Background: Effective interventions for maltreated children are impeded by gaps in our knowledge of the etiopathogenic mechanisms leading from maltreatment to mental disorders. Although some studies have already identified individual risk factors, there is a lack of large-scale multilevel research on how psychosocial, neurobiological, and genetic factors act in concert to modulate risk of internalizing psychopathology in childhood following maltreatment. To help close this gap, we aim to delineate gender-specific pathways from maltreatment to psychological disorder/resilience. To this end, we examine the interplay of specific maltreatment characteristics and psychological, endocrine, metabolomic, and (epi-)genomic stress response patterns as well as cognitive-emotional/social processes as determinants of developmental outcome. Specifically, we will explore endocrine, metabolomic, and epigenetic mechanisms leading from maltreatment to a higher risk of depression and anxiety disorders.

Human genetic data suggests DISC1 (Disrupted-in-schizophrenia 1) is a susceptibility gene for schizophrenia and depression. Disc1 Q31L-/- mutants show depression-like behaviour and Disc1 L100P-/- mutants schizophrenia-like behaviour. Heterozygous mutants show an intermediate phenotype. In a gene-environment interaction study, we exposed heterozygotes to chronic social defeat (CSD) stress and phenotyped behaviour. Disc1, Bdnf(III) and Pde4b mRNA levels were also measured. Moreover, as epigenetic mechanisms may mediate some effects of CSD, we also exposed wildtype mice to CSD concurrently with the histone deacetylase inhibitor valproate. We found that CSD increased anxiety in L100P-/+ mutants, and that levels of Disc1, Bdnf(III) and Pde4b mRNA were higher in this mutant. Valproate treatment did not correct CSD-induced behavioural changes. In conclusion, we have demonstrated an interaction between a strong susceptibility gene for psychiatric disease and an environmental manipulation similar to stressors known to affect mental illness.

Human genetic data suggests DISC1 (Disrupted-in-schizophrenia 1) is a susceptibility gene for schizophrenia and depression. Disc1 Q31L-/- mutants show depression-like behaviour and Disc1 L100P-/- mutants schizophrenia-like behaviour. Heterozygous mutants show an intermediate phenotype. In a gene-environment interaction study, we exposed heterozygotes to chronic social defeat (CSD) stress and phenotyped behaviour. Disc1, Bdnf(III) and Pde4b mRNA levels were also measured. Moreover, as epigenetic mechanisms may mediate some effects of CSD, we also exposed wildtype mice to CSD concurrently with the histone deacetylase inhibitor valproate. We found that CSD increased anxiety in L100P-/+ mutants, and that levels of Disc1, Bdnf(III) and Pde4b mRNA were higher in this mutant. Valproate treatment did not correct CSD-induced behavioural changes. In conclusion, we have demonstrated an interaction between a strong susceptibility gene for psychiatric disease and an environmental manipulation similar to stressors known to affect mental illness.

