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Recent Genetics and Epigenetics Approaches to PTSD

  • Nikolaos P. Daskalakis
  • Chuda M. Rijal
  • Christopher King
  • Laura M. Huckins
  • Kerry J. Ressler
Disaster Psychiatry: Trauma, PTSD, and Related Disorders (MJ Friedman)
Part of the following topical collections:
  1. Topical Collection on Disaster Psychiatry: Trauma, PTSD, and Related Disorders

Abstract

Purpose of Review

Following a life-threatening traumatic exposure, about 10% of those exposed are at considerable risk for developing posttraumatic stress disorder (PTSD), a severe and disabling syndrome characterized by uncontrollable intrusive memories, nightmares, avoidance behaviors, and hyperarousal in addition to impaired cognition and negative emotion symptoms. This review will explore recent genetic and epigenetic approaches to PTSD that explain some of the differential risk following trauma exposure.

Recent Findings

A substantial portion of the variance explaining differential risk responses to trauma exposure may be explained by differential inherited and acquired genetic and epigenetic risk. This biological risk is complemented by alterations in the functional regulation of genes via environmentally induced epigenetic changes, including prior childhood and adult trauma exposure.

Summary

This review will cover recent findings from large-scale genome-wide association studies as well as newer epigenome-wide studies. We will also discuss future “phenome-wide” studies utilizing electronic medical records as well as targeted genetic studies focusing on mechanistic ways in which specific genetic or epigenetic alterations regulate the biological risk for PTSD.

Keywords

PTSD Genetics Epigenetics GWAS DNA methylation 

Notes

Acknowledgements

The work was supported by NIH grants R01MH108665, R01MH094757, and R21MH112956 to KJR, a NARSAD Award to NPD, and the Frazier Foundation Grant for Mood and Anxiety Research to KJR.

Compliance with Ethical Standards

Conflict of Interest

Nikolaos P. Daskalakis, Chuda M. Rijal, Christopher King, and Laura M. Huckins declare no conflict of interest.

