No description available.

<p>Advancements in human genomic technology have helped to improve our understanding of how genetic variation plays a central role in the mechanism of disease susceptibility. However, the very high dimensional nature of the data generated from large-scale genetic association studies has limited our ability to thoroughly examine genetic interactions. A prioritization scheme – Variance Prioritization (VP) – has been developed to select genetic variants based on differences in the quantitative trait variance between the possible genotypes using Levene’s test (Pare et al., 2010). Genetic variants with Levene’s test p-values lower than a pre-determined level of significance are selected to test for interactions using linear regression models. Under a variety of scenarios, VP has increased power to detect interactions over an exhaustive search as a result of reduced search space. Nevertheless, the use of Levene’s test does not take into account that the variance will either monotonically increase or decrease with the number of minor alleles when interactions are present. To address this issue, I propose a maximum likelihood approach to test for trends in variance between the genotypes, and derive a closed-form representation of the likelihood ratio test (LRT) statistic. Using simulations, I examine the performance of LRT in assessing the inequality of quantitative traits variance stratified by genotypes, and subsequently in identifying potentially interacting genetic variants. LRT is also used in an empirical dataset of 2,161 individuals to prioritize genetic variants for gene-environment interactions. The interaction p-values of the prioritized genetic variants are consistently lower than expected by chance compared to the non-prioritized, suggesting improved statistical power to detect interactions in the set of prioritized genetic variants. This new statistical test is expected to complement the existing VP framework and accelerate the process of genetic interaction discovery in future genome-wide studies and meta-analyses.</p> / Master of Health Sciences (MSc)

Alcohol dependence (AD) is a serious and common public health problem that contributes to great societal, medical, and legal costs. It has taken work from multiple disciplines, including developmental psychology, genetic epidemiology, and molecular genetics, to achieve our current understanding of environmental and genetic risk factors for AD as well as its variable developmental trajectories. Nevertheless, there is still much to be learned in order to improve treatment outcomes. One approach to augmenting our understanding of this disorder is through genetically informative study designs that either examine risk in aggregate or assess specific susceptibility variants. In this dissertation, we utilize both study designs and provide support for the idea that they are both important and useful approaches to continue to pursue.

Background: The aim of the present article is to explore interaction and correlation effects between familial depression liability and selected adverse (separation and traumatic) events in predicting the first onset of a major depressive episode (MDE) in a 10-year prospective longitudinal community survey. Methods: Analyses are based on 1982 subjects (14 to 24 years at baseline) without baseline MDE who participated during the whole study period and for whom diagnostic information about psychopathology in both parents was available. The offspring’s familial depression liability was determined by aggregating information on parental depressive symptoms obtained from family history data and direct interviews with parents. Data were assessed with the Munich-Composite International Diagnostic Interview according to its DSM-IV algorithms. Results: Adverse events predicted a substantially increased incidence of MDE among respondents with familial liability but not in those without familial liability. There was a significant interaction between familial liability and traumatic events with the strongest effect for the number of severe traumatic events (risk difference = 11.3%; 95% confidence interval = 3.55–19.15). Associations with familial liability were most pronounced for separation events. Conclusions: Adverse events are particularly pathogenic in individuals with familial liability. The involvement of interactions and correlations between familial liability and adversity might depend on type, severity, and number of events. Both processes are suggested to be concomitant rather than exclusive.

