Single-Nucleus Transcriptome Profiling of Dorsolateral Prefrontal Cortex: Mechanistic Roles for Neuronal Gene Expression, Including the 17q21.31 Locus, in PTSD Stress Response.
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Chatzinakos Chris, Pernia Cameron D, Morrison Filomene G, Iatrou Artemis, McCullough Kenneth M, Schuler Heike, Snijders Clara, Bajaj Thomas, DiPietro Christopher P, Soliva Estruch Marina, Gassen Nils C, Anastasopoulos Constantin, Bharadwaj Rahul A, Bowlby Benjamin C, Hartmann Jakob, Maihofer Adam X, Nievergelt Caroline M, Ressler Nicholas M, Wolf Erika J, Traumatic Stress Brain Research Group, PTSD BrainOmics Project of the PsychENCODE Consortium, PTSD Working Group of the Psychiatric Genomics Consortium, Carlezon William A, Krystal John H, Kleinman Joel E, Girgenti Matthew J, Huber Bertrand R, Kellis Manolis, Logue Mark W, Miller Mark W, Ressler Kerry J, Daskalakis Nikolaos P
Аннотация
METHOD: Profiling of 32 DLPFC samples from 11 individuals with PTSD, 10 with MDD, and 11 control subjects was conducted (∼415K nuclei; >13K cells per sample). A replication sample included 15 DLPFC samples (∼160K nuclei; >11K cells per sample).
RESULTS: Differential gene expression analyses identified significant single-nucleus RNA-seq differentially expressed genes (snDEGs) in excitatory (EX) and inhibitory (IN) neurons and astrocytes, but not in other cell types or bulk tissue. MDD samples had more false discovery rate-corrected significant snDEGs, and PTSD samples had a greater replication rate. In EX and IN neurons, biological pathways that were differentially enriched in PTSD compared with MDD included glucocorticoid signaling. Furthermore, glucocorticoid signaling in induced pluripotent stem cell (iPSC)-derived cortical neurons demonstrated greater relevance in PTSD and opposite direction of regulation compared with MDD, especially in EX neurons. Many snDEGs were from the 17q21.31 locus and are particularly interesting given causal roles in disease pathogenesis and DLPFC-based neuroimaging (PTSD: ARL17B, LINC02210-CRHR1, and LRRC37A2; MDD: LRRC37A and LRP4), while others were regulated by glucocorticoids in iPSC-derived neurons (PTSD: SLC16A6, TAF1C; MDD: CDH3).
CONCLUSIONS: The study findings point to cell-type-specific mechanisms of brain stress response in PTSD and MDD, highlighting the importance of examining cell-type-specific gene expression and indicating promising novel biomarkers and therapeutic targets.