Epigenomic analysis of posttraumatic stress disorder in female rape survivors in South Africa

Thesis (PhD)--Stellenbosch University, 2021.ENGLISH SUMMARY : Compared to other trauma types, rape is associated with a high risk of developing posttraumatic stress disorder (PTSD). Women are at increased risk of developing PTSD compared to men and are also more frequently victims of sexual assault. PTSD is a complex, multifactorial disorder and an array of demographic, trauma-related, psychological and genetic putative risk and protective factors mediate or contribute to the development and course of the disorder. Few studies have comprehensively investigated demographic and psychological risk and protective factors for PTSD in a longitudinal prospective design, especially beyond the 3-month post-rape period and in low- to medium-income countries. There are currently no known epigenome-wide association studies (EWASs) investigating differential methylation in relation to PTSD in (1) an African population and (2) a sample of rape-exposed women exclusively. There are also no known studies investigating longitudinal change in the hypothalamic-pituitary-adrenal (HPA) axis associated candidate gene FK506 binding protein (FKBP5) in relation to PTSD in a sample of rape-exposed women exclusively. In this study we investigated the demographic, rape/assault-related, psychological, genetic (FKBP5) and epigenetic (epigenome-wide differential methylation) risk and protective factors associated with the development and course of PTSD symptoms over six months. Self-report measures and specimen collection was completed at baseline (within 20 day after the rape), 3-months and 6-months post-rape as part of the Rape Impact Cohort Evaluation (RICE) study. The RICE sample consisted of 852 Black African rape-exposed women, between the ages of 16 and 40 years and from a low socio-economic background. We found that baseline demographic, rape/assault-related and psychological protective factors were not significant predictors of PTSD symptoms over time. Baseline depression and rape stigma were significant psychological risk factors for the development and course of PTSD post-rape. We also identified one intergenic CpG site (cg01700569) that was differentially methylated in relation to PTSD status at 3-months post-rape on a genome-wide level. Thirty-four differentially methylated regions were identified and included a region in the HPA-axis-associated adenylate cyclase activating polypeptide 1 (ADCYAP1) gene and the neuroendocrine-associated brain-specific serine/threonine-protein kinase 2 (BRSK2) gene. Decreased BRSK2 and ADCYAP1 methylation at 3-months and 6-months post-rape was associated with increased PTSD symptom scores at the same time-points. Decreased FKBP5 methylation was a predictor of increased PTSD symptom scores at 3-months and 6-months post-rape. High childhood trauma and the CC genotype of FKBP5 rs1360780 resulted in decreased FKBP5 methylation and increased PTSD scores at baseline. The study builds on existing literature, highlighting the psychological risk factors for the development and course of PTSD in rape-exposed women. Methylation findings also build on the existing literature regarding the role of epigenetics in PTSD, although the genome-wide finding implicating differential methylation of BRSK2 in the development of PTSD is a novel finding in human studies. The study provides evidence that both psychological and biological factors have an impact on the symptom trajectory of PTSD and that both should be considered when designing and implementing interventions for the treatment of PTSD post-rape.AFRIKAANSE OPSOMMING : Verkragting word geassosieer met ‘n hoë risiko vir die ontwikkeling van posttraumatiese stresversteuring (PTSV) in vergelyking met ander tipes trauma. Vroue loop ‘n verhoogde risiko om PTSV te ontwikkel in vergelyking met mans en is ook meer gereeld slagoffers van seksuele aanranding in vergelyking met mans. PTSV is ‘n komplekse, multifaktoriese versteuring en ‘n verskeidenheid demografiese, trauma-verwante, sielkundige en genetiese vermeende risiko en beskermende faktore bemiddel of dra by tot die ontwikkeling en verloop van die versteuring. Min studies ondersoek die demografiese en sielkundige risiko en beskermingsfaktore vir PTSV op ‘n omvattende manier deur gebruik te maak van ‘n voornemende longitudinale ontwerp, veral buite die periode van 3 maande na die verkragting en in lae- to middel-inkomste lande. Daar is huidig geen epigenoom-wye assosiasie studies (EWAS’s) wat die verhouding tussen PTSV en differensiële metilering ondersoek in (1) ‘n Afrika-bevolking en (2) uitsluitlik vroue wat aan verkragting blootgesel was nie. Daar is ook huidig geen studies wat die longitudinale veranderinge in die hipotalamus-pituïtêre-adrenale (HPA) as geassosieerde kandidaat geen FK506-bindingsproteïen (FKBP5) in verhouding met PTSV in ‘n steekproef van vroue wat uitsluitlik aan verkragting blootgestel was, bestudeer nie. In hierdie studie het ons die demografiese, verkragtings-/aanrandingsverwante, sielkundige, genetiese (FKBP5) en epigenetiese (epigenoom-wye differensiële metilering) risiko en beskermende faktore in verwant met die ontwikkeling en verloop van PTSV-simptome oor ses maande bestudeer. Selfrapporteringskale en versameling van monsters was by basislyn (binne 20 dae na die verkragting), 3 maande en 6 maande na die verkragting voltooi, as deel van die verkragtingsimpak kohort evaluering (VIKE) studie. Die VIKE steekproef het bestaan uit 852 Swart vroue wat aan verkragting blootgestel was, wat tussen die ouderdom van 16 en 40 jaar was en wat vanuit ‘n lae sosio-ekonomiese agtergrond gekom. het Ons het gevind dat demografiese, verkragtings/aanrandingsverwante en sielkundige beskermende faktore op basislyn nie PTSV-simptome beduidend voorspel het nie. Depressie en verkragtingsstigma op basislyn was wel beduidende sielkundige risikofaktore vir die ontwikkeling en verloop van PTSV na verkragting. Een CpG (cg01700569) wat op ‘n genoomwye vlak differensieel gemetileer was in verhouding met PTSV-status 3 maande na die verkragting was ook geïdentifiseer. Vier en dertig differensieel gemetileerde streke was geïdentifiseer en het ‘n streek in die HPA-as geassosieerde adenilaat-siklase-aktiveerende-polipeptied (ADCYAP1) geen en ‘n streek in die neuro-edokriene geassosieerde berinspesifieke-serine-drieonien-proteïen-kinase 2 (BRSK2) geen ingesluit. ‘n Afname in BRSK2 en ADCYAP1 metilering by 3 maande en 6 maande na die verkragting was geassosieer met ‘n toename in PTSV-simptoomtelling by dieselfde tydpunte. ‘n Afname in FKBP5 metilering het ‘n toename in PTSV-simptoomtelling 3 maande en 6 maande na verkragting voorspel. Hoë kindertrauma en die CC genotipe van rs1360780 het gelei tot ‘n afname in FKBP5 metilering en ‘n toename in PTSV-simptoomtelling by basislyn. Die studie bou voort op die bestaande literatuur en beklemtoon die risikofaktore vir PTSV in vroue wat aan verkragting blootgestel is. Die metilering bevindinge bou ook voort op die bestaande literatuur, alhoewel die genoomwye bevinding dat differensiële metilering van BRSK2 verband hou met die ontwikkeling van PTSV ‘n nuwe bevinding in menslike studies is. Die studie bewys dat sielkundige en biologiese faktore ‘n impak het op die verloop van PTSV-simptome en dat beide oorweeg moet word wanneer intervensies vir die behandeling van PTSV na verkragting ontwerp en geïmplimenteer word.Doctora