Kerry J. Ressler is on the Scientific Advisory Boards for Resilience Therapeutics, Sheppard Pratt-Lieber Research Institute, Laureate Institute for Brain Research, The Army STARRS Project, UCSD VA Center of Excellence for Stress and Mental Health—CESAMH, and the Anxiety and Depression Association of America. He provides fee-for-service consultation for Biogen and Resilience Therapeutics. He holds patents for use of D-cycloserine and psychotherapy, targeting PAC1 receptor for extinction, targeting tachykinin 2 for prevention of fear, targeting angiotensin to improve extinction of fear. Dr. Ressler is also founding member of Extinction Pharmaceuticals to develop d-Cycloserine to augment the effectiveness of psychotherapy, for which he has received no equity or income within the last 3 years. He receives or has received research funding from NIMH, HHMI, NARSAD, and the Burroughs Wellcome Foundation.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Bonanno GA. Loss, trauma, and human resilience: have we underestimated the human capacity to thrive after extremely aversive events? Am Psychol. 2004;59(1):20–8.CrossRefPubMedGoogle Scholar
  2. 2.
    • Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995;52(12):1048–60.  https://doi.org/10.1001/archpsyc.1995.03950240066012. One of the most definitive epidemiology studies of PTSD prevalence. CrossRefPubMedGoogle Scholar
  3. 3.
    Hoge CW, Castro CA, Messer SC, McGurk D, Cotting DI, Koffman RL. Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care. N Engl J Med. 2004;351(1):13–22.  https://doi.org/10.1056/NEJMoa040603.CrossRefPubMedGoogle Scholar
  4. 4.
    Nemeroff CB, Bremner JD, Foa EB, Mayberg HS, North CS, Stein MB. Posttraumatic stress disorder: a state-of-the-science review. J Psychiatr Res. 2006;40(1):1–21.  https://doi.org/10.1016/j.jpsychires.2005.07.005.CrossRefPubMedGoogle Scholar
  5. 5.
    Griffiths AJF. Introduction to genetic analysis. Freeman and Company: W. H; 2012.Google Scholar
  6. 6.
    Sweatt JD, Nestler EJ, Meaney MJ, Akbarian S. Chapter 1-an overview of the molecular basis of epigenetics. In: Epigenetic regulation in the nervous system. San Diego: Academic Press; 2013. p. 3–33.CrossRefGoogle Scholar
  7. 7.
    Dias BG, Maddox S, Klengel T, Ressler KJ. Epigenetic mechanisms underlying learning and the inheritance of learned behaviors. Trends Neurosci. 2015;38(2):96–107.  https://doi.org/10.1016/j.tins.2014.12.003.CrossRefPubMedGoogle Scholar
  8. 8.
    • True WR, Rice J, Eisen SA, Heath AC, Goldberg J, Lyons MJ, et al. A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. Arch Gen Psychiatry. 1993;50(4):257–64. One of the initial seminal manuscripts documenting the heritability of risk for PTSD following trauma. CrossRefPubMedGoogle Scholar
  9. 9.
    Stein MB, Jang KL, Taylor S, Vernon PA, Livesley WJ. Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: a twin study. Am J Psychiatry. 2002;159(10):1675–81.  https://doi.org/10.1176/appi.ajp.159.10.1675.CrossRefPubMedGoogle Scholar
  10. 10.
    Sartor CE, Grant JD, Lynskey MT, McCutcheon VV, Waldron M, Statham DJ, et al. Common heritable contributions to low-risk trauma, high-risk trauma, posttraumatic stress disorder, and major depression. Arch Gen Psychiatry. 2012;69(3):293–9.  https://doi.org/10.1001/archgenpsychiatry.2011.1385.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Sartor CE, McCutcheon VV, Pommer NE, Nelson EC, Grant JD, Duncan AE, et al. Common genetic and environmental contributions to post-traumatic stress disorder and alcohol dependence in young women. Psychol Med. 2011;41(7):1497–505.  https://doi.org/10.1017/S0033291710002072.CrossRefPubMedGoogle Scholar
  12. 12.
    •• Duncan LE, Ratanatharathorn A, Aiello AE, Almli LM, Amstadter AB, Ashley-Koch AE, et al. Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability. Mol Psychiatry. 2017;  https://doi.org/10.1038/mp.2017.77. The largest GWAS of PTSD to date published by the Psychiatric Genomics Consortium—PTSD Working Group.
  13. 13.
    Daskalakis NP, Lehrner A, Yehuda R. Endocrine aspects of post-traumatic stress disorder and implications for diagnosis and treatment. Endocrinol Metab Clin N Am. 2013;42(3):503–13.  https://doi.org/10.1016/j.ecl.2013.05.004.CrossRefGoogle Scholar
  14. 14.
    Yehuda R, Golier JA, Yang RK, Tischler L. Enhanced sensitivity to glucocorticoids in peripheral mononuclear leukocytes in posttraumatic stress disorder. Biol Psychiatry. 2004;55(11):1110–6.  https://doi.org/10.1016/j.biopsych.2004.02.010.CrossRefPubMedGoogle Scholar
  15. 15.
