Epigenetic meta-analysis across three civilian cohorts identifies NRG1 and HGS as blood-based biomarkers for post-traumatic stress disorder
Abstract
Aim: Trauma exposure is a necessary, but not deterministic, contributor to post-traumatic stress disorder (PTSD). Epigenetic factors may distinguish between trauma-exposed individuals with versus without PTSD. Materials & methods: We conducted a meta-analysis of PTSD epigenome-wide association studies in trauma-exposed cohorts drawn from civilian contexts. Whole blood-derived DNA methylation levels were analyzed in 545 study participants, drawn from the three civilian cohorts participating in the PTSD working group of the Psychiatric Genomics Consortium. Results: Two CpG sites significantly associated with current PTSD in NRG1 (cg23637605) and in HGS (cg19577098). Conclusion: PTSD is associated with differential methylation, measured in blood, within HGS and NRG1 across three civilian cohorts.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 Association AP. Diagnostic and Statistical Manual of Mental Disorders. (Fifth Edition) (DSM-5). American Psychiatric Publishing, Arlington, VA, USA (2013).
- 2 . The descriptive epidemiology of commonly occurring mental disorders in the United States. Ann. Rev. Public Health 29, 115–129 (2008).
- 3 Posttraumatic stress disorder in the World Mental Health Surveys. Psychol. Med. 47, 2260–2274 (2017).
- 4 . Posttraumatic stress disorder in the National Comorbidity Survey. Arch. Gen. Psychiatry 52, 1048–1060 (1995).
- 5 . Trauma and posttraumatic stress disorder in the community: the 1996 Detroit Area Survey of Trauma. Arch. Gen. Psychiatry 55, 626–632 (1998).
- 6 The epidemiology of traumatic event exposure worldwide: results from the World Mental Health Survey Consortium. Psychol. Med. 46, 327–343 (2016).
- 7 Intra-individual change over time in DNA methylation with familial clustering. JAMA 299, 2877–2883 (2008).
- 8 . Preclinical and clinical evidence of DNA methylation changes in response to trauma and chronic stress. Chronic Stress (Thousand Oaks) 1, 1–20 (2017).
- 9 . Biological underpinnings of trauma and post-traumatic stress disorder: focusing on genetics and epigenetics. Epigenomics 8, 1553–1569 (2016).
- 10 . Epigenetic modification of hippocampal Bdnf DNA in adult rats in an animal model of post-traumatic stress disorder. J. Psychiatr. Res. 45, 919–926 (2011).
- 11 . Meta-analysis of risk factors for posttraumatic stress disorder in trauma-exposed adults. J. Consult. Clin. Psychol. 68, 317–336 (2000).
- 12 Methylation at the CpG island shore region upregulates Nr3c1 promoter activity after early-life stress. Epigenetics 10, 247–257 (2015).
- 13 Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat. Neurosci. 12, 342–348 (2009).
- 14 Insights into neuroepigenetics through human histone deacetylase PET imaging. Sci. Transl. Med. 8, 351ra106 (2016).
- 15 Epigenetic and immune function profiles associated with posttraumatic stress disorder. Proc. Natl Acad. Sci. USA 107, 9470–9475 (2010). • Early epigenome-wide association studies (EWAS) of blood-derived DNA methylation levels in relation to post-traumatic stress disorder (PTSD) in a community-based setting. Immune system-related loci figured prominently among genes showing PTSD-related differential methylation.
- 16 Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156, 700–708 (2011). • Critical EWAS of blood-derived DNA methylation levels in relation to PTSD in a civilian context that corroborated earlier findings of immune dysregulation in a community-based setting, while also reporting an increase in global DNA methylation and altered cytokine profiles in subjects with PTSD.
- 17 . Expression and methylation in posttraumatic stress disorder and resilience; evidence of a role for odorant receptors. Psychiatry Res. 245, 36–44 (2016).
- 18 Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder. Proc. Natl Acad. Sci. USA 110, 8302–8307 (2013). •• First EWAS integrating DNA methylation and expression data in relation to analyses of PTSD with and without exposure to childhood maltreatment. Distinct biological profiles of PTSD were observed among those with versus without maltreatment exposure.
- 19 An epigenome-wide DNA methylation study of PTSD and depression in World Trade Center responders. Transl. Psychiatry 7, e1158 (2017). • Recent EWAS examining PTSD and depression in the World Trade Center cohort. No false discovery rate-significant associations were identified for either disorders but pathways significant in PTSD included a regulator of synaptic plasticity, oxytocin signaling, cholinergic synapse and inflammatory disease pathways.
- 20 Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder. Mol. Psychiatry 23, 1145–1156 (2017). •• First report of a genome-scale analysis of longitudinal changes in blood DNA methylation profiles in relation to PTSD. Decreasing DNA methylation in HIST1H2APS2 and, especially, in ZFP57 and RNF39 was related to increasing PTSD symptoms over time.