INTRODUCTION AND AIM - Cardiovascular disease is globally a major risk factor for morbidity and mortality. It is caused by various factors, one of which is an abnormal haemostatic process. Fibrinogen is a haemostatic factor that is considered to be an independent risk factor for cardiovascular disease. Elevated fibrinogen can be caused by environmental and genetic factors which increase the risk of the occurrence of thrombosis. The fibrinogen y' chain, which is one of the three chains of fibrinogen, has two different variants, the yA and y’. The presence of the fibrinogen y’ chain has been associated with thrombotic disorders. Many studies have investigated the fibrinogen variables in Caucasian individuals, but only a few such studies have been conducted on non-Caucasian individuals. The genetic diversity of ethnic groups differs and could cause differences in the fibrinogen variables between these groups. Fibrinogen is known to increase with age; therefore to explain changes over time in fibrinogen concentrations it was also important to investigate whether genetic determinants and possible gene–environment interactions influenced fibrinogen over time. In this study the main aim was to determine the change in the fibrinogen variables over a five-year period within a black South African cohort subdivided according to genotypes associated with fibrinogen variables, and to determine whether the observed changes were modulated by environmental factors. PARTICIPANTS AND METHODS - Data [baseline (n=2010) and follow-up (n=1288)] were collected in the Prospective Urban and Rural Epidemiology (PURE) study during 2005 and 2010 from apparently healthy black men and women aged between 35 and 65 years and residing in rural or urban settlements. Experimental methods included analysis of fibrinogen and fibrinogen y’ concentrations, single nucleotide polymorphisms (SNPs) and determination of environmental factors associated with the fibrinogen variables. RESULTS - The fibrinogen variables increased significantly from 2005 to 2010 in both the rural and urban participants, as well as in both men and women. The major environmental factors that affected the fibrinogen variables were C-reactive protein (CRP), interleukin-6 (IL-6), body mass index (BMI), glycated haemoglobin (HbA1c), age, blood lipids, human immunodeficiency virus (HIV) and tobacco use. Fibrinogen increased consistently from 2005 to 2010 in the respective genotypes of all SNPs analysed, except in the FGG 9340 T>C homozygous mutant carriers. Fibrinogen y’ also increased in general in most genotypes from 2005 to 2010, except in the FGG 10034 C>T mutant allele carriers, where a decrease was observed. It was determined that CRP was the only environmental factor that influenced the change in fibrinogen over time and that FGG 10034 C>T was the only SNP that influenced the change in fibrinogen y’ over the five years. Four gene–environment interactions also influenced fibrinogen on a cross-sectional level, i.e. FGA 2224 G>A with age, FGB Arg448Lys with HIV status, FGB 1643 C>T with urbanisation and FGB 1038 G>A with HbA1c. Only the FGG 9340 T>C with HbA1c interaction was found to predict change in fibrinogen concentrations over the five years. CONCLUSION - Both environmental and genetic factors significantly influenced the fibrinogen variables cross-sectionally as well as prospectively. It was clear that the influence of the environmental factors was mediated by genetic polymorphisms and vice versa, as can be seen by the gene–environment interactions found in this study. An important finding of this study was that the interaction of HbA1c with two SNPs on fibrinogen variables may explain the known inconsistent relationship found between fibrinogen concentrations and diabetes. / MSc (Dietetics), North-West University, Potchefstroom Campus, 2014

