To explain why individuals exposed to identical stressors experience divergent clinical outcomes, we determine how molecular encoding of stress modifies genetic risk for brain disorders. Analysis of post-mortem brain (n=304) revealed 8557 stress-interactive expression quantitative trait loci (eQTLs) that dysregulate expression of 915 eGenes in response to stress and lie in stress-related transcription factor binding sites. Response to stress is robust across experimental paradigms: up to 50% of stress-interactive eGenes validate in glucocorticoid-treated hiPSC-derived neurons (n=39 donors). Stress-interactive eGenes show brain region- and cell type-specificity, and, in the post-mortem brain, implicate glial and endothelial mechanisms. Stress dysregulates long-term expression of disorder-risk genes in a genotype-dependent manner; stress-interactive transcriptomic imputation uncovered 139 novel genes conferring brain disorder risk only in the context of traumatic stress. Molecular stress-encoding explains individualized responses to traumatic stress; incorporating trauma into genomic studies of brain disorders is likely to improve diagnosis, prognosis, and drug discovery.Carina Seah, Rebecca Signer, Michael Deans, Heather Bader, Tom Rusielewicz, Emily M. Hicks, Hannah Young, Alanna Cote, Kayla Townsley, Changxin Xu, Christopher J. Hunter, Barry McCarthy, Jordan Goldberg, Saunil Dobariya, Paul E. Holtzherimer, Keith A. Young, NYSCF Global Stem Cell Array® Team, Traumatic Stress Brain Research Group, Scott A. Noggle, John H. Krystal, Daniel Paull, Matthew J. Girgenti, Rachel Yehuda, Kristen J. Brennand, Laura M. HuckinsbioRxiv 2023.12.27.573459; doi: https://doi.org/10.1101/2023.12.27.573459
e. rs11586632, p=0.11, Figure 1D); it is only when 677 considering both genotype and traumatic burden that the eQTL effect emerges (interaction 678 p=3.11e-6, Figure 1B), demonstrating regulation of gene expression in a genotypeand stress679 dependent manner. Findings in both cohorts converged on variants lying in transcription factor 680 binding sites, such as GR, NFkB, and YY1. Genotype-dependent transcriptional responses to 681 stress were cell typeand brain region-specific, implicating GABAergic pathways of memory 682 consolidation and novel oligodendrocyte, microglial, and endothelial contributions to blood brain 683 barrier integrity and myelination. Moreover, this genetically regulated response to traumatic stress bioRxiv preprint doi: ; this version posted December 28, 2023.
id: c85e4714a9a8089b5e4888f78c8bd430 - page: 21
The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 684 is relevant across neuropsychiatric disorders, implicating genes involved in immune, metabolic, 685
id: 4de0de2e99e900de69271889233322bf - page: 22
686 GWAS have examined the complex genetic risk architecture underlying PTSD, most 687 recently identifying 81 loci significantly associated with risk across the genome89, explaining only 688 5.32% of heritability89, consistent with a modification of genetic risk by environmental exposures 689 (e.g., stress)90. Likewise, post-mortem brain studies (e.g. ELFN1)42,73 and transcription-wide 690 association studies (TWAS) (e.g. SNRNP35)91 identify genes associated with PTSD at baseline. 691 Here, in vivo and in vitro approaches indicate that convergent mechanisms underlie long-term 692 encoding of stress exposure. The modification of YY1 transcription factor binding sites by variants 693 conferring genotype-dependent stress response, combined with the blunting of glucocorticoid694 mediated transcriptional response via knockdown of YY1, suggest that it is a causal mediator of 695
id: 5efb70e17aee4742c37fb8ff8f48c51d - page: 22
Towards this, YY1 is a crucial factor in the development 696 and function of the central nervous system92 known to play a role in stress-sensitivity93. Functional 697 disruption of a YY1 binding site by the ADHD-associated SNP rs2271338 mediates genotype698 dependent neurodevelopmental impacts via downregulation of the ADGRL3 gene94; consistent 699 with YY1 underlying hyper-responsivity of gene targets in PTSD to glucocorticoid-induced 700 stress31. 701 Non-neuronal cells, particularly microglia, endothelial cells, and oligodendrocytes, were 702 enriched for genotype-dependent molecular encoding of stress, consistent with the neuroimmune 703 hypothesis of stress-related brain adaptations. Moreover, blood brain barrier integrity, a known 704 mediator of cognition that when disrupted in associated with cognitive decline95, may also 705
id: a9cbc827b8b65123da66b0251a60e059 - page: 22