The purpose of these studies was to examine mediation and moderation processes for the influence of early adversity and current stressful circumstances on maternal sensitivity. Evidence of mediation was found in Study 1 where maternal depression and mothers’ negative appraisal of their infant mediated the influence of early adversity and low family income on maternal sensitivity. Study 1 also examined the influence of the neighborhood. A moderate-mediation model was tested where the mediating influence afore-stated was hypothesized to vary across levels of neighborhood quality. Partial evidence of moderation was found. In the context of a high quality neighborhood, mothers’ early adversity was not associated with maternal depression. Across levels of neighborhood quality, complex relationships emerged between the variables low family income, maternal depression and mothers’ appraisal of infant temperament. In a context of low neighborhood quality, there was no evidence of a direct association between low family income and maternal sensitivity, rather, low family income operated indirectly through maternal depression. In a context of high neighborhood quality, there was evidence for a direct and indirect association between low family income and maternal sensitivity. Study 2 examined associations between variation in the Arginine Vasopressin 1a receptor gene (AVPR1a) and maternal sensitivity, and whether variation in this gene moderated the influence of mothers’ early adversity on sensitivity. Mothers homozygous for the long alleles of the RS3 microsatellite were significantly less sensitive than mothers heterozygous for the long alleles and those homozygous for the short alleles. Homozygosity for the RS3 long alleles moderated the influence of mothers’ early adversity on their sensitivity; the influence of early adversity on maternal sensitivity was most pronounced for mothers with the RS3 long/long genotype. These results suggest that variation in the AVPR1a gene may be important not only for human maternal behavior, but also for stress reactivity.

The purpose of these studies was to examine mediation and moderation processes for the influence of early adversity and current stressful circumstances on maternal sensitivity. Evidence of mediation was found in Study 1 where maternal depression and mothers’ negative appraisal of their infant mediated the influence of early adversity and low family income on maternal sensitivity. Study 1 also examined the influence of the neighborhood. A moderate-mediation model was tested where the mediating influence afore-stated was hypothesized to vary across levels of neighborhood quality. Partial evidence of moderation was found. In the context of a high quality neighborhood, mothers’ early adversity was not associated with maternal depression. Across levels of neighborhood quality, complex relationships emerged between the variables low family income, maternal depression and mothers’ appraisal of infant temperament. In a context of low neighborhood quality, there was no evidence of a direct association between low family income and maternal sensitivity, rather, low family income operated indirectly through maternal depression. In a context of high neighborhood quality, there was evidence for a direct and indirect association between low family income and maternal sensitivity. Study 2 examined associations between variation in the Arginine Vasopressin 1a receptor gene (AVPR1a) and maternal sensitivity, and whether variation in this gene moderated the influence of mothers’ early adversity on sensitivity. Mothers homozygous for the long alleles of the RS3 microsatellite were significantly less sensitive than mothers heterozygous for the long alleles and those homozygous for the short alleles. Homozygosity for the RS3 long alleles moderated the influence of mothers’ early adversity on their sensitivity; the influence of early adversity on maternal sensitivity was most pronounced for mothers with the RS3 long/long genotype. These results suggest that variation in the AVPR1a gene may be important not only for human maternal behavior, but also for stress reactivity.

The frontostriatal dopamine system modulates brain function and is affected by both genetic and environmental factors. Dysfunction of this system is associated with many pathological states, including schizophrenia. The enzyme catechol-O- methyltransferase (COMT) metabolises dopamine and its gene contains a polymorphism (Val¹⁵⁸Met) that affects enzyme activity. Delta-9- tetrahydrocannabinol (THC), the main psychoactive component of cannabis, has been suggested to interact with this polymorphism to increase the risk for psychosis and cognitive impairments. Dopaminergic mechanisms are a plausible candidate for mediating this interaction. I used microdialysis coupled with high performance liquid chromatography (HPLC) to examine the effects of THC on extracellular dopamine and its metabolites in the nucleus accumbens, dorsal striatum and medial prefrontal cortex (mPFC) in freely moving mice. Following acute COMT inhibition with tolcapone, THC increased extracellular dopamine levels in the nucleus accumbens in tolcapone-, but not in vehicle-, treated mice. The introduction of the low activity Met allele into the COMT gene produced a highly specific, novel mouse model of the Val158Met polymorphism. In contrast to the effects of acute COMT inhibition, the Met allele protected against THC-induced changes in accumbal dopamine. No interactive neurochemical effects were observed in the dorsal striatum (pharmacological and genetic study) or in a preliminary study of the mPFC (genetic study only). On a progressive ratio task measuring motivational salience, the direction of the interactive effect between COMT genotype and THC differed between 2 independent cohorts and provided tentative leads that stress/arousal-dependent effects on COMT may have a confounding effect. My data provide evidence that COMT activity modulates the effect of THC on accumbal dopamine function, and suggest the mechanism through which this interaction is mediated differs between acute and lifelong reduction in COMT activity. Through the interactive effect on the dopaminergic system, the data provide a potential mechanism for the reported interaction between COMT and cannabis/THC in determining psychosis risk and cognitive impairments.