- 21 . A comparison of posttraumatic stress disorder between combat casualties and civilians treated at a military burn center. J. Trauma 66, S191–S195 (2009).
- 22 . Clinical profile differences between PTSD-diagnosed military veterans and crime victims. J. Trauma Dissociation 9, 321–334 (2008).
- 23 Anatomical and functional connectivity in the default mode network of post-traumatic stress disorder patients after civilian and military-related trauma. Hum. Brain Mapp. 37, 589–599 (2016).
- 24 Post-traumatic stress disorder and smoking: a systematic review. Nicotine Tob. Res. 9, 1071–1084 (2007).
- 25 Epigenetic signatures of cigarette smoking. Circ. Cardiovasc. Genet. 9, 436–447 (2016).
- 26 The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: posttraumatic stress disorder enters the age of large-scale genomic collaboration. Neuropsychopharmacology 40, 2287–2297 (2015). • An important review paper introducing the goals of the PTSD workgroup of the Psychiatric Genomics Consortium.
- 27 . Psychometric properties of the PTSD Checklist (PCL). Behav. Res. Ther. 34, 669–673 (1996).
- 28 . Measuring intrafamily conflict and violence: the conflict tactics (CT) scales. J. Marriage Fam. 41, 75–88 (1979).
- 29 . Validity of the Childhood Trauma Questionnaire in an adolescent psychiatric population. J. Am. Acad. Child. Adolesc. Psychiatry 36, 340–348 (1997).
- 30 . The sexual abuse of Afro–American and white-American women in childhood. Child Abuse Negl. 9, 507–519 (1985).
- 31 Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 299, 1291–1305 (2008).
- 32 . Posttraumatic stress disorder in DSM-5: new criteria, new measures, and implications for assessment. Psychol. Inj. Law 7, 93–107 (2014).
- 33 The Mini International Neuropsychiatric Interview (MINI). A short diagnostic structured interview: reliability and validity according to the CIDI. Eur. Psychiatry 12, 224–231 (1997).
- 34 The validity of the Mini International Neuropsychiatric Interview (MINI) according to the SCID-P and its reliability. Eur. Psychiatry 12, 232–241 (1997).
- 35 The World Trade Center disaster and the health of workers: 5-year assessment of a unique medical screening program. Environ. Health Perspect. 1853–1858 (2006).
- 36 Epigenome-wide association of PTSD from heterogeneous cohorts with a common multi-site analysis pipeline. Am. J. Med. Genet. B Neuropsychiatr. Genet. 174(6), 619–630 (2017).
- 37 . R: a language for data analysis and graphics. J. Comput. Graphical Stat. 5, 299–314 (1996).
- 38 . CpGassoc: an R function for analysis of DNA methylation microarray data. Bioinformatics 28, 1280–1281 (2012).
- 39 Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray. Epigenetics 8, 203–209 (2013).
- 40 A β-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data. Bioinformatics 29, 189–196 (2013).
- 41 . The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 28, 882–883 (2012).
- 42 Comparison of β-value and M-value methods for quantifying methylation levels by microarray analysis. BMC Bioinformatics 11, 587 (2010).
- 43 Accounting for population stratification in DNA methylation studies. Genet. Epidemiol. 38, 231–241 (2014).
- 44 Minfi: a flexible and comprehensive bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics 30, 1363–1369 (2014).
- 45 . Accounting for cellular heterogeneity is critical in epigenome-wide association studies. Genome Biol. 15, R31 (2014).
- 46 . Limma: Linear Models for Microarray Data. Bioinformatics and Computational Biology Solutions Using R and Bioconductor. Gentleman R, Carey V, Dudoit S, Irizarry R, Huber W (Eds). Springer, NY, USA (2005).
- 47 . Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. Series B (Methodological) 57, 289–300 (1995).
- 48 . The combination of estimates from different experiments. Biometrics 10, 101–129 (1954).
- 49 . Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539–1558 (2002).
- 50 . Sample size estimation while controlling false discovery rate for microarray experiments using the size. FDR package. R J. 1, 47–53 (2009).
- 51 . Quick calculation for sample size while controlling false discovery rate with application to microarray analysis. Bioinformatics 23, 739–746 (2007).
- 52 An analysis of gene expression in PTSD implicates genes involved in the glucocorticoid receptor pathway and neural responses to stress. Psychoneuroendocrinology 57, 1–13 (2015).
- 53 DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression. Nat. Commun. 6, 10106 (2015).
- 54 Biological studies of post-traumatic stress disorder. Nat. Rev. Neurosci. 13, 769–787 (2012).
- 55 GTEx Consortium. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).
