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Background\ud Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWAS).\ud Methods\ud GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European Ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with LD-score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program (MVP) GWAS of PTSD total symptoms.\ud Results\ud GWAS of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four out of these 9 PTSD loci were independently replicated in MVP.\ud Conclusion\ud Through using a quantitative trait measure of PTSD, we identify novel risk loci not previously identified using prior case/control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD., PTSD has been associated with DNA methylation of specific loci in the genome, but studies have been limited by small sample sizes. Here, the authors perform a meta-analysis of DNA methylation data from 10 different cohorts and identify CpGs in AHRR that are associated with PTSD.

Objective: The first two years of life are a critical period of rapid brain development. Since early neurodevelopment is influenced by prenatal risk factors and genetics, neonatal biomarkers can potentially provide the opportunity to detect early signs of neurodevelopmental delay. We analyzed associations between DNA methylation levels from cord blood, neonatal MRI imaging data, and neurodevelopmental delay at two years of age. Methods: Neurodevelopment was assessed in 161 children from the South African Drakenstein Child Health Study at two years of age using the Bayley Scales of Infant and Toddler Development. We performed an epigenome-wide association study of neurodevelopmental delay using DNA methylation levels from cord blood. A mediation analysis was conducted to analyze if associations between differential methylation and neurodevelopmental delay were mediated by changes in neonatal brain volumes. Results: We found epigenome-wide significant associations between severe neurodevelopmental delay and differential methylation in the SPTBN4 locus (cg26971411, p-value=3.10x10-08), an intergenic region on chromosome 11 (cg00490349, p-value=2.41x10-08) and in the NBPF8 locus (FDR p-value for the region=9.06x10-05). While these associations were not mediated by neonatal brain volume, neonatal caudate volumes were independently associated with severe neurodevelopmental delay, particularly with language development (p-value=0.0443) and delay in motor function (p-value=0.0082). Conclusion: Differential methylation levels from cord blood and increased neonatal caudate volumes were associated with severe neurodevelopmental delay at two years of age. If confirmed by future studies, our findings could have implications for early detection of developmental delay and timely implementation of interventions, which are essential for positive child development.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

Background There have been considerable recent advances in understanding the genetic architecture of anxiety disorders and posttraumatic stress disorder (PTSD), as well as the underlying neurocircuitry of these disorders. However, there is little work on the concordance of genetic variations that increase risk for these conditions, and that influence subcortical brain structures. We undertook a genome-wide investigation of the overlap between the genetic influences from single nucleotide polymorphisms (SNPs) on volumes of subcortical brain structures and genetic risk for anxiety disorders and PTSD. Method We obtained summary statistics of genome-wide association studies (GWAS) of anxiety disorders (Ncases=?7016, Ncontrols=?14,745), PTSD (European sample; Ncases=?2424, Ncontrols=?7113) and of subcortical brain structures (N?=?13,171). SNP Effect Concordance Analysis (SECA) and Linkage Disequilibrium (LD) Score Regression were used to examine genetic pleiotropy, concordance, and genome-wide correlations respectively. SECAs conditional false discovery was used to identify specific risk variants associated with anxiety disorders or PTSD when conditioning on brain related traits. Results For anxiety disorders, we found evidence of significant concordance between increased anxiety risk variants and variants associated with smaller amygdala volume. Further, by conditioning on brain volume GWAS, we identified novel variants that associate with smaller brain volumes and increase risk for disorders: rs56242606 was found to increase risk for anxiety disorders, while two variants (rs6470292 and rs683250) increase risk for PTSD, when conditioning on the GWAS of putamen volume. Limitations Despite using the largest available GWAS summary statistics, the analyses were limited by sample size. Conclusions These preliminary data indicate that there is genome wide concordance between genetic risk factors for anxiety disorders and those for smaller amygdala volume, which is consistent with research that supports the involvement of the amygdala in anxiety disorders. It is notable that a genetic variant that contributes to both reduced putamen volume and PTSD plays a key role in the glutamatergic system. Further work with GWAS summary statistics from larger samples, and a more extensive look at the genetics underlying brain circuits, is needed to fully delineate the genetic architecture of these disorders and their underlying neurocircuitry.