Les gènes du métabolisme des xénobiotiques (MX) impliqués dans l’activation et l’élimination des cancérogènes environnementaux pourraient moduler le risque de cancer du sein, mais leurs effets dans ce cancer ont été peu étudiés et sont mal connus. Les objectifs de la thèse étaient d’étudier le rôle des gènes MX dans le cancer du sein d’une part, et dans les niveaux biologiques de cancérogènes mammaires suspectés, d’autre part. Les analyses ont porté sur les données d’une étude cas-témoins en population sur les cancers du sein (étude CECILE). L’association avec le cancer du sein a été étudiée (1) avec les variants du gène NAT2 qui déterminent le type d’acétyleur lent ou rapide de chaque individu ; (2) les polymorphismes des gènes MX étudiés conjointement au niveau de chacun des gènes et au niveau de l’ensemble du pathway à l’aide d’une méthode exploratoire de type « gene-set ». Dans chacune de ces approches, les interactions avec la consommation de tabac ont été étudiées. Dans une dernière partie, nous avons cherché à identifier les polymorphismes des gènes MX prédictifs des concentrations sanguines de polluants organochlorés persistants (p,p’-DDE et PCB153) chez les témoins de l’étude CECILE. Le risque de cancer du sein était augmenté chez les femmes ayant un profil génétique NAT2 d’acétyleuses rapides par rapport aux femmes ayant un profil d’acétyleuses lentes. Parmi les acétyleuses lentes, les femmes fumeuses avaient un risque de cancer du sein augmenté par rapport aux non fumeuses indiquant l’existence d’une interaction tabac-NAT2. L’approche « gene-set » montrait que les polymorphismes au niveau de plusieurs gènes MX et au niveau de l’ensemble du pathway étaient associés collectivement au cancer du sein. L’association entre le cancer du sein et l’ensemble des polymorphismes du pathway XM était observée chez les fumeuses, indiquant le rôle de la consommation de tabac dans cette association. Enfin, nous avons montré l’effet du gène CYP2B6 en tant que déterminant des niveaux sanguins de p,p’-DDE et PCB153. Nos résultats mettent en évidence un rôle des gènes XM dans le cancer du sein qui peut être expliqué par leur fonction dans le métabolisme et l’élimination des cancérogènes environnementaux. / The xenobiotic metabolism (XM) genes involved in the activation and elimination of environmental carcinogens may modulate breast cancer risk, but their effects in breast cancer have been little studied and are poorly understood. The objectives of the PhD were to study the role of XM genes in breast cancer on the one hand, and in the biological levels of suspected breast carcinogens on the other. The analyses were based on a population-based case-control study on breast cancer (CECILE study). We investigated the association of breast cancer (1) with NAT2 gene variants that determine the type of slow or rapid acetylator in each individual; (2) with polymorphisms of XM genes that were studied jointly at the gene and at the XM pathway level using a gene set method. In each of these approaches, interactions with tobacco consumption were studied. In a final section, we sought to identify polymorphisms of XM genes that predict blood concentrations of persistent organochlorine pollutants (p,p'-DDE and PCB153) among the controls of the CECILE study.The risk of breast cancer was increased in women with a NAT2 genetic profile of rapid acetylators compared to women with a profile of slow acetylators. Among slow acetylators, current smokers had an increased risk of breast cancer compared to non-smokers, indicating an interaction between tobacco smoking and NAT2 genotype. The gene set approach showed that polymorphisms at the level of some XM genes and at the level of the entire pathway were collectively associated with breast cancer. The association between breast cancer and all pathway XM polymorphisms was observed in female smokers, indicating a role for tobacco smoking in this association. Finally, we have shown that CYP2B6 gene was a determinant of blood levels of p,p'-DDE and PCB153. Our results highlight a role of XM genes in breast cancer that is explained by their function in the metabolism and elimination of environmental carcinogens.

Background: The aim of the present article is to explore interaction and correlation effects between familial depression liability and selected adverse (separation and traumatic) events in predicting the first onset of a major depressive episode (MDE) in a 10-year prospective longitudinal community survey. Methods: Analyses are based on 1982 subjects (14 to 24 years at baseline) without baseline MDE who participated during the whole study period and for whom diagnostic information about psychopathology in both parents was available. The offspring’s familial depression liability was determined by aggregating information on parental depressive symptoms obtained from family history data and direct interviews with parents. Data were assessed with the Munich-Composite International Diagnostic Interview according to its DSM-IV algorithms. Results: Adverse events predicted a substantially increased incidence of MDE among respondents with familial liability but not in those without familial liability. There was a significant interaction between familial liability and traumatic events with the strongest effect for the number of severe traumatic events (risk difference = 11.3%; 95% confidence interval = 3.55–19.15). Associations with familial liability were most pronounced for separation events. Conclusions: Adverse events are particularly pathogenic in individuals with familial liability. The involvement of interactions and correlations between familial liability and adversity might depend on type, severity, and number of events. Both processes are suggested to be concomitant rather than exclusive.

