Offspring of trauma survivors are more likely to develop PTSD, mood, and anxiety disorders and demonstrate endocrine and molecular alterations compared to controls. This study reports the association between parental Holocaust exposure and genome-wide gene expression in peripheral blood mononuclear cells (PBMC) from 77 Holocaust survivor offspring and 15 comparison subjects. Forty-two differentially expressed genes (DEGs) were identified in association with parental Holocaust exposure (FDR-adjusted p < 0.05); most of these genes were downregulated and co-expressed in a gene network related to immune cell functions. When both parental Holocaust exposure and maternal age at Holocaust exposure shared DEGs, fold changes were in the opposite direction. Similarly, fold changes of shared DEGs associated with maternal PTSD and paternal PTSD were in opposite directions, while fold changes of shared DEGs associated with both maternal and paternal Holocaust exposure or associated with both maternal and paternal age at Holocaust exposure were in the same direction. Moreover, the DEGs associated with parental Holocaust exposure were enriched for glucocorticoid-regulated genes and immune pathways with some of these genes mediating the effects of parental Holocaust exposure on C-reactive protein. The top gene across all analyses was MMP8, encoding the matrix metalloproteinase 8, which is a regulator of innate immunity. To conclude, this study identified a set of glucocorticoid and immune-related genes in association with parental Holocaust exposure with differential effects based on parental exposure-related factors.
Subscribe to Journal
Get full journal access for 1 year
only $38.38 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Yehuda R, Lehrner A. Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms. World Psychiatry. 2018;17:243–57.
Yahyavi ST, Zarghami M, Marwah U. A review on the evidence of transgenerational transmission of posttraumatic stress disorder vulnerability. Braz J Psychiatry. 2014;36:89–94.
Field NP, Muong S, Sochanvimean V. Parental styles in the intergenerational transmission of trauma stemming from the Khmer Rouge regime in Cambodia. Am J Orthopsychiatry. 2013;83:483–94.
Roth M, Neuner F, Elbert T. Transgenerational consequences of PTSD: risk factors for the mental health of children whose mothers have been exposed to the Rwandan genocide. Int J Ment Health Syst. 2014;8:12.
Shmotkin D, Shrira A, Goldberg S, Palgi Y. Resilience and vulnerability among aging holocaust survivors and their families: an intergenerational overview. J Intergeneration Relationsh. 2011;9:7–21.
Yehuda R, Bierer LM, Schmeidler J, Aferiat DH, Breslau I, Dolan S. Low cortisol and risk for PTSD in adult offspring of holocaust survivors. Am J Psychiatry. 2000;157:1252–9.
Lehrner A, Bierer LM, Passarelli V, Pratchett LC, Flory JD, Bader HN, et al. Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of Holocaust survivors. Psychoneuroendocrinology. 2014;40:213–20.
Bierer LM, Bader HN, Daskalakis NP, Lehrner AL, Makotkine I, Seckl JR, et al. Elevation of 11beta-hydroxysteroid dehydrogenase type 2 activity in Holocaust survivor offspring: evidence for an intergenerational effect of maternal trauma exposure. Psychoneuroendocrinology. 2014;48:1–10.
Daskalakis NP, Lehrner A, Yehuda R. Endocrine aspects of post-traumatic stress disorder and implications for diagnosis and treatment. Endocrinol Metab Clin North Am. 2013;42:503–13.
Yehuda R, Daskalakis NP, Bierer LM, Bader HN, Klengel T, Holsboer F, et al. Holocaust exposure induced intergenerational effects on FKBP5 methylation. Biol Psychiatry. 2016;80:372–80.
Bierer LM, Bader HN, Daskalakis NP, Lehrner A, Provencal N, Wiechmann T, et al. Intergenerational effects of maternal holocaust exposure on FKBP5 methylation. Am J Psychiatry. 2020;177:744–53.
Yehuda R, Daskalakis NP, Lehrner A, Desarnaud F, Bader HN, Makotkine I, et al. Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring. Am J Psychiatry. 2014;171:872–80.
Spitzer RL, Williams JBW, Gibbon M. Structured clinical interview for DSM-IV (SCID). New York State Psychiatric Institute Biometrics Research. 1995.
