TY - JOUR
T1 - Single-Nucleus Transcriptome Profiling of Dorsolateral Prefrontal Cortex
T2 - Mechanistic Roles for Neuronal Gene Expression, Including the 17q21.31 Locus, in PTSD Stress Response
AU - Chatzinakos, Chris
AU - Pernia, Cameron D
AU - Morrison, Filomene G
AU - Iatrou, Artemis
AU - McCullough, Kenneth M
AU - Schuler, Heike
AU - Snijders, Clara
AU - Bajaj, Thomas
AU - DiPietro, Christopher P
AU - Soliva Estruch, Marina
AU - Gassen, Nils C
AU - Anastasopoulos, Constantin
AU - Bharadwaj, Rahul A
AU - Bowlby, Benjamin C
AU - Hartmann, Jakob
AU - Maihofer, Adam X
AU - Nievergelt, Caroline M
AU - Ressler, Nicholas M
AU - Wolf, Erika J
AU - Carlezon, William A
AU - Krystal, John H
AU - Kleinman, Joel E
AU - Girgenti, Matthew J
AU - Huber, Bertrand R
AU - Kellis, Manolis
AU - Logue, Mark W
AU - Miller, Mark W
AU - Ressler, Kerry J
AU - Daskalakis, Nikolaos P
AU - Traumatic Stress Brain Research Group
AU - PTSD BrainOmics Project of the PsychENCODE Consortium
AU - PTSD Working Group of the Psychiatric Genomics Consortium
PY - 2023/10/1
Y1 - 2023/10/1
N2 - OBJECTIVE: Multidisciplinary studies of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) implicate the dorsolateral prefrontal cortex (DLPFC) in disease risk and pathophysiology. Postmortem brain studies have relied on bulk-tissue RNA sequencing (RNA-seq), but single-cell RNA-seq is needed to dissect cell-type-specific mechanisms. The authors conducted the first single-nucleus RNA-seq postmortem brain study in PTSD to elucidate disease transcriptomic pathology with cell-type-specific resolution. 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.
AB - OBJECTIVE: Multidisciplinary studies of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) implicate the dorsolateral prefrontal cortex (DLPFC) in disease risk and pathophysiology. Postmortem brain studies have relied on bulk-tissue RNA sequencing (RNA-seq), but single-cell RNA-seq is needed to dissect cell-type-specific mechanisms. The authors conducted the first single-nucleus RNA-seq postmortem brain study in PTSD to elucidate disease transcriptomic pathology with cell-type-specific resolution. 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.
KW - Biological Markers
KW - Genetics/Genomics
KW - Glucocorticoid
KW - Major Depressive Disorder
KW - Posttraumatic Stress Disorder
KW - RNA Sequencing
U2 - 10.1176/appi.ajp.20220478
DO - 10.1176/appi.ajp.20220478
M3 - Article
SN - 1535-7228
VL - 180
SP - 739
EP - 754
JO - The American journal of psychiatry
JF - The American journal of psychiatry
IS - 10
ER -