Abstract Both genetic and biological and psychosocial environmental risk factors contribute to the aetiology of schizophrenia spectrum disorders. Among the much studied environmental risk indicators are parental Communication Deviance (CD) and the winter or spring birth of a child. Genetic and environmental risk factors do not function in isolation from each other, but gene-environment interactions play a major role in the aetiology of psychotic disorders. The aim of this doctoral thesis is to investigate the role of parental CD as a risk factor (together with other risk indicators) for thought disorders and schizophrenia spectrum disorders in an adoptive child. A systematised review was performed concerning the association between parental Communication Deviance and schizophrenia spectrum and thought disorders in offspring. A meta-analysis could only be performed for the association of parental CD with schizophrenia spectrum disorders in offspring. A large overall effect size was found (0.79, 95%CI 0.21–1.37). The studies included in the systematised review suggest that frequent parental CD and thought disorders in the offspring are connected with each other. The two original studies are based on the data derived from the total sample of the Finnish Adoptive Family Study (n=382). First, the association between parental Communication Deviance scored from individual and family Rorschach protocols and the characteristics of the adoptive child and the parents themselves was investigated. The variability of CD in the adoptive parents in individual and family Rorschach situations was most closely associated with the characteristics of the parents themselves. The association of an adoptive child’s thought and schizophrenia spectrum disorders with the child’s genetic risk for schizophrenia spectrum disorders, winter or spring birth, and parental Communication Deviance, and their interactions was also explored. The adoptive child’s thought disorders were associated only with parental CD. None of the risk indicators or their interactions predicted the adoptee’s schizophrenia spectrum diagnosis. In conclusion, the results indicate that the amount of Communication Deviance is a stable trait of an individual. It may be considered as a risk indicator for schizophrenia spectrum disorders in offspring and, with a lower level of confidence, also for thought disorders in offspring. / Tiivistelmä Skitsofreniaspektrin sairauksien varsinaisia syytekijöitä ei tunneta, mutta niillä on lukuisia sekä perimään että biologiseen ja psykososiaaliseen ympäristöön liittyviä riskitekijöitä. Nykytietämyksen mukaan riskitekijät eivät vaikuta sairauden syntyyn itsenäisesti, vaan perimän ja ympäristön vuorovaikutuksella on merkittävä osuus. Paljon tutkittuja ympäristöön liittyviä riskitekijöitä ovat lapsen talvi- tai kevätsyntymä ja vanhempien hajanainen kommunikaatio. Tässä väitöskirjassa tutkitaan vanhempien hajanaista kommunikaatiota adoptiolapsen ajatushäiriöiden ja skitsofreniaspektrin sairauksien riskitekijänä. Vanhempien hajanaisen kommunikaation ja lapsen skitsofreniaspektrin sairauksien ja ajatushäiriöiden yhteydestä laadittiin systemaattinen katsaus. Meta-analyysi voitiin tehdä vain skitsofreniaspektrin sairauksiin liittyen. Vanhempien hajanaisen kommunikaation ja lapsen skitsofreniaspektrin sairauksien välisellä yhteydellä havaittiin olevan suuri efektikoko (0,79, 95 % luottamusväli 0,21–1,37). Katsaukseen sisällytetyt tutkimukset viittaavat siihen, että vanhempien hajanaisella kommunikaatiolla ja lapsen ajatushäiriöillä on myös yhteys. Väitöskirjan alkuperäistutkimukset perustuvat Suomalaisen adoptiolapsiperhetutkimuksen aineistoon (n= 382). Aluksi tutkittiin vanhempien yksilö- ja perhe-Rorschach-tilanteissa mitatun hajanaisen kommunikaation määrän ja lapsen ja vanhempien ominaisuuksien välistä yhteyttä. Hajanaisen kommunikaation määrän vaihtelu selittyi pääosin vanhempien ominaisuuksilla. Seuraavaksi tutkittiin adoptiolapsen ajatushäiriöiden ja skitsofreniaspektrin sairauksien yhteyttä lapsen skitsofreniaspektrin sairauksille altistavan perimän, talvi- tai kevätsyntymän ja vanhempien hajanaisen kommunikaation kanssa. Huomioon otettiin myös riskitekijöiden yhteisvaikutukset. Mikään riskitekijä tai niiden yhteisvaikutus ei ollut yhteydessä lapsen skitsofreniaspektrin sairauteen. Lapsen ajatushäiriöt olivat yhteydessä ainoastaan vanhempien hajanaiseen kommunikaatioon. Tutkimuksen tulokset osoittavat, että vanhempien hajanainen kommunikaatio on kohtalaisen muuttumaton piirre, joka on lapsen skitsofreniaspektrin sairauksien riskitekijä. Tulokset viittaavat myös siihen, että vanhempien hajanainen kommunikaatio voi olla lapsen ajatushäiriöiden riskitekijä.

Memory deficits and executive dysfunction are highly prevalent among HIV-infected adults. These conditions can affect their quality of life, antiretroviral adherence, and HIV risk behaviors. Several factors have been suggested including the role of genetics in relation to HIV disease progression. This dissertation aimed to determine whether genetic differences in HIV-infected individuals were correlated with impaired memory, cognitive flexibility and executive function and whether cognitive decline moderated alcohol use and sexual transmission risk behaviors among HIV-infected alcohol abusers participating in an NIH-funded clinical trial comparing the efficacy of the adapted Holistic Health Recovery Program (HHRP-A) intervention to a Health Promotion Control (HPC) condition in reducing risk behaviors. A total of 267 individuals were genotyped for polymorphisms in the dopamine and serotonin gene systems. Results yielded significant associations for TPH2, GALM, DRD2 and DRD4 genetic variants with impaired executive function, cognitive flexibility and memory. SNPs TPH2 rs4570625 and DRD2 rs6277 showed a risk association with executive function (odds ratio = 2.5, p = .02; 3.6, p = .001). GALM rs6741892 was associated with impaired memory (odds ratio = 1.9, p = .006). At the six-month follow-up, HHRP-A participants were less likely to report trading sex for food, drugs and money (20.0%) and unprotected insertive or receptive oral (11.6%) or vaginal and/or anal sex (3.2%) than HPC participants (49.4%, p