In just over ten years, internet-based technologies revolutionized several aspects of daily human life, including social interactions. Social media sites (SNSs), such as Facebook, Instagram, and Twitter, have dramatically changed the way people keep in touch or make new acquaintances. On the flipside, recent research have highlighted the risk for and inappropriate use of SNSs, which might result in personal discomfort or a mental disorder. For this reason, it is important to understand how these issues develop starting from the diverse contexts and individual features. The main aim of the present Ph.D. project is to identify to which extent the interaction between psychological components, like perceived parental warmth, and genetic susceptibility to the familiar environment can describe the social behavior online and offline. The underlying hypothesis is that sensibility to the familiar context will represent a positive factor, if the person recalls a good perception of parental care, leading to confident psychological mechanisms in adulthood, hence to more optimal neural responses to social stressors in real life, and to the appropriate use of social media. To this aim, three studies have been performed: •Study 1. Analysis of the impact of perceived early social experience on the formation of interactional patterns in adult social interaction in two different countries (Italy and Singapore); •Study 2. Investigation on how the interaction between genetic features of oxytocin receptor gene polymorphisms and perceived early social experience affect the neurophysiological responses to cries; •Study 3. Exploration of the link between adult psychological dimensions related to social behavior and metrics of usage on Instagram platform. The experimental activities have been performed in two different laboratories: as for the Italian samples, questionnaires and genetic information were collected at the Affiliative Behavior and PhysiologyLaboratory in Rovereto; with regards to the Singaporean sample, participants completed the questionnaires, then were tested for genetics, Near InfraRed Spectroscopy (NIRS), Electrocardiogram (ECG) at the Social and Affective Neuroscience set in Nanyang Technological University. One of the purposes of the overall project was the construction of a rich database, which aims to include information about genetic polymorphisms proved to be sensitive to social environment (oxytocin receptor gene rs53576, rs2254298, and serotonin rs25531), recalled parental warmth, main dimensions of adult attachment, neural and physiological responses to social distress, like listening to cries, and behavior on two main social media platforms, such are Facebook and Instagram. This complex design gives the project several strengths, such as the possibility to focus on the contribution of diverse factors within a bio-psycho-i social frame, that is claimed to be the more appropriate by scientific community standard, in order to have a wider and deeper understanding of human behavior. Secondly, results generated from studies based on this database would allow filling the present gap about social media usage and psychological mechanisms, providing a further comparison with offline behavior. Lastly, results might be helpful when implemented in clinical work to understand if and how social media can become a useful mean in clinical work. The temporary fragility of this project is related to the genetic sample size, as a broader sampling would be necessary to have a comparable amount of the different variants and generate more reliable explanations. However, this data collection represents a starting point, as it resents of temporal constraints. Future efforts are necessary to enrich the dataset and to find appropriate methodologies to examine in depth the interaction between all the factors

