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)

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.

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.

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.

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