    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 U S A. 2014;111(37):13529–34.  https://doi.org/10.1073/pnas.1401660111.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    • Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299(11):1291–305.  https://doi.org/10.1001/jama.299. One of the most robust demonstrations of a mechanistic pathway mediating gene x environmental risk for PTSD. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Mehta D, Gonik M, Klengel T, Rex-Haffner M, Menke A, Rubel J, et al. Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: evidence from endocrine and gene expression studies. Arch Gen Psychiatry. 2011;68(9):901–10.  https://doi.org/10.1001/archgenpsychiatry.2011.50.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Binder EB. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology. 2009;34(Suppl 1):S186–95.  https://doi.org/10.1016/j.psyneuen.2009.05.021.CrossRefPubMedGoogle Scholar
  19. 19.
    •• Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM, et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci. 2013;16(1):33–41.  https://doi.org/10.1038/nn.3275. The most mechanistic study to-date demonstrating the intersection of genetic risk and acquired epigenetic traits on the effects of glucocorticoid responsiveness of GxE effects on the FKBP5 protein in regulating HPA axis function. CrossRefPubMedGoogle Scholar
  20. 20.
    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(5):372–80.  https://doi.org/10.1016/j.biopsych.2015.08.005.CrossRefPubMedGoogle Scholar
  21. 21.
    Yehuda R, Daskalakis NP, Desarnaud F, Makotkine I, Lehrner AL, Koch E, et al. Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD. Front Psychiatry. 2013;4:118.  https://doi.org/10.3389/fpsyt.2013.00118.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Sawamura T, Klengel T, Armario A, Jovanovic T, Norrholm SD, Ressler KJ, et al. Dexamethasone treatment leads to enhanced fear extinction and dynamic Fkbp5 regulation in amygdala. Neuropsychopharmacology. 2016;41(3):832–46.  https://doi.org/10.1038/npp.2015.210.CrossRefPubMedGoogle Scholar
  23. 23.
    • Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, et al. Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature. 2011;470(7335):492–7.  https://doi.org/10.1038/nature09856. With the Mercer et al., 2016, paper below, among the first to show a mechanistic process by which estrogen modulation of a risk-related gene pathway may regulate trauma response and PTSD symptoms. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Mercer KB, Dias B, Shafer D, Maddox SA, Mulle JG, Hu P, et al. Functional evaluation of a PTSD-associated genetic variant: estradiol regulation and ADCYAP1R1. Transl Psychiatry. 2016;6(12):e978.  https://doi.org/10.1038/tp.2016.241.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Breslau N, Kessler RC, Chilcoat HD, Schultz LR, Davis GC, Andreski P. Trauma and posttraumatic stress disorder in the community: the 1996 Detroit area survey of trauma. Arch Gen Psychiatry. 1998;55(7):626–32.CrossRefPubMedGoogle Scholar
  26. 26.
    Ramikie TS, Ressler KJ. Stress-related disorders, pituitary adenylate cyclase-activating peptide (PACAP)ergic system, and sex differences. Dialogues Clin Neurosci. 2016;18(4):403–13.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Boscarino JA. Posttraumatic stress disorder and physical illness: results from clinical and epidemiologic studies. Ann N Y Acad Sci. 2004;1032:141–53.  https://doi.org/10.1196/annals.1314.011.CrossRefPubMedGoogle Scholar
  28. 28.
    Passos IC, Vasconcelos-Moreno MP, Costa LG, Kunz M, Brietzke E, Quevedo J, et al. Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression. Lancet Psychiat. 2015;2(11):1002–12.  https://doi.org/10.1016/S2215-0366(15)00309-0.CrossRefGoogle Scholar
  29. 29.
    Klaassens ER, Giltay EJ, Cuijpers P, van Veen T, Zitman FG. Adulthood trauma and HPA-axis functioning in healthy subjects and PTSD patients: a meta-analysis. Psychoneuroendocrinology. 2012;37(3):317–31.  https://doi.org/10.1016/j.psyneuen.2011.07.003.CrossRefPubMedGoogle Scholar
  30. 30.