Obsessive-compulsive disorder (OCD) is heterogeneous. Clinical presentation of OCD differs by sex and age-of-onset and evidence supports classification based on these subtypes. The prevalence of OCD in the general population is 2%. However, it has been established that women tend to experience onset and exacerbation of OCD during reproductive milestones. In particular, the prevalence of postpartum OCD is between 4 to 9%. This study seeks to examine the effects of past childhood maltreatment and S/Lg-allele status of the 5-HTTLPR polymorphism on perinatal obsessive-compulsive symptoms and aberrant resting state functional connectivity in the postpartum period. Forty women participated in the first visit and sixteen women have been followed up with in the postpartum period. 5-HTTLPR genotype was determined from whole blood samples via polymerase chain reaction and a restriction fragment length digest. We used the Yale-Brown Obsessive-Compulsive Scale and Perinatal Obsessive-Compulsive scale to measure symptom severity. Resting state functional connectivity was determined from functional magnetic resonance imaging data. Obsessive-compulsive symptoms during late pregnancy are significantly predicted by 5-HTTLPR genotype, past history of total childhood maltreatment or childhood emotional neglect and trait anxiety symptoms. Whereas obsessive-compulsive symptoms during the postpartum period are predicted by poor sleep quality and childhood emotional maltreatment or 5-HTTLPR genotype, childhood emotional maltreatment and trait anxiety symptoms. Seed to region-of-interest analysis was employed to evaluate resting state functional connectivity differences between OCD patients and healthy controls in the postpartum period. Compared to healthy controls, OCD patients show greater connectivity between the caudate nucleus with the orbitofrontal cortex, the pars triangularis and the cingulate area. The insular cortex shows decreased connectivity between the right and left, the dorsal anterior cingulate area and the pars opercularis. The amygdala has increased connectivity with the cingulate area, the calcarine fissure, the supramarginal gyrus and decreased connectivity with the gyrus rectus. The above clinical and neuroimaging findings are in line with past work. However, this is the first study to show both 5-HTTLPR genotype and history of childhood maltreatment predict obsessive-compulsive symptoms in a perinatal population. Further, the resting state data replicates findings in the OCD literature but the study is the first to show this in postpartum women. This study serves as a platform for future work to further investigate both gene-environment interactions and distinct neuroimaging correlates in perinatal OCD. / Thesis / Master of Science (MSc)