Beck AT. A systematic investigation of depression. Compr Psychiatry. 1961;2:163–70.
Spielberger CD. The state-trait anxiety inventory (S T A I): test manual for Form X. Consulting Psychologists Press: Palo Alto; 1968.
Bernstein DP, Stein JA, Newcomb MD, Walker E, Pogge D, Ahluvalia T, et al. Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abuse Negl. 2003;27:169–90.
Yehuda R, Labinsky E, Tischler L, Brand SR, Lavin Y, Blair W, et al. Are adult offspring reliable informants about parental PTSD? A validation study. Ann NY Acad Sci. 2006;1071:484–7.
Lin SM, Du P, Huber W, Kibbe WA. Model-based variance-stabilizing transformation for Illumina microarray data. Nucleic Acids Res. 2008;36:e11.
Mecham BH, Nelson PS, Storey JD. Supervised normalization of microarrays. Bioinformatics. 2010;26:1308–15.
Arloth J, Bader DM, Roh S, Altmann A. Re-annotator: annotation pipeline for microarray probe sequences. PLoS One. 2015;10:e0139516.
Miller JA, Cai C, Langfelder P, Geschwind DH, Kurian SM, Salomon DR, et al. Strategies for aggregating gene expression data: the collapseRows R function. BMC Bioinformatics. 2011;12:322.
Staedtler F, Hartmann N, Letzkus M, Bongiovanni S, Scherer A, Marc P, et al. Robust and tissue-independent gender-specific transcript biomarkers. Biomarkers. 2013;18:436–45.
Smyth GK. Limma: linear models for microarray data. Bioinformatics and computational biology solutions using R and Bioconductor. Springer; 2005. p. 397–420.
Steegenga WT, Boekschoten MV, Lute C, Hooiveld GJ, de Groot PJ, Morris TJ, et al. Genome-wide age-related changes in DNA methylation and gene expression in human PBMCs. Age. 2014;36:9648.
Whitney AR, Diehn M, Popper SJ, Alizadeh AA, Boldrick JC, Relman DA, et al. Individuality and variation in gene expression patterns in human blood. Proc Natl Acad Sci USA. 2003;100:1896–901.
Wehrwein EA, Joyner MJ. Regulation of blood pressure by the arterial baroreflex and autonomic nervous system. Handb Clin Neurol. 2013;117:89–102.
Nance DM, Sanders VM. Autonomic innervation and regulation of the immune system (1987-2007). Brain Behav Immun. 2007;21:736–45.
Ciobanu LG, Sachdev PS, Trollor JN, Reppermund S, Thalamuthu A, Mather KA, et al. Differential gene expression in brain and peripheral tissues in depression across the life span: a review of replicated findings. Neurosci Biobehav Rev. 2016;71:281–93.
Corkum CP, Ings DP, Burgess C, Karwowska S, Kroll W, Michalak TI. Immune cell subsets and their gene expression profiles from human PBMC isolated by Vacutainer Cell Preparation Tube (CPT) and standard density gradient. BMC Immunol. 2015;16:48.
Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA. 2001;98:5116–21.
Plaisier SB, Taschereau R, Wong JA, Graeber TG. Rank-rank hypergeometric overlap: identification of statistically significant overlap between gene-expression signatures. Nucleic Acids Res. 2010;38:e169.
Zhang B, Horvath S. A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Biol. 2005;4:Article17.
Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinform. 2008;9:559.
Langfelder P, Luo R, Oldham MC, Horvath S. Is my network module preserved and reproducible? PLoS Comput Biol. 2011;7:e1001057.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.
Korotkevich G, Sukhov V, Sergushichev A. Fast gene set enrichment analysis. bioRxiv. 2019:060012.
Arloth J, Bogdan R, Weber P, Frishman G, Menke A, Wagner KV, et al. Genetic differences in the immediate transcriptome response to stress predict risk-related brain function and psychiatric disorders. Neuron. 2015;86:1189–202.
Breen MS, Bierer LM, Daskalakis NP, Bader HN, Makotkine I, Chattopadhyay M, et al. Differential transcriptional response following glucocorticoid activation in cultured blood immune cells: a novel approach to PTSD biomarker development. Transl Psychiatry. 2019;9:201.