    Daskalakis NP, Cohen H, Nievergelt CM, Baker DG, Buxbaum JD, Russo SJ, et al. New translational perspectives for blood-based biomarkers of PTSD: From glucocorticoid to immune mediators of stress susceptibility. Exp Neurol. 2016;284(Pt B):133–40.  https://doi.org/10.1016/j.expneurol.2016.07.024.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Breen MS, Maihofer AX, Glatt SJ, Tylee DS, Chandler SD, Tsuang MT, et al. Gene networks specific for innate immunity define post-traumatic stress disorder. Mol Psychiatry. 2015;20(12):1538–45.  https://doi.org/10.1038/mp.2015.9.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Glatt SJ, Tylee DS, Chandler SD, Pazol J, Nievergelt CM, Woelk CH, et al. Blood-based gene-expression predictors of PTSD risk and resilience among deployed marines: a pilot study. Am J Med Genet B Neuropsychiatr Genet. 2013;162B(4):313–26.  https://doi.org/10.1002/ajmg.b.32167.CrossRefPubMedGoogle Scholar
  33. 33.
    van Zuiden M, Heijnen CJ, Maas M, Amarouchi K, Vermetten E, Geuze E, et al. Glucocorticoid sensitivity of leukocytes predicts PTSD, depressive and fatigue symptoms after military deployment: a prospective study. Psychoneuroendocrinology. 2012;37(11):1822–36.  https://doi.org/10.1016/j.psyneuen.2012.03.018.CrossRefPubMedGoogle Scholar
  34. 34.
    Eraly SA, Nievergelt CM, Maihofer AX, Barkauskas DA, Biswas N, Agorastos A, et al. Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry. 2014;71(4):423–31.  https://doi.org/10.1001/jamapsychiatry.2013.4374.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Michopoulos V, Rothbaum AO, Jovanovic T, Almli LM, Bradley B, Rothbaum BO, et al. Association of CRP genetic variation and CRP level with elevated PTSD symptoms and physiological responses in a civilian population with high levels of trauma. Am J Psychiatry. 2015;172(4):353–62.  https://doi.org/10.1176/appi.ajp.2014.14020263.CrossRefPubMedGoogle Scholar
  36. 36.
    Ligthart S, Marzi C, Aslibekyan S, Mendelson MM, Conneely KN, Tanaka T, et al. DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. Genome Biol. 2016;17(1):255.  https://doi.org/10.1186/s13059-016-1119-5.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Miller MW, Maniates H, Wolf EJ, Logue MW, Schichman SA, Stone A, et al. CRP polymorphisms and DNA methylation of the AIM2 gene influence associations between trauma exposure, PTSD, and C-reactive protein. Brain Behav Immun. 2018;67:194–202.  https://doi.org/10.1016/j.bbi.2017.08.022.CrossRefPubMedGoogle Scholar
  38. 38.
    Zass LJ, Hart SA, Seedat S, Hemmings SM, Malan-Muller S. Neuroinflammatory genes associated with post-traumatic stress disorder: implications for comorbidity. Psychiatr Genet. 2017;27(1):1–16.  https://doi.org/10.1097/YPG.0000000000000143.CrossRefPubMedGoogle Scholar
  39. 39.
    Logue MW, Baldwin C, Guffanti G, Melista E, Wolf EJ, Reardon AF, et al. A genome-wide association study of post-traumatic stress disorder identifies the retinoid-related orphan receptor alpha (RORA) gene as a significant risk locus. Mol Psychiatry. 2013;18(8):937–42.  https://doi.org/10.1038/mp.2012.113.CrossRefPubMedGoogle Scholar
  40. 40.
    Xie P, Kranzler HR, Yang C, Zhao H, Farrer LA, Gelernter J. Genome-wide association study identifies new susceptibility loci for posttraumatic stress disorder. Biol Psychiatry. 2013;74(9):656–63.  https://doi.org/10.1016/j.biopsych.2013.04.013.CrossRefPubMedGoogle Scholar
  41. 41.
    • Guffanti G, Galea S, Yan L, Roberts AL, Solovieff N, Aiello AE, et al. Genome-wide association study implicates a novel RNA gene, the lincRNA AC068718.1, as a risk factor for post-traumatic stress disorder in women. Psychoneuroendocrinology. 2013;38(12):3029–38.  https://doi.org/10.1016/j.psyneuen.2013.08.014. One of the early positive GWAS findings for PTSD demonstrating a possible role for long noncoding RNAs. CrossRefPubMedGoogle Scholar
  42. 42.
    Wolf EJ, Rasmusson AM, Mitchell KS, Logue MW, Baldwin CT, Miller MW. A genome-wide association study of clinical symptoms of dissociation in a trauma-exposed sample. Depress Anxiety. 2014;31(4):352–60.  https://doi.org/10.1002/da.22260.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    • Nievergelt CM, Maihofer AX, Mustapic M, Yurgil KA, Schork NJ, Miller MW, et al. Genomic predictors of combat stress vulnerability and resilience in U.S. marines: a genome-wide association study across multiple ancestries implicates PRTFDC1 as a potential PTSD gene. Psychoneuroendocrinology. 2015;51:459–71.  https://doi.org/10.1016/j.psyneuen.2014.10.017. A robust GWAS of PTSD in a Marine military cohort. CrossRefPubMedGoogle Scholar
  44. 44.
