Common genetic variation impacts molecular stress response in the brain

The mechanisms underlying the molecular encoding of stress in modifying complex genetic risk for brain disorders have not been well elucidated. Towards explaining why individuals exposed to identical stressors may present with divergent clinical outcomes, we explore genotype by environment (G x E) interactions, asking whether common genetic risk factors determine individual differences in molecular encoding of stress response on a genome-wide scale. Analysis of post-mortem brain tissue revealed non-coding stress-interactive expression quantitative trait loci (eQTLs) that regulate transcriptomic responses to stress in a genotype-dependent manner. In total, we find 8557 eQTLs where interactions with prior traumatic exposures impact expression of 915 eGenes in the post-mortem brain (n=304). These effects are cell type- and brain region- specific, persisting for up to 45 years post-trauma. These dynamic variants tend to lie in stress-related transcription factor binding sites. Up to 50% of stress-interactive eGenes validate in hiPSC-derived glutamatergic and GABAergic neurons treated with glucocorticoids (n=39 donors), unexpectedly demonstrating that response to stress (whether trauma in vivo or glucocorticoid treatment in vitro) is highly robust across experimental paradigms. Stress-interactive eGenes show cell type-specificity, and, in the post-mortem brain, implicate glial and endothelial mechanisms. The neural response to stress broadly dysregulates long-term expression of neuropsychiatric disorder and neurodegenerative disease risk genes in a genotype-dependent manner; in fact, stress-aware transcriptomic imputation uncovered 124 novel psychiatric and 15 novel neurodegenerative risk genes that conferred risk only in the context of traumatic stress. Convergent genetic mechanisms of molecular stress-encoding explain individualized responses to traumatic stress; thus, incorporating trauma burden into genomic studies of brain disease, disorders, and traits is likely to improve diagnosis, prognosis, and drug discovery. ### Competing Interest Statement J.H.K. has consulting agreements (less than US$10,000 per year) with the following: Aptinyx, Inc. Biogen, Idec, MA, Bionomics, Limited (Australia), Boehringer Ingelheim International, Epiodyne, Inc., EpiVario, Inc., Janssen Research & Development, Jazz Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc., Spring Care, Inc., Sunovion Pharmaceuticals, Inc.; is the co-founder for Freedom Biosciences, Inc.; serves on the scientific advisory boards of Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc. (Clinical Advisory Board), Cerevel Therapeutics, LLC, Delix Therapeutics, Inc., Eisai, Inc., EpiVario, Inc., Jazz Pharmaceuticals, Inc., Neumora Therapeutics, Inc. , Neurocrine Biosciences, Inc., Novartis Pharmaceuticals Corporation, PsychoGenics, Inc., Takeda Pharmaceuticals, Tempero Bio, Inc., Terran Biosciences, Inc..; has stock options with Biohaven Pharmaceuticals Medical Sciences, Cartego Therapeutics, Damona Pharmaceuticals, Delix Therapeutics, EpiVario, Inc., Neumora Therapeutics, Inc., Rest Therapeutics, Tempero Bio, Inc., Terran Biosciences, Inc., Tetricus, Inc.; and is editor of Biological Psychiatry with income greater than $10,000. K.J.B. is on the scientific advisory board of Neuro Pharmaka and Rumi Scientific. P.E.H receives royalties from Oxford University Press and UpToDate.