Chapter 3, I present findings from the first genome-wide microRNA (miRNA) expression profiling and follow-up proteomics analysis in post-mortem PTSD brain. It was identified that miRNAs and co-regulated modules that were disturbed in PTSD. The results confirmed regulatory relationships between several differentially expressed miRNAs and their putative target proteins and protein co-expression modules. Integrative analysis identified miRNA hsa-mir-589 as a core regulating miRNA in the translational process of disease-associated protein modules for PTSD. In addition, significant enrichment of genetic risk genes for other neurodegenerative and psychiatric disorders was identified within these co-expression modules, indicating a shared molecular pathology. These findings support a role for miRNA dysfunction in the pathological alterations of PTSD and provide a novel framework for future studies integrating small RNA transcriptomics with proteomic profiling. In conclusion, this dissertation presents three chapters of work that highlight the most recent discoveries in the field of psychiatric genomics, especially those of MDD and PTSD. Disease-specific transcripts, proteins and their regulator miRNAs were identified. Converging sex dimorphisms exhibited in the multi-omics data of these diseases were carefully reviewed and investigated. Moreover, network and pathway analyses have pointed to gene modules and biological pathways underlying the pathological mechanisms of MDD and PTSD. These findings are a latest part of the ongoing effort that I share with numerous academic and clinical researchers in our journey to fully elucidate the molecular mechanisms of the psychiatric disorders and our fight against them.

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