    Almli LM, Stevens JS, Smith AK, Kilaru V, Meng Q, Flory J, et al. A genome-wide identified risk variant for PTSD is a methylation quantitative trait locus and confers decreased cortical activation to fearful faces. Am J Med Genet B Neuropsychiatr Genet. 2015;168B(5):327–36.  https://doi.org/10.1002/ajmg.b.32315.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Ashley-Koch AE, Garrett ME, Gibson J, Liu Y, Dennis MF, Kimbrel NA, et al. Genome-wide association study of posttraumatic stress disorder in a cohort of Iraq-Afghanistan era veterans. J Affect Disord. 2015;184:225–34.  https://doi.org/10.1016/j.jad.2015.03.049.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    • Stein MB, Chen CY, Ursano RJ, Cai T, Gelernter J, Heeringa SG, et al. Genome-wide association studies of posttraumatic stress disorder in 2 cohorts of US Army soldiers. JAMA Psychiatry. 2016;73(7):695–704.  https://doi.org/10.1001/jamapsychiatry.2016.0350. A robust GWAS of PTSD in two military cohorts. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Kilaru V, Iyer SV, Almli LM, Stevens JS, Lori A, Jovanovic T, et al. Genome-wide gene-based analysis suggests an association between Neuroligin 1 (NLGN1) and post-traumatic stress disorder. Transl Psychiatry. 2016;6:e820.  https://doi.org/10.1038/tp.2016.69.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Melroy-Greif WE, Wilhelmsen KC, Yehuda R, Ehlers CL. Genome-wide association study of post-traumatic stress disorder in two high-risk populations. Twin Res Hum Genet. 2017;20(3):197–207.  https://doi.org/10.1017/thg.2017.12.CrossRefPubMedGoogle Scholar
  49. 49.
    Daskalakis NP, Provost AC, Hunter RG, Guffanti G. Noncoding RNAs: stress, glucocorticoids and PTSD. Biol Psychiatry. 2018;Google Scholar
  50. 50.
    Akashi M, Takumi T. The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1. Nat Struct Mol Biol. 2005;12(5):441–8.  https://doi.org/10.1038/nsmb925.CrossRefPubMedGoogle Scholar
  51. 51.
    El Helou J, Belanger-Nelson E, Freyburger M, Dorsaz S, Curie T, La Spada F, et al. Neuroligin-1 links neuronal activity to sleep-wake regulation. Proc Natl Acad Sci U S A. 2013;110(24):9974–9.  https://doi.org/10.1073/pnas.1221381110.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Boland EM, Ross RJ. Recent advances in the study of sleep in the anxiety disorders, obsessive-compulsive disorder, and posttraumatic stress disorder. Psychiatr Clin North Am. 2015;38(4):761–76.  https://doi.org/10.1016/j.psc.2015.07.005.CrossRefPubMedGoogle Scholar
  53. 53.
    Logue MW, Amstadter AB, Baker DG, Duncan L, Koenen KC, Liberzon I, et al. The psychiatric genomics consortium posttraumatic stress disorder workgroup: posttraumatic stress disorder enters the age of large-scale genomic collaboration. Neuropsychopharmacology. 2015;40(10):2287–97.  https://doi.org/10.1038/npp.2015.118.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    • Uddin M, Aiello AE, Wildman DE, Koenen KC, Pawelec G, de Los Santos R, et al. Epigenetic and immune function profiles associated with posttraumatic stress disorder. Proc Natl Acad Sci U S A. 2010;107(20):9470–5.  https://doi.org/10.1073/pnas.0910794107. Evidence that epigenetic regulation of peripheral immune processes are associated with PTSD risk. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Smith AK, Conneely KN, Kilaru V, Mercer KB, Weiss TE, Bradley B, et al. Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. Am J Med Genet B Neuropsychiatr Genet. 2011;156B(6):700–8.  https://doi.org/10.1002/ajmg.b.31212.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Uddin M, Galea S, Chang SC, Koenen KC, Goldmann E, Wildman DE, et al. Epigenetic signatures may explain the relationship between socioeconomic position and risk of mental illness: preliminary findings from an urban community-based sample. Biodemography Soc Biol. 2013;59(1):68–84.  https://doi.org/10.1080/19485565.2013.774627.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    • Mehta D, Klengel T, Conneely KN, Smith AK, Altmann A, Pace TW, et al. Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder. Proc Natl Acad Sci U S A. 2013;110(20):8302–7.  https://doi.org/10.1073/pnas.1217750110. Demonstration that environmental trauma in the form of childhood maltreatment leads to different epigenetic profiles and likely distinct biological subgroups of adult PTSD. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Mehta D, Bruenig D, Carrillo-Roa T, Lawford B, Harvey W, Morris CP, et al. Genomewide DNA methylation analysis in combat veterans reveals a novel locus for PTSD. Acta Psychiatr Scand. 2017;136(5):493–505.  https://doi.org/10.1111/acps.12778.CrossRefPubMedGoogle Scholar
  59. 59.
    Rutten BPF, Vermetten E, Vinkers CH, Ursini G, Daskalakis NP, Pishva E, et al. Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder. Mol Psychiatry. 2017;  https://doi.org/10.1038/mp.2017.120.
  60. 60.