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

Le but de cette thèse était d’analyser les associations entre plusieurs facteurs environnementaux (consommations maternelles de tabac, d’alcool et de boissons caféinées pendant la grossesse) et médicaux (antécédents d’asthme ou d’eczéma) et les leucémies aiguës de l’enfant, et d’étudier des polymorphismes génétiques susceptibles de modifier ces associations. Les analyses ont été réalisées à partir de l’étude cas-témoins nationale ESCALE réalisée en population générale en 2003 et 2004. Les données sur les antécédents médicaux et les consommations maternelles pendant la grossesse ont été recueillies au cours d’un entretien téléphonique standardisé des mères. Les polymorphismes génétiques d’intérêt ont été sélectionnés suivant une approche candidate sur leur fonctionnalité, dans des gènes impliqués dans le métabolisme du tabac (CYP1A1*2, CYP2E1*5, NQO1*2, EPHX1 et NAT2*5), de l’alcool (CYP2E1*5, ADH1C*2) et de la caféine (NAT2*5), et dans l’allergie (IL4, IL4R, IL10 et IL13). Les données génétiques ont été obtenues à partir de prélèvements de sang chez les cas et de salive chez les témoins, par génotypage de 370 000 SNPs chez les cas et sur puce à façon de 4 500 SNPs chez les témoins, complété par des imputations génotypiques lorsque les polymorphismes candidats n’étaient pas disponibles au génotypage. Au total, les données étaient disponibles pour 493 cas de leucémie aiguë et 442 témoins d’origine européenne.La consommation maternelle de café pendant la grossesse était positivement associée aux leucémies aiguës de l’enfant dans cette étude. Aucune association significative n’était observée avec le tabagisme maternel ou la consommation d’alcool pendant la grossesse. La présence de deux allèles NAT2*5 était associée aux leucémies aiguës lymphoblastiques (Odds Ratio OR=1.9 [1.3-2.7]), mais les analyses ne montraient pas d’association avec les autres polymorphismes des enzymes du métabolisme. Aucune interaction significative n’a été observée entre les polymorphismes candidats et le tabagisme maternel ou les consommations d’alcool ou de boissons caféinées pendant la grossesse. Cependant, les allèles candidats de CYP2E1, NQO1 et EPHX1, trois enzymes impliquées dans le métabolisme du benzène, semblaient interagir entre eux.Les allèles variants dans les gènes IL13, IL4, IL10 et IL4R n’étaient pas associés au risque de leucémie de l’enfant. Les antécédents d’asthme ou d’eczéma étaient plus fréquemment retrouvés chez les témoins que chez les cas (OR=0.7 [0.6-0.9]). Cette association inverse était essentiellement retrouvée chez les enfants porteurs d’un haplotype variant régulant l’expression de l’IL10 (p interaction=0.08) et porteurs de deux allèles de référence pour IL13-rs20541 (p interaction=0.06).En conclusion, ces résultats suggèrent un rôle de la consommation de café dans le risque de leucémie, déjà observé dans la précédente étude de l’équipe, qui devra être répliqué et approfondi. En revanche, aucune association n’a été observée avec la consommation maternelle de tabac ou d’alcool, même en tenant compte des polymorphismes génétiques candidats. L’interaction gène-gène des trois enzymes impliquées dans le métabolisme du benzène est intéressante et devra être explorée dans d’autres études. Enfin, l’association inverse entre le risque de leucémie aiguë et les antécédents d’asthme ou d’eczéma semble limitée aux enfants porteurs de certains polymorphismes des interleukines IL10 et IL13, ce qui pourrait refléter des mécanismes biologiques sous-jacents. Ces hypothèses pourront être testées d’autres études, et en particulier dans l’étude ESTELLE, récemment réalisée par l’équipe. / The aim of this thesis was to analyze the associations between several environmental (maternal consumption of tobacco, alcohol or caffeinated drinks during pregnancy) and medical (history of asthma or eczema) factors and childhood acute leukemia, and to study genetic polymorphisms suspected to modify those associations.The analyses were performed using data from the national population-based case-control ESCALE study conducted in 2003 and 2004. Information about medical history and maternal consumptions during pregnancy was obtained through a standardized telephone interview with the mothers. The genetic polymorphisms were selected using a candidate approach based on their functionality, in genes involved in the metabolism of tobacco (CYP1A1*2, CYP2E1*5, NQO1*2, EPHX1 and NAT2*5), alcohol (CYP2E1*5, ADH1C*2) or caffeine (NAT2*5), and in allergy (IL4, IL4R, IL10 and IL13). Biological samples consisting of blood for cases and saliva for controls allowed for the genotyping of 370,000 SNPs in the cases and 4,500 SNPs in the controls. Where the candidate polymorphisms were not available from the genotyping, genotypic imputation was used to infer those. In total, data was available for 493 acute leukemia cases and 442 controls of European origin. Maternal coffee drinking during pregnancy and, to a lesser extent, cola soda drinking, was positively associated with childhood leukemia in the ESCALE study. No significant association was observed with maternal smoking or alcohol consumption during pregnancy. Carrying two NAT2*5 alleles was associated with acute lymphoblastic leukemia (Odds Ratio OR=1.9 [1.3-2.7]), although the analyses showed no association with the other candidate alleles involved in metabolism. There was no significant interaction between the candidate genetic polymorphisms and maternal consumptions of tobacco, alcohol or caffeinated drinks during pregnancy. However, the candidate alleles of CYP2E1, NQO1 and EPHX1, three enzymes involved in benzene metabolism, seemed to interact together.The variant alleles in IL13, IL4, IL10 and IL4R genes were not associated with childhood leukemia. A history of asthma or eczema was more frequently reported in controls than in cases (OR=0.7 [0.6-0.9]). This inverse association was mostly observed in children carrying a variant haplotype regulating the expression of IL10 (p for interaction=0.08), and carrying two reference alleles for IL13-rs20541 (p for interaction=0.06).As a conclusion, these results suggest a role of maternal coffee drinking during pregnancy in childhood leukemia that had already been reported in a previous French study of the same research team, and needing in-depth study and replication. However, no association was observed with maternal smoking or alcohol drinking, even after taking into account the candidate genetic polymorphisms. The gene-gene interaction of the three enzymes involved in benzene metabolism is interesting and needs to be investigated in other studies. Finally, the inverse association between childhood acute leukemia risk and medical history of asthma or eczema seems to be limited to the children with specific polymorphisms of interleukins IL10 and IL13, which could reflect underlying biological mechanisms. Those hypotheses should be further tested in other studies, such as the ESTELLE study, that has been recently conducted by the team.