Background: Effective interventions for maltreated children are impeded by gaps in our knowledge of the etiopathogenic mechanisms leading from maltreatment to mental disorders. Although some studies have already identified individual risk factors, there is a lack of large-scale multilevel research on how psychosocial, neurobiological, and genetic factors act in concert to modulate risk of internalizing psychopathology in childhood following maltreatment. To help close this gap, we aim to delineate gender-specific pathways from maltreatment to psychological disorder/resilience. To this end, we examine the interplay of specific maltreatment characteristics and psychological, endocrine, metabolomic, and (epi-)genomic stress response patterns as well as cognitive-emotional/social processes as determinants of developmental outcome. Specifically, we will explore endocrine, metabolomic, and epigenetic mechanisms leading from maltreatment to a higher risk of depression and anxiety disorders.

No description available.

Worldwide, alcohol is the third leading risk factor for disease burden, while its harmful use leads to 2.5 million deaths every year. Alcohol dependence (AD) is a complex disease, with devastating effects on individuals, families, and society. It is estimated that 76.3 million people worldwide have suffered from alcohol use disorders (AUD), including alcohol abuse and AD. Alcohol withdrawal or alcohol withdrawal symptom (AWS) refers to a cluster of symptoms that may occur when a heavy drinker suddenly stops or significantly reduces their alcohol intake. These symptoms can start as early as 2 h after the last drink, persist for weeks, and range from mild anxiety and shakiness to severe complications, such as seizures and delirium tremens. Family, twin, and adoption studies have indicated that genetic and environmental factors and their interactions contribute to the development of AD and related phenotypes, with a heritability coefficient of more than 0.5 for AD. Whole-genome linkage and candidate gene association studies have successfully identified several chromosome regions and genes that are related to AD and AWS. Furthermore, gene expression analysis, epigenetic studies, and genome-wide association studies (GWAS) have provided regions and loci for AWS. This chapter reviews the recent findings in genetic studies of AWS.

