Oxytocin Genetic and Epigenetic Variation: Association with Social Adversity and Behavioral and Health Outcomes 公开

Smearman, Erica Lauren (2015)

Permanent URL: https://etd.library.emory.edu/concern/etds/c821gk57b?locale=zh
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Abstract

Exposure to environmental stress can increase an individual's risk for behavioral problems, psychopathology, and chronic health conditions. Importantly individuals with different genetic profiles vary in their responsiveness to these environments, and thus their likelihood of developing adverse outcomes. Given the social nature of many stressful environments, genetic factors related to the oxytonergic system may be relevant to environmental differential susceptibility. Oxytocin is a hormone important for perceiving social cues. Therefore, the oxytonergic system may influence perception of, and thus sensitivity towards, both nurturing and adverse social environments. While much of the initial human oxytocin work draws from positive social environments, more recent work has incorporated adverse social contexts. This dissertation expands this literature, exploring genetic differences in the oxytocin receptor gene (sequence variation and methylation patterns) in the association between adverse social environments and behavioral and health outcomes, including responsiveness to intervention.

First, in a prospective cohort of youth (N=404), we tested the role of OXTR genetics in the association between interpersonal conflict and conduct and antisocial behaviors at age 15 and 20, finding that individuals with the rs53576 GG genotype engaged in more disordered behavior when exposed to high levels of interpersonal conflict. Second, in a sample of adults (N=393), we assessed the role of OXTR DNA methylation in the association between abuse and psychopathology, finding that individuals with specific OXTR CpG methylation patterns reported higher levels of depression and anxiety when exposed to abuse, compared to those without those patterns. OXTR sequence variation and methylation were also considered together, with OXTR genotypes associating with methylation of nearby CpG sites. Third, in a sample of parent-youth pairs (N=191), we explored the role of OXTR genetics on responsiveness to a family-based intervention. Youth with the rs53576 GG genotype again showed the greatest sensitivity to environmental context, exhibiting the shortest telomeres when exposed to high parent-youth conflict and randomized to the control intervention condition, and telomere lengths similar to the non at-risk group when randomized to the intervention.

The combined findings suggest a role for OXTR in sensitivity to the social environment and in the prediction of behavioral and health outcomes.

Table of Contents

CHAPTER 1: Introductory Literature Review 1 Genetics 2 Differential Susceptibility 3 Epigenetics 4

Differential Susceptibility and Epigenetics

5 Epigenetics and the Environment 5 Role of Oxytocin 6 Oxytocin Genetics 9 OXTR rs53576 9 OXTR Epigenetics 10

OXTR Epigenetics in Humans

11 Prevention & OXTR 12 Summary 12 References 14

CHAPTER 2: Social stress and the oxytocin receptor gene interact to predict antisocial behavior in an at-risk cohort

23 Abstract 24 Introduction 25 Methods 27 Results 33 Discussion 34 References 40

CHAPTER 3: Oxytocin receptor genetic and epigenetic variation: association with child abuse and adult psychiatric symptoms

52 Abstract 53 Introduction 54 Methods 56 Results 60 Discussion 63 References 71

CHAPTER 4: Variation in the Oxytocin Receptor Gene Moderates the Protective Effects of a Family-Based Prevention Program on Telomere Length

85 Abstract 86 Introduction 87 Methods 90 Results 95 Discussion 97 References 101 CHAPTER 5: Summary and Conclusions 110 References 122 LIST OF FIGURES

Figure 2.1 The Influence of the OXTR rs53576 Polymorphism on Antisocial Behaviors at age 20 in the Presence of High versus Low Social Stress: Homozygous Grouping (GG vs AA)

50

Figure 2.2 The Influence of the OXTR rs53576 Polymorphism on Antisocial Behaviors at age 20 in the Presence of High versus Low Social Stress: Heterozygous Grouping (GG/AG vs AA)

51 Figure 3.1 OXTR structure and variant location. 78

Figure 3.2 OXTR methylation moderates the association between childhood abuse and adult psychiatric symptoms

79

Figure 4.1 Non-Supportive Parenting and Telomere Length Outcomes by Intervention and Genotype Status

107 LIST OF TABLES

Table 2.1 Descriptive Statistics By OXTR rs53576 Genotype

47

Table 2.2 Correlations Between Variables

48

Table 2.3 Exploring Allelic Grouping. OXTR Beta Weight & P-Value in the Homozygous, G Dominant, and A Dominant Models

49

Table 3.1 Study Variables Among those with None to Mild, Moderate, or Severe Abuse

80

Table 3.2 Association between Single Nucleotide Polymorphisms and Methylation of Specific CpG Sites

81

Table 3.3 Association between Childhood Abuse and Depression and Anxiety Symptoms: Potential Moderating Role of OXTR CpG site Methylation

84

Table 4.1 Descriptive Statistics and Correlations among Study Variable (N = 191)

108

Table 4.2 Non-supportive Parenting, Intervention Status, and OXTR rs53576 as Predictors of Telomere Length (N = 191)

109

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