Publisher's version (útgefin grein), Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk., We want to thank Susanne Sauer and Maik Ködel for their technical assistance and Jessica Keverne for language editing. We thank all mothers who took part in the on-going PREDO study. We are grateful to all the families in Norway who participate in the on-going MoBa cohort study. We thank the Drakenstein Child Health Study staff, and the clinical and administrative staff of the Western Cape Government Department of Health at Paarl Hospital and at the clinics for support of the Study. We also thank our collaborators and students. Finally, we thank all mothers and children enroled in the Drakenstein Child Health Study. We thank the research participants and employees of 23andMe, Inc. for their contribution to this study. This work was supported by the Academy of Finland (E.K., H.L., K.R., and J.L.); University of Helsinki Research Funds (J.L., M.L.P., and H.L.), British Heart Foundation (RMR); Tommy’s (RMR); European Commission (EK, KR, Horizon 2020 Award SC1–2016-RTD-733280 RECAP); NorFace DIAL (E.K., KR PremLife); Foundation for Pediatric Research (E.K.); Juho Vainio Foundation (E.K.); Novo Nordisk Foundation (E.K.); Signe and Ane Gyllenberg Foundation (E.K., K.R.); Sigrid Jusélius Foundation (E.K.); Finnish Medical Foundation (H.L.); Jane and Aatos Erkko Foundation (H.L.); Päivikki and Sakari Sohlberg Foundation (H.L., P.M.V.); the Clinical Graduate school in Pediatrics and Obstetrics/Gynaecology in University of Helsinki (P.M.V.). The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no N01-ES-75558), NIH/NINDS (grant no.1 UO1 NS 047537–01 and grant no.2 UO1 NS 047537–06A1). For this work, MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and the Norwegian Research Council/BIOBANK (grant no 221097). This work was also partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. The Drakenstein Child Health Study is supported by the Bill and Melinda Gates Foundation (OPP 1017641); with additional support for this work from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NICHD) under Award Number R21HD085849; and the Fogarty International Center (FIC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support for H.J.Z., D.J.S. and N.K., and for research reported in this publication was by the South African Medical Research Council (SAMRC); N.K. receives support from the SAMRC under a Self-Initiated Research Grant. The views and opinions expressed are those of the authors and do not necessarily represent the official views of the SAMRC. This work was also funded by the German Federal Ministry of Education and Research through the Research Consortium Integrated Network IntegraMent (grant 01ZX1314H) under the auspices of the e:Med Programme (NSM). The UCI cohort was supported by a European Research Area Network (ERA Net) Neuron grant (01EW1407A, CB) and National Institutes of Health grant (R01 HD-060628, CB) as well as NIH grant R01 MH-105538 (PDW). This work was also funded by the Canadian Institute for Advanced Research, Child and Brain Development Program, Toronto, ON, Canada (KJOD).

DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity. Here, through genome-wide differential gene expression survey of post-traumatic stress disorder (PTSD) with comorbid depression (PTSD&Dep), we find that blood DICER1 expression is significantly reduced in cases versus controls, and replicate this in two independent cohorts. Our follow-up studies find that lower blood DICER1 expression is significantly associated with increased amygdala activation to fearful stimuli, a neural correlate for PTSD. Additionally, a genetic variant in the 3′ un-translated region of DICER1, rs10144436, is significantly associated with DICER1 expression and with PTSD&Dep, and the latter is replicated in an independent cohort. Furthermore, genome-wide differential expression survey of miRNAs in blood in PTSD&Dep reveals miRNAs to be significantly downregulated in cases versus controls. Together, our novel data suggest DICER1 plays a role in molecular mechanisms of PTSD&Dep through the DICER1 and the miRNA regulation pathway.

Psychological trauma - including exposure to intimate partner violence (IPV) - is highly prevalent in South Africa, and may result in posttraumatic stress disorder (PTSD) in a subset of individuals. Pregnant women and new mothers are particularly vulnerable; and trauma exposure and PTSD in this sub-group may be associated with a number of adverse maternal-child sequelae including poor birth outcomes and impaired infant neurodevelopment. Risk factors for psychological trauma exposure, and for subsequent PTSD, are likely to include environmental and genetic influences. Given the high burden of trauma and related disorders, the unique genetic ancestry, and the relative paucity of empirical data, further work in South African populations is warranted. This thesis aimed to investigate a number of questions about trauma and PTSD in the Drakenstein Child Health Study (an ongoing South African birth cohort study), including their risk factors, their impact on infant birth anthropometry and development, and their genetic correlations. This thesis includes five publications, all presenting data from the Drakenstein Child Health Study. Pregnant women were recruited from two clinics in the Drakenstein sub-district - a peri-urban community outside Cape Town, Western Cape. Sociodemographic characteristics; psychosocial risk factors (including depression, stressful life events, psychological distress and alcohol and substance misuse); trauma exposure (childhood trauma, IPV and lifetime trauma); and PTSD were assessed using validated and reliable self-reported questionnaires, as well as diagnostic psychiatric interviews.