- 56 Ensembl 2018. Nucleic Acids Res. 46, D754–D761 (2018).
- 57 National Center for Biotechnology Information (NCBI). Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information (1988). www.ncbi.nlm.nih.gov/.
- 58 . Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol. Psychiatry 60, 132–140 (2006).
- 59 . Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat. Rev. Neurosci. 9, 437–452 (2008).
- 60 Specific regulation of NRG1 isoform expression by neuronal activity. J. Neurosci. 31, 8491–8501 (2011).
- 61 Inhibition of endoplasmic reticulum stress by neuregulin-1 protects against myocardial ischemia/reperfusion injury. Peptides 88, 196–207 (2017).
- 62 . Hrs and hbp: possible regulators of endocytosis and exocytosis. Biochem. Biophys. Res. Commun. 281, 1065–1069 (2001).
- 63 . Function of Hrs in endocytic trafficking and signalling. Biochem. Soc. Trans. 29, 472–475 (2001).
- 64 . Neuregulin-ERBB signaling in the nervous system and neuropsychiatric diseases. Neuron 83, 27–49 (2014).
- 65 . Disruption of the neuregulin 1 gene in the rat alters HPA axis activity and behavioral responses to environmental stimuli. Physiol. Behav. 104, 205–214 (2011).
- 66 . Sex-specific neuroendocrine and behavioral phenotypes in hypomorphic type II neuregulin 1 rats. Behav. Brain Res. 224, 223–232 (2011).
- 67 . The interaction of disrupted type II neuregulin 1 and chronic adolescent stress on adult anxiety- and fear-related behaviors. Neuroscience 249, 31–42 (2013).
- 68 . Behavioral profile of a heterozygous mutant mouse model for EGF-like domain neuregulin 1. Behav. Neurosci. 122, 748–759 (2008).
- 69 . Effects of schizophrenia risk variation in the NRG1 gene on NRG1-IV splicing during fetal and early postnatal human neocortical development. Am. J. Psychiatry 171, 979–989 (2014).
- 70 Meta-analysis reveals associations between genetic variation in the 5′ and 3′ regions of neuregulin-1 and schizophrenia. Translational Psychiatry 7, e1004 (2017).
- 71 Meta-analysis of positive and negative symptoms reveals schizophrenia modifier genes. Schizophr. Bull. 42, 279–287 (2016).
- 72 . Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia. Hum. Mol. Genet. 15, 1995–2002 (2006).
- 73 . Association of the NRG1 gene and schizophrenia: a meta-analysis. Mol. Psychiatry 11, 539–546 (2006).
- 74 Support for involvement of neuregulin 1 in schizophrenia pathophysiology. Mol. Psychiatry 10, 366–374 328 (2005).
- 75 . An association study of the neuregulin 1 gene, bipolar affective disorder and psychosis. Psychiatr. Genet. 19, 113–116 (2009).
- 76 Genetic association between NRG1 and schizophrenia, major depressive disorder, bipolar disorder in Han Chinese population. Am. J. Med. Genet. B Neuropsychiatr. Genet. 171B, 468–478 (2016).
- 77 Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability. Mol. Psychiatry 23(3), 666–673 (2017).
- 78 Search for age-related macular degeneration risk variants in Alzheimer disease genes and pathways. Neurobiol. Aging 35, 1510 e7–1510 e18 (2014).
- 79 Post-traumatic stress disorder. Nat. Rev. Dis. Primers 1, 15057 (2015). •• An elegant review that provides an overview of how PTSD affects multiple biological systems and recent advances in understanding the pathophysiology and treatment of the disorder.
- 80 . Role of ubiquitination in endocytic trafficking of G-protein-coupled receptors. Traffic 12, 137–148 (2011).
- 81 . Modulating neuromodulation by receptor membrane traffic in the endocytic pathway. Neuron 76, 22–32 (2012).
- 82 Hepatocyte growth factor regulated tyrosine kinase substrate in the peripheral development and function of B-cells. Biochem. Biophys. Res. Commun. 443, 351–356 (2014).
- 83 Exosome secretion of dendritic cells is regulated by Hrs, an ESCRT-0 protein. Biochem. Biophys. Res. Commun. 399, 384–390 (2010).
- 84 c-Cbl-dependent monoubiquitination and lysosomal degradation of gp130. Mol. Cell Biol. 28, 4805–4818 (2008).
- 85 PID: the Pathway Interaction Database. Nucleic Acids Res. 37, D674–D679 (2009).
- 86 Loss of hrs in the central nervous system causes accumulation of ubiquitinated proteins and neurodegeneration. Am. J. Pathol. 173, 1806–1817 (2008).
- 87 Innovative biomarkers in psychiatric disorders: a major clinical challenge in psychiatry. Expert Rev. Proteomics 14, 809–824 (2017).