    Hammamieh R, Chakraborty N, Gautam A, Muhie S, Yang R, Donohue D, et al. Whole-genome DNA methylation status associated with clinical PTSD measures of OIF/OEF veterans. Transl Psychiatry. 2017;7(7):e1169.  https://doi.org/10.1038/tp.2017.129.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Kuan PF, Waszczuk MA, Kotov R, Marsit CJ, Guffanti G, Gonzalez A, et al. An epigenome-wide DNA methylation study of PTSD and depression in world trade center responders. Transl Psychiatry. 2017;7(6):e1158.  https://doi.org/10.1038/tp.2017.130.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Ratanatharathorn A, Boks MP, Maihofer AX, Aiello AE, Amstadter AB, Ashley-Koch AE, et al. Epigenome-wide association of PTSD from heterogeneous cohorts with a common multi-site analysis pipeline. Am J Med Genet B Neuropsychiatr Genet. 2017;174(6):619–30.  https://doi.org/10.1002/ajmg.b.32568.CrossRefPubMedGoogle Scholar
  63. 63.
    Bell CG, Finer S, Lindgren CM, Wilson GA, Rakyan VK, Teschendorff AE, et al. Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. PLoS One. 2010;5(11):e14040.  https://doi.org/10.1371/journal.pone.0014040.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Tsuang MT, Faraone SV, Lyons MJ. Identification of the phenotype in psychiatric genetics. Eur Arch Psychiatry Clin Neurosci. 1993;243(3–4):131–42.  https://doi.org/10.1007/bf02190719.CrossRefPubMedGoogle Scholar
  65. 65.
    Smoller JW. Disorders and borders: psychiatric genetics and nosology. Am J Med Genet B Neuropsychiatr Genet. 2013;162B(7):559–78.  https://doi.org/10.1002/ajmg.b.32174.CrossRefPubMedGoogle Scholar
  66. 66.
    Cosgrove VE, Suppes T. Informing DSM-5: biological boundaries between bipolar I disorder, schizoaffective disorder, and schizophrenia. BMC Med. 2013;11:127.  https://doi.org/10.1186/1741-7015-11-127.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Charney AW, Ruderfer DM, Stahl EA, Moran JL, Chambert K, Belliveau RA, et al. Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder. Transl Psychiatry. 2017;7(1):e993.  https://doi.org/10.1038/tp.2016.242.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Ruderfer DM, Fanous AH, Ripke S, McQuillin A, Amdur RL. Schizophrenia Working Group of the Psychiatric Genomics C et al. polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia. Mol Psychiatry. 2014;19(9):1017–24.  https://doi.org/10.1038/mp.2013.138.CrossRefPubMedGoogle Scholar
  69. 69.
    Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):617–27.  https://doi.org/10.1001/archpsyc.62.6.617.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Koenen KC, Sumner JA, Gilsanz P, Glymour MM, Ratanatharathorn A, Rimm EB, et al. Post-traumatic stress disorder and cardiometabolic disease: improving causal inference to inform practice. Psychol Med. 2017;47(2):209–25.  https://doi.org/10.1017/S0033291716002294.CrossRefPubMedGoogle Scholar
  71. 71.
    Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160(4):636–45.CrossRefPubMedGoogle Scholar
  72. 72.
    Flint J, Munafo MR. The endophenotype concept in psychiatric genetics. Psychol Med. 2007;37(2):163–80.  https://doi.org/10.1017/S0033291706008750.CrossRefPubMedGoogle Scholar
  73. 73.
    Quednow BB, Ejebe K, Wagner M, Giakoumaki SG, Bitsios P, Kumari V, et al. Meta-analysis on the association between genetic polymorphisms and prepulse inhibition of the acoustic startle response. Schizophr Res. 2017;  https://doi.org/10.1016/j.schres.2017.12.011.
  74. 74.
    Palmer C, Pe'er I. Statistical correction of the Winner's curse explains replication variability in quantitative trait genome-wide association studies. PLoS Genet. 2017;13(7):e1006916.  https://doi.org/10.1371/journal.pgen.1006916.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Gilad Y, Rifkin SA, Pritchard JK. Revealing the architecture of gene regulation: the promise of eQTL studies. Trends Genet. 2008;24(8):408–15.  https://doi.org/10.1016/j.tig.2008.06.001.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    • Cookson W, Liang L, Abecasis G, Moffatt M, Lathrop M. Mapping complex disease traits with global gene expression. Nat Rev Genet. 2009;10(3):184–94.  https://doi.org/10.1038/nrg2537. Important review related to how gene expression profiles will help to elucidate genetic risk processes. CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Albert FW, Kruglyak L. The role of regulatory variation in complex traits and disease. Nat Rev Genet. 2015;16(4):197–212.  https://doi.org/10.1038/nrg3891.CrossRefPubMedGoogle Scholar
  78. 78.