Violence against women is a global public health problem. Exposure to intimate partner violence (IPV) during pregnancy has been associated with a number of adverse maternal and fetal outcomes, including delivery of a low birthweight (LBW) infant. However, there is a paucity of data from low-middle income countries (LMIC). We examined the association between antenatal IPV and subsequent LBW in a South African birth cohort. This study reports data from the Drakenstein Child Lung Health Study (DCLHS), a multidisciplinary birth cohort investigation of the influence of a number of antecedent risk factors on maternal and infant health outcomes over time. Pregnant women seeking antenatal care were recruited at two different primary care clinics in a low income, semi-rural area outside Cape Town, South Africa. Antenatal trauma exposure was assessed using the Childhood Trauma Questionnaire (CTQ) and an IPV assessment tool specifically designed for the purposes of this study. Potential confounding variables including maternal sociodemographics, pregnancy intention, partner support, biomedical and mental illness, substance use and psychosocial risk were also assessed. Bivariate and multiple regression analyses were performed to determine the association between IPV during pregnancy and delivery of an infant with LBW and/or low weight-for-age z (WAZ) scores. The final study sample comprised 263 mother-infant dyads. In multiple regression analyses, the model run was significant [r2 = 0.14 (adjusted r2 = 0.11, F(8, 212) = 4.16, p = 0.0001]. Exposure to physical IPV occurring during the past year was found to be significantly associated with LBW [t = -2.04, p = 0.0429] when controlling for study site (clinic), maternal height, ethnicity, socioeconomic status, substance use and childhood trauma. A significant association with decreased WAZ scores was not demonstrated. Exposure of pregnant women to IPV may impact newborn health. Further research is needed in this field to assess the relevant underlying mechanisms, to inform public health policies and to develop appropriate trauma IPV interventions for LMIC settings.

Violence against women is a global public health problem. Exposure to intimate partner violence (IPV) during pregnancy has been associated with a number of adverse maternal and fetal outcomes, including delivery of a low birthweight (LBW) infant. However, there is a paucity of data from low-middle income countries (LMIC). We examined the association between antenatal IPV and subsequent LBW in a South African birth cohort. This study reports data from the Drakenstein Child Lung Health Study (DCLHS), a multidisciplinary birth cohort investigation of the influence of a number of antecedent risk factors on maternal and infant health outcomes over time. Pregnant women seeking antenatal care were recruited at two different primary care clinics in a low income, semi-rural area outside Cape Town, South Africa. Antenatal trauma exposure was assessed using the Childhood Trauma Questionnaire (CTQ) and an IPV assessment tool specifically designed for the purposes of this study. Potential confounding variables including maternal sociodemographics, pregnancy intention, partner support, biomedical and mental illness, substance use and psychosocial risk were also assessed. Bivariate and multiple regression analyses were performed to determine the association between IPV during pregnancy and delivery of an infant with LBW and/or low weight-for-age z (WAZ) scores. The final study sample comprised 263 mother-infant dyads. In multiple regression analyses, the model run was significant [r2 = 0.14 (adjusted r2 = 0.11, F(8, 212) = 4.16, p = 0.0001]. Exposure to physical IPV occurring during the past year was found to be significantly associated with LBW [t = -2.04, p = 0.0429] when controlling for study site (clinic), maternal height, ethnicity, socioeconomic status, substance use and childhood trauma. A significant association with decreased WAZ scores was not demonstrated. Exposure of pregnant women to IPV may impact newborn health. Further research is needed in this field to assess the relevant underlying mechanisms, to inform public health policies and to develop appropriate trauma IPV interventions for LMIC settings.

Background: Cord blood is a commonly used tissue in environmental, genetic, and epigenetic population studies due to its ready availability and potential to inform on a sensitive period of human development. However, the introduction of maternal blood during labor or cross-contamination during sample collection may complicate downstream analyses. After discovering maternal contamination of cord blood in a cohort study of 150 neonates using Illumina 450K DNA methylation (DNAm) data, we used a combination of linear regression and random forest machine learning to create a DNAm-based screening method. We identified a panel of DNAm sites that could discriminate between contaminated and non-contaminated samples, then designed pyrosequencing assays to pre-screen DNA prior to being assayed on an array. Results: Maternal contamination of cord blood was initially identified by unusual X chromosome DNA methylation patterns in 17 males. We utilized our DNAm panel to detect contaminated male samples and a proportional amount of female samples in the same cohort. We validated our DNAm screening method on an additional 189 sample cohort using both pyrosequencing and DNAm arrays, as well as 9 publically available cord blood 450K data sets. The rate of contamination varied from 0 to 10% within these studies, likely related to collection specific methods. Conclusions: Maternal blood can contaminate cord blood during sample collection at appreciable levels across multiple studies. We have identified a panel of markers that can be used to identify this contamination, either post hoc after DNAm arrays have been completed, or in advance using a targeted technique like pyrosequencing.

