University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 12-2017 Mediation and Moderation of Intergenerational Epigenetic Effects of Trauma Stefanie Renee Pilkay University of Tennessee, Knoxville, [email protected] Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Other Genetics and Genomics Commons, and the Social Work Commons Recommended Citation Pilkay, Stefanie Renee, "Mediation and Moderation of Intergenerational Epigenetic Effects of Trauma. " PhD diss., University of Tennessee, 2017. https://trace.tennessee.edu/utk_graddiss/4753 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Stefanie Renee Pilkay entitled "Mediation and Moderation of Intergenerational Epigenetic Effects of Trauma." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the equirr ements for the degree of Doctor of Philosophy, with a major in Social Work. Terri Combs-Orme, Major Professor We have read this dissertation and recommend its acceptance: John G. Orme, Shandra Forrest-Bank, Matthew Cooper, Alicia K. Smith Accepted for the Council: Dixie L. Thompson Vice Provost and Dean of the Graduate School (Original signatures are on file with official studentecor r ds.) Mediation and Moderation of Intergenerational Epigenetic Effects of Trauma A Dissertation Presented for the Doctor of Philosophy Degree The University of Tennessee, Knoxville Stefanie Renee Pilkay December 2017 Copyright © 2017 by Stefanie R. Pilkay All rights reserved. ii DEDICATION I dedicate this work to my tirelessly patient and supportive husband who made this dream possible, and to my children who sparked my passion for change. iii ACKNOWLEDGEMENTS I would like to thank my committee members for their support and guidance in helping me develop as a professional. Your consistent openness to my endless questions and pursuit of learning opportunities has fostered a spirit of sharing and encouragement that I will pour into my career-long teaching and research. iv ABSTRACT Trauma and early-life stress have been linked to poor mental and physical health outcomes. In fact, research has identified trauma and stress can influence epigenetic marks on genes that can alter gene activity. It is suspected that epigenetically altered gene activity is involved in behavior and mental health. This may help explain why some individuals don’t experience great benefit from treatment for the effects of stress, and severe mental health symptoms can be chronic for decades or a lifetime. Moreover, some trauma-related mental health symptoms have shown generational patterns that appear linked to epigenetic marks. Therefore, this study sought to investigate the potential inter-generational influence of mother’s trauma history and mental health on her offspring’s DNA methylation and gene expression in umbilical cord blood. Standardized measures were used to assess mother’s trauma history and cumulative experienced fear (TLEQ), as well as mother’s mental health status during pregnancy (BSI). Genome-wide and candidate gene analyses were conducted after standard quality control data cleaning procedures. Batch and chip adjustments were made using the Combat package in R software, and the False Discovery Rate was employed to control for multiple comparisons. Results indicate mother’s exposure to trauma in childhood predicts DNA methylation and gene expression in offspring. Additionally, mother’s mental health status during pregnancy significantly predicts differential gene expression on 245 genes in males only. Finally, mother’s fear completely mediates the influence of trauma on her mental health functioning. In conclusion, a mother’s traumatic experience has potential v to influence gene regulation in her offspring. Most importantly, mother’s mental health during pregnancy appears to exert a great influence on gene regulation in males compared to female offspring. vi TABLE OF CONTENTS Introduction ....................................................................................................................... 1 Chapter I Trauma and Genetics: An Influence Across Generations ............................... 6 Abstract ............................................................................................................................ 7 Background ...................................................................................................................... 9 Introduction ................................................................................................................... 9 Understanding Trauma ............................................................................................... 11 Stress and Trauma ..................................................................................................... 12 Understanding Consequences of Stress and Trauma ................................................ 12 Epigenetics and Trauma: The Environment and Gene Regulation ............................ 14 Methods .......................................................................................................................... 16 Results ........................................................................................................................... 17 Genes That Influence Stress Reactivity ...................................................................... 18 Stress response dysfunction ................................................................................... 19 Stress response dysfunction symptoms .................................................................. 20 Stress response dysfunction predictors .................................................................. 21 Glucocorticoid receptors ......................................................................................... 22 Linking GR and mental health ................................................................................. 23 Serotonin and Emotionality ......................................................................................... 25 Emotionality predictors ............................................................................................ 25 Serotonin receptor genes and emotion ................................................................... 26 Serotonin gene-environment mechanisms .............................................................. 28 Other contributors ................................................................................................... 29 Brain Development ..................................................................................................... 30 Genes and Brain Development ............................................................................... 31 Altered Brain Structure and Function ...................................................................... 32 BDNF and Mental Health ........................................................................................ 34 Inter-generational Effects ............................................................................................ 35 Prenatal Exposure ................................................................................................... 36 Limitations ...................................................................................................................... 37 Discussion ...................................................................................................................... 40 Chapter II Mother’s History of Trauma and Fear Predicts Differential DNA Methylation and Gene Expression in Newborn .................................................................................. 43 Abstract .......................................................................................................................... 44 Introduction ..................................................................................................................... 45 Insight from Epigenetics ............................................................................................. 46 Epigenetic Influence Parent to Child ........................................................................... 48 Methods .......................................................................................................................... 51 Sample and Procedures ............................................................................................. 51 Measures .................................................................................................................... 52 Analyses ..................................................................................................................... 54 Results ........................................................................................................................... 55 Limitations ...................................................................................................................... 60 vii Discussion .....................................................................................................................