Kramer A, Green J, Pollard J Jr, Tugendreich S. Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics. 2014;30:523–30.
Daskalakis NP, Cohen H, Cai G, Buxbaum JD, Yehuda R. Expression profiling associates blood and brain glucocorticoid receptor signaling with trauma-related individual differences in both sexes. Proc Natl Acad Sci USA. 2014;111:13529–34.
Tingley D, Yamamoto T, Hirose K, Keele L, Imai K. Mediation: R package for causal mediation analysis. 2014.
Sobel ME. Asymptotic confidence intervals for indirect effects in structural equation models. Sociol Methodol. 1982;13:290–312.
Mascha EJ, Dalton JE, Kurz A, Saager L. Statistical grand rounds: understanding the mechanism: mediation analysis in randomized and nonrandomized studies. Anesth Analg. 2013;117:980–94.
Bliese P. Multilevel modeling in R (2.5).
Houtepen LC, Vinkers CH, Carrillo-Roa T, Hiemstra M, van Lier PA, Meeus W, et al. Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans. Nat Commun. 2016;7:10967.
Oster H, Challet E, Ott V, Arvat E, de Kloet ER, Dijk DJ, et al. The functional and clinical significance of the 24-hour rhythm of circulating glucocorticoids. Endocr Rev. 2017;38:3–45.
Chan JC, Nugent BM, Bale TL. Parental advisory: maternal and paternal stress can impact offspring neurodevelopment. Biol Psychiatry. 2018;83:886–94.
Bowers ME, Yehuda R. Intergenerational transmission of stress in humans. Neuropsychopharmacology. 2016;41:232–44.
Tobi EW, Goeman JJ, Monajemi R, Gu H, Putter H, Zhang Y, et al. DNA methylation signatures link prenatal famine exposure to growth and metabolism. Nat Commun. 2014;5:5592.
Peter CJ, Fischer LK, Kundakovic M, Garg P, Jakovcevski M, Dincer A, et al. DNA methylation signatures of early childhood malnutrition associated with impairments in attention and cognition. Biol Psychiatry. 2016;80:765–74.
Daskalakis NP, Yehuda R. Site-specific methylation changes in the glucocorticoid receptor exon 1F promoter in relation to life adversity: systematic review of contributing factors. Front Neurosci. 2014;8:369.
Jablonska-Trypuc A, Matejczyk M, Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhib Med Chem. 2016;31(sup1):177–83.
Gajendrareddy PK, Engeland CG, Junges R, Horan MP, Rojas IG, Marucha PT. MMP-8 overexpression and persistence of neutrophils relate to stress-impaired healing and poor collagen architecture in mice. Brain Behav Immun. 2013;28:44–8.
Loffek S, Schilling O, Franzke CW. Series “matrix metalloproteinases in lung health and disease”: biological role of matrix metalloproteinases: a critical balance. Eur Respir J. 2011;38:191–208.
Rodgers AB, Morgan CP, Bronson SL, Revello S, Bale TL. Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation. J Neurosci. 2013;33:9003–12.
Tobi EW, Slieker RC, Luijk R, Dekkers KF, Stein AD, Xu KM, et al. DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood. Sci Adv. 2018;4:eaao4364.
Monk C, Spicer J, Champagne FA. Linking prenatal maternal adversity to developmental outcomes in infants: the role of epigenetic pathways. Dev Psychopathol. 2012;24:1361–76.
Morgan CP, Bale TL. Early prenatal stress epigenetically programs dysmasculinization in second-generation offspring via the paternal lineage. J Neurosci. 2011;31:11748–55.
Schwaiger M, Grinberg M, Moser D, Zang JC, Heinrichs M, Hengstler JG, et al. Altered stress-induced regulation of genes in monocytes in adults with a history of childhood adversity. Neuropsychopharmacology. 2016;41:2530–40.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Daskalakis, N.P., Xu, C., Bader, H.N. et al. Intergenerational trauma is associated with expression alterations in glucocorticoid- and immune-related genes. Neuropsychopharmacol. (2020). https://doi.org/10.1038/s41386-020-00900-8