Introduction: Cardiovascular disorders contribute significantly to mortality and morbidity amongst patient's psychotic disorders such as schizophrenia and bipolar mood disorders. In addition to conventional risk factors for cardiovascular disorders (smoking, alcohol use, inadequate physical activity, hypertension, diabetes, dyslipidaemia, obesity and metabolic syndrome, and non-modifiable factors such as sex, age and social-economic status) exposure to potentially traumatic events, psychological distress, comorbidity of other medical conditions, and use of antipsychotics may also increase cardiovascular risk in patients with psychosis. There is also evidence to suggest that intervention to mitigate such cardiovascular risk factors are suboptimal, hence contributing to poor outcomes. Despite growing interest in cardiovascular health, there remains a paucity of data on the prevalence of the various cardiovascular risk factors among patients with psychosis in low resource settings such as Sub-Saharan Africa. This is likely to differ from high resource contexts given social-cultural and economic differences as well as differences in the health systems. In order to design contextually relevant cardiovascular risk screening, treatment and prevention guidelines that can be integrated into routine care of the mentally ill patients in low- and middle-income countries (LMICs), further work in this setting is warranted. Objectives: The aim of this thesis was to establish the cardiovascular risk profile among patients treated for psychotic disorders at Moi Teaching and Referral Hospital (MTRH) in Eldoret, Western Kenya. Specific objectives were as follows: 1. To conduct a literature review on the burden and etiological mechanisms of cardiovascular risk in patients with psychosis, with a focus on LMIC. 2. To compare the prevalence, as well as sociodemographic and clinical correlates, of conventional cardiovascular risk factors (smoking, alcohol intake, poor diet, and lack of exercise, diabetes mellitus, hypertension, obesity, dyslipidaemia and metabolic syndrome) in patients with psychosis versus matched controls. 3. To establish the prevalence and correlates of non-conventional risk factors; psychological distress, traumatic events (lifetime and childhood trauma) and comorbid medical disorders in patients with psychosis and controls, and to delineate how these risk factors contribute to the overall cardiovascular risk. 4. To describe current psychopharmacological treatments and explore potential associations with cardiovascular risk among patients with psychosis. 5. To explore the overall 10-year cardiovascular disease risk, as well as the social demographic and clinical correlates among patients and controls. 6 .To determine the proportion of untreated metabolic disorders (hypertension, diabetes mellitus, and dyslipidaemia) in patients with psychotic disorders and matched controls. Methods: This was a cross-sectional descriptive survey comparing 300 patients with psychosis and 300 controls at Moi Teaching and Referral Hospital, Western Kenya. A paper based researcher-administered questionnaire was used to collect data on demographic variables (age, sex, education level, and marital status), and risk factors (smoking, alcohol intake, diet, physical activity). We used the Composite International Diagnostic Interview (CIDI) to assess for presence of other chronic medical disorders. Data on childhood trauma were obtained using the Childhood Trauma Questionnaire (CTQ) while the Life Events Checklist (LEC) was used to obtain data on lifetime exposure to potentially traumatic events. Data on psychological distress among controls were obtained using the Kessler-10 questionnaire. Measurements of weight, height, abdominal circumference and blood pressure were taken from each of the participants. Blood was drawn for measurement of glucose level and lipid profile. Data analysis was undertaken using Stata version 15. T-tests were used to compare continuous variables while Pearson chi-squared tests was used for categorical variables. Regression modelling was undertaken to assess associations between sociodemographic and clinical predictor variables and the cardiovascular risk factors. Results: Data collection took place between July 2018 and March 2019. The mean age of patients was 33 years and of controls was 35 years. Compared to controls, patients were more likely to be unmarried (46% vs 33% p< 0.001), and were reduced among females (OR 0.41 p20). The estimated 10 year cardiovascular risk was significantly associated with female Sex (p=0.007), age (p