Contexte : Le développement cognitif est important pour la santé et le bien-être, car il permet aux individus de s’épanouir socialement, psychologiquement et physiquement. Pour assurer un développement cognitif optimal, nous devons mieux comprendre comment l’environnement de la petite enfance influence le développement du jeune enfant. La dépression maternelle au cours de la petite enfance est une problématique de santé prévalente (11-25%) et un facteur de risque reconnu pour les difficultés cognitives des jeunes enfants. Il existe des lacunes importantes dans notre compréhension des mécanismes longitudinaux via lesquels la dépression maternelle est associée au développement cognitif des enfants. Mieux comprendre comment la dépression maternelle est associée à un développement cognitif sous optimal et les conditions sous lesquelles cette association est plus ou moins forte permettrait l’élaboration d’interventions plus efficaces. Objectifs : L’objectif général de cette thèse est d’examiner les médiateurs et modérateurs de l’association entre la dépression maternelle et le développement cognitif des enfants en utilisant le « Developmental Model for Understanding Mechanisms of Transmission » comme cadre conceptuel. Les objectifs spécifiques sont de : (1) résumer la littérature portant sur les médiateurs de l’association entre la dépression maternelle et le développement cognitif; (2) examiner le rôle médiateur des expériences scolaires dans l’association entre la dépression maternelle et la performance scolaire, ainsi que le rôle modérateur du sexe de l’enfant; (3) examiner le rôle des mécanismes gène-environnement dans l’association entre la dépression maternelle et la maturité scolaire; et (4) effectuer une méta-analyse sur le rôle modérateur du sexe dans l’association entre la dépression maternelle et les difficultés cognitives. Méthodes : La réalisation d’une revue systématique et d’une méta-analyse a permis d’accomplir les objectifs 1 et 4. Les données de l’Étude Longitudinale du Développement des enfants du Québec ont été utilisées pour répondre à l’objectif 2 : la dépression maternelle a été auto-rapportée entre la naissance de l’enfant et ses 5 ans; la victimisation par les pairs et l’engagement scolaire ont été rapportés par les parents, l’enseignant et l’enfant (entre 6 et 10 ans); la performance scolaire a été évalué à l’âge de 12 ans. Les données de l’Étude sur les Jumeaux Nouveau-nés du Québec ont été utilisées pour répondre à l’objectif 3 : la dépression maternelle a été auto-rapportée à 6 et 18 mois et la maturité scolaire a été évaluée lorsque l’enfant avait 5 ans. Des modèles d’équations structurelles, ajustés pour les facteurs de confusion, ont été utilisés pour estimer les associations dans les deux cohortes. Résultats : Les articles dans cette thèse démontrent que (1) la majorité des études ont identifié les émotions, les cognitions, et les comportements maternels comme des médiateurs de l'association entre la dépression maternelle et le développement cognitif; (2) l'engagement scolaire est un médiateur de l'association entre la dépression maternelle et la performance scolaire, mais ce, seulement chez les filles; (3) il existe une interaction environnement-environnement dans l'association entre la dépression maternelle et la maturité scolaire; et (4) les garçons sont plus à risque que les filles d’obtenir de faibles scores cognitifs après avoir été exposés à la dépression maternelle. Conclusions : Dans l’ensemble, les résultats suggèrent que la dépression maternelle est plus fortement associée au développement cognitif des garçons que celui des filles. De plus, pour les filles, l’engagement scolaire est un médiateur important de l’association entre la dépression maternelle et la performance scolaire. Enfin, promouvoir les pratiques parentales positives pourrait atténuer l’association négative entre la dépression maternelle et les faibles résultats cognitifs des enfants. Des études additionnelles portant sur d’autres médiateurs et modérateurs, en particulier chez les garçons, permettront d’améliorer nos connaissances sur l’association entre la dépression maternelle et le développement cognitif. / Context: Cognitive development is an important building block of health and wellbeing because it equips individuals with the necessary skills to increase control over and improve their health as they age. To ensure healthy cognitive development, we need to better understand how the early childhood environment influences development. Maternal depression in early childhood is a prevalent (11-25%) public health problem and a robust risk factor for poor cognitive outcomes in the child. However, there remain important gaps in our understanding of the longitudinal mechanisms through which it influences children’s cognitive outcomes. Understanding why and for whom this association exists can inform the development of interventions to promote healthy child development. Objectives: The overall aim of this dissertation is to examine mediating and moderating factors of the association between maternal depression and children’s cognitive development using the Developmental Model for Understanding Mechanisms of Transmission as a framework. Specific objectives – each corresponding to a research paper forming the body of this dissertation – are to: (1) summarize existing evidence on mediators of the association between maternal depression and children’s cognitive development; (2) examine the mediating role of children’s school experiences in the association between maternal depression and academic performance, including the moderating role of child’s sex in these associations; (3) examine the role of gene-environment mechanisms in the association between maternal depression and children’s cognitive school readiness; and (4) perform a meta-analysis of the moderating role of child’s sex in the association between maternal depression and cognitive outcomes across childhood and adolescence. Methods: Systematic review and meta-analytic methods were used to address objectives 1 and 4. For objective 2, data from the Québec Longitudinal Study of Child Development were used. Maternal depression was self-reported (between child’s ages 5 months and 5 years); peer victimization and school engagement were parent, teacher, and child-reported (6-10 years); and academic performance was assessed when children were 12 years. Data from the Québec Newborn Twin Study were used for objective 3: self-reported maternal depression (6 and 18 months) and assessment of children’s cognitive school readiness (5 years). Structural equation models, adjusted for confounders where necessary, were used to estimate associations in both cohorts. Results: The studies in this dissertation show that (1) only a handful of studies have examined mediators of the association between maternal depression and cognitive development, with most identifying maternal cognitions, behaviours, and affect as a mediator; (2) school engagement mediates the association between maternal depression and academic performance in girls only; (3) genetic contributions to children’s cognitive school readiness decrease – while environmental contributions increase – as the level of maternal depression increases; and (4) sex moderates the association between maternal depression and cognitive development, with boys at higher risk of poor cognitive outcomes. Conclusion: These findings suggest that addressing maternal cognitions, behaviours, and affect can help mitigate the negative effect of maternal depression on children’s cognitive outcomes at the population level. They also suggest that boys are more negatively affected by maternal depression, and that for girls, addressing the impact of maternal depression on their school engagement may lead to improved cognitive outcomes. Further research on additional mediators and moderators can help strengthen our understanding of the association between maternal depression and children’s cognitive development.