AUTHOR=Garrett Melanie E. , Qin Xue Jun , Mehta Divya , Dennis Michelle F. , Marx Christine E. , Grant Gerald A. , VA Mid-Atlantic MIRECC Workgroup , PTSD Initiative , Injury and Traumatic Stress (INTRuST) Clinical Consortium , Psychiatric Genomics Consortium PTSD Group , Stein Murray B. , Kimbrel Nathan A. , Beckham Jean C. , Hauser Michael A. , Ashley-Koch Allison E. , Brancu Mira , Calhoun Patrick S. , Dedert Eric , Elbogen Eric B. , Fairbank John A. , Hurley Robin A. , Kilts Jason D. , Kirby Angela , Martindale Sara , McDonald Scott D. , Moore Scott D. , Morey Rajendra A. , Naylor Jennifer C. , Rowland Jared , Shura Robert , Swinkels Cindy , Szabo Steven T. , Taber Katherine H. , Tupler Larry A. , Yoash-Gantz Ruth E. , McLeay Sarah , Harvey Wendy , Romaniuk Madeline , Crawford Darrell , Colquhoun David , McD Young Ross , Dwyer Miriam , Gibson John , O’Sullivan Robyn , Cooksley Graham , Strakosch Christopher , Thomson Rachel , Voisey Joanne , Lawford Bruce TITLE=Gene Expression Analysis in Three Posttraumatic Stress Disorder Cohorts Implicates Inflammation and Innate Immunity Pathways and Uncovers Shared Genetic Risk With Major Depressive Disorder JOURNAL=Frontiers in Neuroscience VOLUME=15 YEAR=2021 URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.678548 DOI=10.3389/fnins.2021.678548 ISSN=1662-453X ABSTRACT=

Posttraumatic stress disorder (PTSD) is a complex psychiatric disorder that can develop following exposure to traumatic events. The Psychiatric Genomics Consortium PTSD group (PGC-PTSD) has collected over 20,000 multi-ethnic PTSD cases and controls and has identified both genetic and epigenetic factors associated with PTSD risk. To further investigate biological correlates of PTSD risk, we examined three PGC-PTSD cohorts comprising 977 subjects to identify differentially expressed genes among PTSD cases and controls. Whole blood gene expression was quantified with the HumanHT-12 v4 Expression BeadChip for 726 OEF/OIF veterans from the Veterans Affairs (VA) Mental Illness Research Education and Clinical Center (MIRECC), 155 samples from the Injury and Traumatic Stress (INTRuST) Clinical Consortium, and 96 Australian Vietnam War veterans. Differential gene expression analysis was performed in each cohort separately followed by meta-analysis. In the largest cohort, we performed co-expression analysis to identify modules of genes that are associated with PTSD and MDD. We then conducted expression quantitative trait loci (eQTL) analysis and assessed the presence of eQTL interactions involving PTSD and major depressive disorder (MDD). Finally, we utilized PTSD and MDD GWAS summary statistics to identify regions that colocalize with eQTLs. Although not surpassing correction for multiple testing, the most differentially expressed genes in meta-analysis were interleukin-1 beta (IL1B), a pro-inflammatory cytokine previously associated with PTSD, and integrin-linked kinase (ILK), which is highly expressed in brain and can rescue dysregulated hippocampal neurogenesis and memory deficits. Pathway analysis revealed enrichment of toll-like receptor (TLR) and interleukin-1 receptor genes, which are integral to cellular innate immune response. Co-expression analysis identified four modules of genes associated with PTSD, two of which are also associated with MDD, demonstrating common biological pathways underlying the two conditions. Lastly, we identified four genes (UBA7, HLA-F, HSPA1B, and RERE) with high probability of a shared causal eQTL variant with PTSD and/or MDD GWAS variants, thereby providing a potential mechanism by which the GWAS variant contributes to disease risk. In summary, we provide additional evidence for genes and pathways previously reported and identified plausible novel candidates for PTSD. These data provide further insight into genetic factors and pathways involved in PTSD, as well as potential regions of pleiotropy between PTSD and MDD.