In recent years, screening approaches known as two-step methods have been proposed to detect gene-environment interactions for genome-wide association studies (GWAS). Genetic and environmental factors are believed to affect disease outcome as well as various quantitative traits such as height and blood pressure. The performance of the two-step methods has not been demonstrated in the quantitative trait setting. This thesis examines the method proposed by Wang and Abbott (2008) for generating genotyped markers in linkage disequilibrium (LD) and takes this approach in simulating data pertaining to a quantitative trait. The simulation results demonstrate that the two-step methods maintain type I error and have power to detect the quantitative trait locus. In this setting, the EG method (Murcray et al., 2009) is influenced by the strength and structure of the gene-environment dependency, the sample type, and the disease model. As such, the power of the EG method can fluctuate depending on the type of data while the DG method (Kooperberg and LeBlanc, 2008) remains fairly robust across a wide range of scenarios. The performance of the combined two-step approaches (EDGE (Gauderman et al., 2013) and H2 (Murcray et al., 2011) methods) tends to favour the more powerful underlying method. The power of the EDGE method can be improved if DG and EG demonstrates similar power while the H2 method can be made more powerful by choosing the appropriate parameters. / Thesis / Master of Science (MSc)

No description available.

Interest in women's reproductive variation within the subfield of Physical Anthropology known as Human Reproductive Ecology is dominated by energetic models for fecundity that disregard genetic variation as a potential cause of differences in reproduction. Further, a strong correlation between ovarian and uterine markers of fecundity is assumed, although this assumption is not supported by the available data. A polymorphism in the progesterone receptor gene, called PROGINS, shows diminished progesterone response in vitro and is associated with a number of uterine disorders in women. To elucidate the discrepancy between ovarian and uterine markers of fecundity, carriers of the PROGINS variant were compared to non-carriers with regard to endometrial thickness and menstrual cycle characteristics. Gene-environment interactions between PROGINS and life history, lifestyle factors, progesterone levels, anthropometric measures, and physical activity were also considered. The PROGINS polymorphism was found to impact both luteal phase length and menses duration, as well as to modify endometrial sensitivity to life history factors, progesterone levels, anthropometric measures, and physical activity. These results support the notion that PROGINS diminishes progesterone response, and indicate that the polymorphism also alters endometrial sensitivity to acute and chronic energetic stress. The findings of this study indicate that Human Reproductive Ecologists must consider genetically-based variation in sensitivity to energetic stress in future adaptive models of women's reproduction. / Anthropology

