Investigation of genetic variation and molecular mechanism sassociated with risk for posttraumatic stress disorder Open Access

Mercer, Kristina Butze (2016)

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Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition that affects 5-12% of the U.S. adult population. Symptoms of the disorder include re-experiencing the trauma through nightmares or flashbacks, avoiding places or things that trigger memory of the trauma, and an increased arousal response that can cause problems with concentration or sleep. Those who suffer from PTSD find day-to-day life difficult and are more likely to have comorbid psychiatric conditions, chronic health problems, abuse drugs and alcohol, and attempt suicide. Treatment options have limited efficacy and most individuals with PTSD remain symptomatic for years to a lifetime, leading to an economic burden estimated in the billions of dollars. To reduce the impact of this disorder on public health, we must understand the underlying mechanisms that lead to PTSD in some individuals but not others when exposed to a similarly traumatic event. Estimates of heritability range from 30-40%, indicating a large fraction of risk is attributable to genetics. This dissertation focuses on potential molecular mechanisms responsible for increased PTSD symptoms and the identification of novel genetic variants that associate with risk for PTSD. I provide evidence that a single nucleotide polymorphism (SNP) that we previously associated with PTSD (rs2267735) is located within an estrogen response element that binds to estradiol-activated estrogen receptor, increasing gene expression of ADCYAP1R1 and activating a mechanism hypothesized to be involved in the normal stress response. Homozygosity for the C allele at this SNP alters estrogen-dependent regulation, resulting in stress response dysregulation that may lead to a preferential increase in PTSD symptoms among women. To uncover other types of genomic variants that have not yet been examined in risk for PTSD, I also explored the association of PTSD with copy number variants (CNVs), large and relatively rare duplications and deletions found throughout the genome. I present preliminary findings of CNV associations with PTSD, involving CNTN5 and IMMP2L, two genes that have been implicated in neuronal synaptic plasticity and other psychiatric conditions, respectively. This work has expanded our knowledge of genetic factors and the mechanisms associated with risk and resilience for PTSD in the aftermath of severe trauma.

Table of Contents

Chapter 1: The genetics of posttraumatic stress disorder (PTSD)

Clinical characteristics and epidemiology of PTSD 1

The impact of PTSD on public health 2

Current treatment options for PTSD 6

Known risk factors for PTSD 8

History and challenges in determining genetic causes of PTSD 9

Summary of current PTSD-associated polymorphisms 12

Using copy number variation to gain novel insight into the genetic architecture of PTSD 15

Conclusion 17

References 21

Chapter 2: Functional evaluation of a PTSD-associated genetic variant: estradiol regulation and ADCYAP1R1

Introduction 36

Materials and Methods 38

Results 42

Discussion 48

Supplementary Materials and Methods 53

References 64

Chapter 3: Beyond SNPs: the discovery of CNVs associated with PTSD

Introduction 68

Materials and Methods 70

Results 83

Discussion 89

References 112

Chapter 4: Enrichment of clinically significant copy number variants in a medically underserved population

Introduction 116

Materials and Methods 118

Results 126

Discussion 129

References 210

Chapter 5: Summary of Findings and Future Directions

Summary 215

Conclusion 222

References 223

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