Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood

• 成果类型: Article
• 署名作者: Daskalakis, Nikolaos P.; Iatrou, Artemis; Chatzinakos, Chris; Jajoo, Aarti; Snijders, Clara; Wylie, Dennis; Dipietro, Christopher P.; Tsatsani, Ioulia; Chen, Chia-Yen; Pernia, Cameron D.; Soliva-Estruch, Marina; Arasappan, Dhivya; Bharadwaj, Rahul A.; Collado-Torres, Leonardo; Wuchty, Stefan; Alvarez, Victor E.; Dammer, Eric B.; Deep-Soboslay, Amy; Duong, Duc M.; Eagles, Nick; Huber, Bertrand R.; Huuki, Louise; Holstein, Vincent L.; Logue, Mark W.; Lugenbuhl, Justina F.; Maihofer, Adam X.; Miller, Mark W.; Nievergelt, Caroline M.; Pertea, Geo; Ross, Deanna; Sendi, Mohammad S. E.; Sun, Benjamin B.; Tao, Ran; Tooke, James; Wolf, Erika J.; Zeier, Zane; Berretta, Sabina; Champagne, Frances A.; Hyde, Thomas; Seyfried, Nicholas T.; Shin, Joo Heon; Weinberger, Daniel R.; Nemeroff, Charles B.; Kleinman, Joel E.; Ressler, Kerry J.
• 署名单位: Harvard University; Harvard University Medical Affiliates; McLean Hospital; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; State University of New York (SUNY) System; SUNY Downstate Health Sciences University; University of Texas System; University of Texas Austin; Maastricht University; Biogen; Johns Hopkins University; Johns Hopkins Medicine; University of Miami; University of Miami; Boston University; Harvard University; Harvard University Medical Affiliates; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Boston Healthcare System; Emory University; Harvard University; Harvard University Medical Affiliates; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Boston Healthcare System; Boston University; Boston University; Boston University; University of California System; University of California San Diego; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA San Diego Healthcare System; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA San Diego Healthcare System; University of Texas System; University of Texas Austin; University of Miami; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; University of Texas System; University of Texas Austin
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8974
• DOI: 10.1126/science.adh3707
• 发表日期: 2024-05-24
• 关键词: posttraumatic-stress-disorder; individual-differences; gene-expression; immune-system; heritability; DEPRESSION; package; PATHWAY

摘要

The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the amygdala, hippocampal dentate gyrus, and medial prefrontal cortex (mPFC). Genes and exons within the mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal and synaptic regulation, and stress hormones. Multiomic factor and gene network analyses provided the underlying genomic structure. Single nucleus RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) signals in neuronal and non-neuronal cell types. Analyses of brain-blood intersections in >50,000 UK Biobank participants were conducted along with fine-mapping of the results of PTSD and MDD genome-wide association studies to distinguish risk from disease processes. Our data suggest shared and distinct molecular pathology in both disorders and propose potential therapeutic targets and biomarkers.