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Aberrant Epigenomic Modulation of Glucocorticoid Receptor Gene (NR3C1) in Early Life Stress and Major Depressive Disorder Correlation: Systematic Review and Quantitative Evidence Synthesis

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  • Laurens Holmes

    (Nemours Healthcare System for Children, Translational Health Disparities Science Research Program, Wilmington, DE 19803, USA
    Biological Sciences Department, University of Delaware, Newark, DE 19716, USA
    College of Population Health, Thomas Jefferson University, Philadelphia, PA 19107, USA)

  • Emily Shutman

    (Nemours Healthcare System for Children, Translational Health Disparities Science Research Program, Wilmington, DE 19803, USA
    Biological Sciences Department, Haverford College, Haverford, PA 19041, USA)

  • Chinacherem Chinaka

    (Nemours Healthcare System for Children, Translational Health Disparities Science Research Program, Wilmington, DE 19803, USA
    Department of public health, Eastern Virginia Medical School, Norfolk, VA 23507, USA
    Community Environmental Health Department, Old Dominion University, Norfolk, VA 23507, USA)

  • Kerti Deepika

    (Nemours Healthcare System for Children, Translational Health Disparities Science Research Program, Wilmington, DE 19803, USA)

  • Lavisha Pelaez

    (Nemours Healthcare System for Children, Translational Health Disparities Science Research Program, Wilmington, DE 19803, USA)

  • Kirk W. Dabney

    (Nemours Healthcare System for Children, Translational Health Disparities Science Research Program, Wilmington, DE 19803, USA
    Sidney Kimmel Medical School, Thomas Jefferson University, Philadelphia, PA 19107, USA)

Abstract

Early life stress (ELS) induced by psychological trauma, child maltreatment, maternal separation, and domestic violence predisposes to psycho-behavioral pathologies during adulthood, namely major depressive disorder (MDD), anxiety, and bipolar affective disorder. While environmental data are available in illustrating this association, data remain to be established on the epigenomic underpinning of the nexus between ELS and MDD predisposition. Specifically, despite the observed aberrant epigenomic modulation of the NR3C1, a glucocorticoid receptor gene, in early social adversity and social threats in animal and human models, reliable scientific data for intervention mapping in reducing social adversity and improving human health is required. We sought to synthesize the findings of studies evaluating (a) epigenomic modulations, mainly DNA methylation resulting in MDD following ELS, (b) epigenomic modifications associated with ELS, and (c) epigenomic alterations associated with MDD. A systematic review and quantitative evidence synthesis (QES) were utilized with the random effect meta-analytic procedure. The search strategy involved both the PubMed and hand search of relevant references. Of the 1534 studies identified through electronic search, 592 studies were screened, 11 met the eligibility criteria for inclusion in the QES, and 5 examined ELS and MDD; 4 studies assessed epigenomic modulation and ELS, while 2 studies examined epigenomic modulations and MDD. The dense DNA methylation of the 1F exon of the NR3C1, implying the hypermethylated region of the glucocorticoid receptor gene, was observed in the nexus between ELS and MDD, common effect size (CES) = 14.96, 95%CI, 10.06–19.85. With respect to epigenomic modulation associated with child ELS, hypermethylation was observed, CES = 23.2%, 95%CI, 8.00–38.48. In addition, marginal epigenomic alteration was indicated in MDD, where hypermethylation was associated with increased risk of MDD, CES = 2.12%, 95%CI, −0.63–4.86. Substantial evidence supports the implication of NR3C1 and environmental interaction, mainly DNA methylation, in the predisposition to MDD following ELS. This QES further supports aberrant epigenomic modulation identified in ELS as well as major depressive episodes involving dysfunctional glucocorticoid-mediated negative feedback as a result of allostatic overload. These findings recommend prospective investigation of social adversity and its predisposition to the MDD epidemic via aberrant epigenomic modulation. Such data will facilitate early intervention mapping in reducing MDD in the United States population.

Suggested Citation

  • Laurens Holmes & Emily Shutman & Chinacherem Chinaka & Kerti Deepika & Lavisha Pelaez & Kirk W. Dabney, 2019. "Aberrant Epigenomic Modulation of Glucocorticoid Receptor Gene (NR3C1) in Early Life Stress and Major Depressive Disorder Correlation: Systematic Review and Quantitative Evidence Synthesis," IJERPH, MDPI, vol. 16(21), pages 1-17, November.
  • Handle: RePEc:gam:jijerp:v:16:y:2019:i:21:p:4280-:d:283451
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    References listed on IDEAS

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    1. Monika Lachner & Dónal O'Carroll & Stephen Rea & Karl Mechtler & Thomas Jenuwein, 2001. "Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins," Nature, Nature, vol. 410(6824), pages 116-120, March.
    2. Lotte C. Houtepen & Christiaan H. Vinkers & Tania Carrillo-Roa & Marieke Hiemstra & Pol A. van Lier & Wim Meeus & Susan Branje & Christine M. Heim & Charles B. Nemeroff & Jonathan Mill & Leonard C. Sc, 2016. "Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans," Nature Communications, Nature, vol. 7(1), pages 1-10, April.
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    Cited by:

    1. Laurens Holmes Jr. & Leah O’Neill & Hikma Elmi & Chinaka Chinacherem & Camillia Comeaux & Lavisha Pelaez & Kirk W. Dabney & Olumuyiwa Akinola & Michael Enwere, 2020. "Implication of Vaginal and Cesarean Section Delivery Method in Black–White Differentials in Infant Mortality in the United States: Linked Birth/Infant Death Records, 2007–2016," IJERPH, MDPI, vol. 17(9), pages 1-12, April.
    2. Laurens Holmes & Michael Enwere & Janille Williams & Benjamin Ogundele & Prachi Chavan & Tatiana Piccoli & Chinacherem Chinaka & Camillia Comeaux & Lavisha Pelaez & Osatohamwen Okundaye & Leslie Staln, 2020. "Black–White Risk Differentials in COVID-19 (SARS-COV2) Transmission, Mortality and Case Fatality in the United States: Translational Epidemiologic Perspective and Challenges," IJERPH, MDPI, vol. 17(12), pages 1-18, June.

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