    Dobbyn A, Huckins LM, Boocock J, Sloofman LG, Glicksberg BS, Giambartolomei C, et al. Co-localization of Conditional eQTL and GWAS Signatures in Schizophrenia. bioRxiv. 2017;  https://doi.org/10.1101/129429.
  79. 79.
    Nicolae DL, Gamazon E, Zhang W, Duan S, Dolan ME, Cox NJ. Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet. 2010;6(4):e1000888.  https://doi.org/10.1371/journal.pgen.1000888.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    • Hannon E, Spiers H, Viana J, Pidsley R, Burrage J, Murphy TM, et al. Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci. Nat Neurosci. 2016;19(1):48–54.  https://doi.org/10.1038/nn.4182. Demonstration that genetic loci associated with differential methylation are of enhanced importance in the biology of disease. CrossRefPubMedGoogle Scholar
  81. 81.
    Giambartolomei C, Vukcevic D, Schadt EE, Franke L, Hingorani AD, Wallace C, et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 2014;10(5):e1004383.  https://doi.org/10.1371/journal.pgen.1004383.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    He X, Fuller CK, Song Y, Meng Q, Zhang B, Yang X, et al. Sherlock: detecting gene-disease associations by matching patterns of expression QTL and GWAS. Am J Hum Genet. 2013;92(5):667–80.  https://doi.org/10.1016/j.ajhg.2013.03.022.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Zhu Z, Zhang F, Hu H, Bakshi A, Robinson MR, Powell JE, et al. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat Genet. 2016;48(5):481–7.  https://doi.org/10.1038/ng.3538.CrossRefPubMedGoogle Scholar
  84. 84.
    Giambartolomei C, Zhenli Liu J, Zhang W, Hauberg M, Shi H, Boocock J, et al. A Bayesian framework for multiple trait Colocalization from summary association statistics. Cold Spring Harbor. Laboratory. 2017;Google Scholar
  85. 85.
    Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM, et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci. 2016;19(11):1442–53.  https://doi.org/10.1038/nn.4399.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Bharadwaj RA, Jaffe AE, Chen Q, Deep-Soboslay A, Goldman AL, Mighdoll MI, et al. Genetic risk mechanisms of posttraumatic stress disorder in the human brain. J Neurosci Res. 2018;96(1):21–30.  https://doi.org/10.1002/jnr.23957.CrossRefPubMedGoogle Scholar
  87. 87.
    Gamazon ER, Wheeler HE, Shah KP, Mozaffari SV, Aquino-Michaels K, Carroll RJ, et al. A gene-based association method for mapping traits using reference transcriptome data. Nat Genet. 2015;47(9):1091–8.  https://doi.org/10.1038/ng.3367.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Gusev A, Ko A, Shi H, Bhatia G, Chung W, Penninx BW, et al. Integrative approaches for large-scale transcriptome-wide association studies. Nat Genet. 2016;48(3):245–52.  https://doi.org/10.1038/ng.3506.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    •• Consortium GT. Human genomics. The genotype-tissue expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348(6235):648–60.  https://doi.org/10.1126/science.1262110. Description of one of the most important public databases to-date, GTEx, for the identification of genetic–gene expression functional relationships across different human tissues and brain regions. CrossRefGoogle Scholar
  90. 90.
    Mele M, Ferreira PG, Reverter F, DeLuca DS, Monlong J, Sammeth M, et al. Human genomics. The human transcriptome across tissues and individuals. Science. 2015;348(6235):660–5.  https://doi.org/10.1126/science.aaa0355.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Mancuso N, Shi H, Goddard P, Kichaev G, Gusev A, Pasaniuc B. Integrating gene expression with summary association statistics to identify susceptibility genes for 30 complex traits. Cold Spring Harbor Laboratory; 2016.Google Scholar
  92. 92.
    Geschwind DH, Flint J. Genetics and genomics of psychiatric disease. Science. 2015;349(6255):1489–94.  https://doi.org/10.1126/science.aaa8954.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Huckins LM, Dobbyn A, Ruderfer D, Hoffman G, Wang W, Pardinas AF, et al. Gene expression imputation across multiple brain regions reveals schizophrenia risk throughout development. bioRxiv. 2017;  https://doi.org/10.1101/222596.
  94. 94.
    Gusev A, Mancuso N, Finucane HK, Reshef Y, Song L, Safi A, et al. Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Cold Spring Harbor. Laboratory. 2016;Google Scholar
  95. 95.
    Barbeira AN, Dickinson SP, Torres JM, Bonazzola R, Zheng J, Torstenson ES. et al, MetaXcan: summary statistics based gene-level association method infers accurate PrediXcan results. bioRxiv. 2017;  https://doi.org/10.1101/045260.
  96. 96.
