Browsing by Author "Toikumo, Sylvanus"

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    Genome-wide differentially methylated genes associated with posttraumatic stress disorder and longitudinal change in methylation in rape survivors
    (Springer Nature, 2019) Nothling, Jani; Abrahams, Naeemah; Toikumo, Sylvanus; Suderman, Matthew; Mhlongo, Shibe; Lombard, Carl; Seedat, Soraya; Hemmings, Sian Megan Joanna
    ENGLISH ABSTRACT: Rape is associated with a high risk for posttraumatic stress disorder (PTSD). DNA methylation changes may confer risk or protection for PTSD following rape by regulating the expression of genes implicated in pathways affected by PTSD. We aimed to: (1) identify epigenome-wide differences in methylation profiles between rape-exposed women with and without PTSD at 3-months post-rape, in a demographically and ethnically similar group, drawn from a low-income setting; (2) validate and replicate the findings of the epigenome-wide analysis in selected genes (BRSK2 and ADCYAP1); and (3) investigate baseline and longitudinal changes in BRSK2 and ADCYAP1 methylation over six months in relation to change in PTSD symptom scores over 6 months, in the combined discovery/validation and replication samples (n = 96). Rape-exposed women (n = 852) were recruited from rape clinics in the Rape Impact Cohort Evaluation (RICE) umbrella study. Epigenome-wide differentially methylated CpG sites between rape-exposed women with (n = 24) and without (n = 24) PTSD at 3-months post-rape were investigated using the Illumina EPIC BeadChip in a discovery cohort (n = 48). Validation (n = 47) and replication (n = 49) of BRSK2 and ADCYAP1 methylation findings were investigated using EpiTYPER technology. Longitudinal change in BRSK2 and ADCYAP1 was also investigated using EpiTYPER technology in the combined sample (n = 96). In the discovery sample, after adjustment for multiple comparisons, one differentially methylated CpG site (chr10: 61385771/ cg01700569, p = 0.049) and thirty-four differentially methylated regions were associated with PTSD status at 3-months post-rape. Decreased BRSK2 and ADCYAP1 methylation at 3-months and 6-months post-rape were associated with increased PTSD scores at the same time points, but these findings did not remain significant in adjusted models. In conclusion, decreased methylation of BRSK2 may result in abnormal neuronal polarization, synaptic development, vesicle formation, and disrupted neurotransmission in individuals with PTSD. PTSD symptoms may also be mediated by differential methylation of the ADCYAP1 gene which is involved in stress regulation. Replication of these findings is required to determine whether ADCYAP1 and BRSK2 are biomarkers of PTSD and potential therapeutic targets.
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    Understanding the shared epigenetic roots of posttraumatic stress disorder and metabolic syndrome : a DNA methylation study
    (Stellenbosch : Stellenbosch University, 2020-12) Toikumo, Sylvanus; Hemmings, Sian Megan Joanna; Malan-Muller, Stefanie; Seedat, Soraya, 1966-; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Psychiatry.
    ENGLISH SUMMARY: Background: Posttraumatic stress disorder (PTSD) can develop after exposure to trauma and has been linked to increased prevalence of metabolic syndrome (MetS), a cluster of traits that increase risk for cardiovascular disease. Epigenetics provides a molecular framework for gene-environment interaction effects and may explain the association between PTSD and metabolic outcomes. This study aimed to (i) identify epigenome-wide profiles associated with PTSD and PTSD-MetS comorbidity by investigating genome-wide DNA methylation profiles, and (ii) determine whether PTSD and PTSD-MetS comorbidity are associated with accelerated cellular ageing, as indexed by DNA methylation age (DNAm age). Methods: Clinical assessments of trauma exposure, PTSD symptoms and diagnosis were based on the Life Events Checklist for DSM-5, PTSD Checklist for DSM-5, Clinician Administered PTSD Scale. MetS was diagnosed according to the harmonised Joint Interim Statement (JIS) criteria. The sample comprised 61 individuals with PTSD (n = 29 with MetS) and 59 trauma-exposed controls (n = 29 with MetS). DNA methylation profiling was performed using the Illumina Infinium EPIC BeadChip. Sample quality control, data normalization and epigenome-wide association testing (EWAS) was performed using the R package, meffil. Analysis of differentially methylated regions (DMRs) was performed using the R package, Bumphunter. The associations of PTSD-MetS comorbidity and PTSD with genome-wide DNA methylation profiles were assessed per CpG site using generalised linear models and included correction for possible genomic inflation. CpG sites differentially methylated at FDR < 0.05 were considered significant. Gene ontology and pathway analyses were conducted using the WebGestalt analysis tool kit with an applied FDR < 0.1. The Horvath DNAm age, Hannum DNAm age and Levine PhenoAge predictors were calculated from normalized methylation intensity values, and subsequently regressed on chronological age to provide epigenetic ageing estimates. Results: Seven epigenome-wide significant CpG sites in genes encoding ubiquitin containing domain 2 (UBTD2), protein kinase C alpha (PRKCA), mitochondrial translational activator (MSS51), MHC class I chain-related gene A (MICA) and GTPase IMAP family member 7 (GIMAP7), were associated with PTSD-MetS comorbidity. Two hypomethylated CpG sites, in Src homolog 2 domain containing (SHC1) and protein kinase C substrate 80K-H (PRKCSH) genes, were associated with PTSD. Three DMRs were associated with PTSD-MetS comorbidity and 169 DMRs were associated with PTSD alone (FWER < 0.1). Based on the top 300 differentially methylated CpG sites for PTSD-MetS, significant pathways involved in phospholipase signalling, long-term depression, cholinergic synapse, synthesis and hormone secretion were identified. Pathways associated with ribosome activity, parathyroid hormone secretion and long-term potentiation were enriched in PTSD. PTSD-MetS comorbidity, but not PTSD alone, was marginally associated with accelerated epigenetic ageing (Horvath; p = 0.05). Conclusions: EWAS and DMR analyses identified differentially methylated CpG sites located in genes implicated in innate and autoimmune response, lipid and amino acid metabolism, and mitochondrial activation in PTSD-MetS comorbidity, suggesting differential epigenetic effects on immune function and energy homeostasis. PTSD was associated with differential methylation of genes involved in phospholipid metabolism and neurotransmission. Identifying differentially methylated genes and correlates of epigenetic ageing in PTSD-MetS advances our understanding of the biology underlying this comorbidity and can be used to explore novel therapeutic targets.