    Huckins L, Dobbyn A, Ruderfer D, Fromer M, CommonMind Consortium CC, Cox N, et al. Novel bipolar and schizophrenia risk genes identified through genic associations in Transcriptome imputation. Eur Neuropsychopharmacol. 2017;27:S487.  https://doi.org/10.1016/j.euroneuro.2016.09.577.CrossRefGoogle Scholar
  97. 97.
    Huckins LM, Breen MS, Girdhar K, van Rooij SJH, ..., CommonMind Consortium et al. Genetically predicted gene expression in the brain and peripheral tissues associated with PTSD. In Preparation.Google Scholar
  98. 98.
    Popejoy AB, Fullerton SM. Genomics is failing on diversity. Nature. 2016;538(7624):161–4.  https://doi.org/10.1038/538161a.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Burchard EG. Medical research: missing patients. Nature. 2014;513(7518):301–2.  https://doi.org/10.1038/513301a.CrossRefPubMedGoogle Scholar
  100. 100.
    Pendergrass SA, Brown-Gentry K, Dudek S, Frase A, Torstenson ES, Goodloe R, et al. Phenome-wide association study (PheWAS) for detection of pleiotropy within the population architecture using genomics and epidemiology (PAGE) network. PLoS Genet. 2013;9(1):e1003087.  https://doi.org/10.1371/journal.pgen.1003087.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Namjou B, Marsolo K, Caroll RJ, Denny JC, Ritchie MD, Verma SS, et al. Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to eosinophilic esophagitis. Front Genet. 2014;5:401.  https://doi.org/10.3389/fgene.2014.00401.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Pendergrass SA, Dudek SM, Crawford DC, Ritchie MD. Visually integrating and exploring high throughput phenome-wide association study (PheWAS) results using PheWAS-view. BioData Min. 2012;5(1):5.  https://doi.org/10.1186/1756-0381-5-5.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Hall MA, Verma A, Brown-Gentry KD, Goodloe R, Boston J, Wilson S, et al. Detection of pleiotropy through a phenome-wide association study (PheWAS) of epidemiologic data as part of the environmental architecture for genes linked to environment (EAGLE) study. PLoS Genet. 2014;10(12):e1004678.  https://doi.org/10.1371/journal.pgen.1004678.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    • Denny JC, Ritchie MD, Basford MA, Pulley JM, Bastarache L, Brown-Gentry K, et al. PheWAS: demonstrating the feasibility of a phenome-wide scan to discover gene-disease associations. Bioinformatics. 2010;26(9):1205–10.  https://doi.org/10.1093/bioinformatics/btq126. Among first description and methods for phenome-wide association analyses. CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Carroll RJ, Bastarache L, Denny JC. R PheWAS: data analysis and plotting tools for phenome-wide association studies in the R environment. Bioinformatics. 2014;30(16):2375–6.  https://doi.org/10.1093/bioinformatics/btu197.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Cortes A, Dendrou C, Motyer A, Jostins L, Vukcevic D, Dilthey A et al. Bayesian analysis of genetic association across tree-structured routine healthcare data in the UK Biobank. Cold Spring Harbor Laboratory; 2017.Google Scholar
  107. 107.
    Denny JC, Bastarache L, Ritchie MD, Carroll RJ, Zink R, Mosley JD, et al. Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data. Nat Biotechnol. 2013;31(12):1102–10.  https://doi.org/10.1038/nbt.2749.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Edmondson D, Kronish IM, Shaffer JA, Falzon L, Burg MM. Posttraumatic stress disorder and risk for coronary heart disease: a meta-analytic review. Am Heart J. 2013;166(5):806–14.  https://doi.org/10.1016/j.ahj.2013.07.031.CrossRefPubMedGoogle Scholar
  109. 109.
    Edmondson D, von Kanel R. Post-traumatic stress disorder and cardiovascular disease. Lancet Psychiat. 2017;4(4):320–9.  https://doi.org/10.1016/S2215-0366(16)30377-7.CrossRefGoogle Scholar
  110. 110.
    Yesavage JA, Kinoshita LM, Noda A, Lazzeroni LC, Fairchild JK, Friedman L, et al. Longitudinal assessment of sleep disordered breathing in Vietnam veterans with post-traumatic stress disorder. Nat Sci Sleep. 2014;6:123–7.  https://doi.org/10.2147/NSS.S65034.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Nikolaos P. Daskalakis
    • 1
  • Chuda M. Rijal
    • 1
  • Christopher King
    • 1
  • Laura M. Huckins
    • 2
  • Kerry J. Ressler
    • 1
  1. 1.Division of Depression & Anxiety Disorders, McLean Hospital, Department of PsychiatryHarvard Medical SchoolBelmontUSA
  2. 2.Department of Psychiatry, Genetics and Genomic SciencesIcahn School of MedicineNew YorkUSA

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