The human gut and brain have a bidirectional communication that has shown to play a pivotal role in our health and disease. Literature has shown that microbiota composition and diversity can be influenced by both genetic and environmental factors, contributing to shaping an individual’s microbial composition. The current work includes analysis of the microbiome of several mouse models to better understand how gene-environmental interactions during early development can influence the composition of microbiota within the gut. Here, male and female mice from several strains (C57BL/6, Balb/C, FVB, CD1) and genetically modified mice including T-cell receptor knock out mice (TCRβ-/-δ-/-) and Fragile-X-mice (FMR1-KO) were exposed to early life stressors including lipopolysaccharide (LPS) injection on postnatal day 3 (P3) and/or overnight maternal separation on P9. Fecal samples were collected at P24 and microbiota composition was determined by amplifying the 16s rRNA gene variable 3(v3) region and sequenced using the MiSeq Illumina platform. DADA2, was used to analyze this data in R software. Among the group, strain was found to be significant among alpha and beta diversity metrics while sex and stress were found to contribute to within strain variation, which demonstrated that both genetic and environmental factors are important in shaping an individual’s microbial composition. Secondly, we also explored the role of gut microbiota on the development of the immune system in TCRβ-/-δ-/- and C57BL/6 mice. Mice that lack T-lymphocytes were found to have a lower alpha diversity, as well as separated from their wild-type controls by beta diversity. Several bacterial taxa were found to be influenced by the immune system, demonstrating a bidirectional communication between the gut and T-cells. Lastly, the influence of litter, an environmental factor on microbial composition was explored within inbred mouse strains, C57BL/6 and Balb/C. Litter was found to influence alpha diversity, in which litters among C57BL/6 exhibited the greatest variation in such diversity. Beta diversity was also found to be influenced by litter, as related litters were found to cluster together. Differences in bacterial taxa between the inbred strains were observed and a subset of those taxa were found to be influenced by litter. Hierarchical clustering and co-occurrence analysis revealed different clusters of co-occurring taxa between both strains. These findings demonstrate that environmental factors can contribute to influence the composition of microbiota. / Thesis / Master of Science (MSc)

Estimations of heritability and variance explained due to environmental exposures and interaction effects help in understanding complex diseases. Current methods to detect such interactions rely on variance component methods. These methods have been neces- sary due to the m » n problem, where the number of predictors (m) vastly outnumbers the number of observations (n). These methods are all computationally intensive, which is further exacerbated when considering gene-environment interactions, as the number of predictors increases from m to 2m+1 in the case of a single environmental exposure. Novel methods are thus needed to enable fast and unbiased calculations of the variance explained (R2) for gene-environment interactions in very large samples on multiple traits. Taking advantage of the large number of participants in contemporary genetic studies, we herein propose a novel method for continuous trait R2 estimates that are up to 20 times faster than current methods. We have devised a novel method, monsterlm, that enables multiple linear regression on large regions encompassing tens of thousands of variants in hundreds of thousands of participants. We tested monsterlm with simulations using real genotypes from the UK Biobank. During simulations we verified the properties of monsterlm to estimate the variance explained by interaction terms. Our preliminary results showcase potential interactions between blood biochemistry biomarkers such as HbA1c, Triglycerides and ApoB with an environmental factor relating to obesity-related lifestyle factor: Waist-hip Ratio (WHR). We further investigate these results to reveal that more than 50% of the interaction variance calculated can be attributed to ∼5% of the single-nucleotide polymorphisms (SNPs) interacting with the environmental trait. Lastly, we showcase the impact of interactions on improving polygenic risk scores. / Thesis / Master of Science (MSc)

No / This article describes how the teaching of variation and genetics can give rise to the mistaken idea that genes are the sole determinants of our characteristics, that genes work in isolation to produce genetic disorders, such as cystic fibrosis. It goes on to discuss examples of gene environment interactions that give a more relevant and realistic account of how genes and environment interact in human genetic disease and stem cell technology. Finally, a conceptual model is introduced that might be useful for teaching, in which genes and environment are given equal status in explaining development.

The present thesis is based on four studies focusing on alcohol consumption among Swedish adolescents, and therewith related psychosocial and genetic factors. One main objective was to study the reasons for drinking alcohol among different population - representative samples of adolescents in order to identify motives for drinking. Relationships between these drinking motives, alcohol consumption, and alcohol - related problems were also investigated. Three motives emerged from this study: social - enhancement, coping and dominance. The association with alcohol consumption and alcohol - related problems was positive for social - enhancement and coping motives, but negative for the dominance motive. A significant heritability of alcohol use disorders has been demonstrated by family, adoption and twin studies. Environmental influences have also been acknowledged to play an important role in the development of alcohol use disorders. Moreover, the interaction between genetic and environmental factors is likely to influence the risk - resilience for alcohol use disorders. In view of this knowledge, plausible candidate polymorphisms were considered in gene - environment interaction models. An effect of the genetic polymorphisms was only present when a G x E model was considered. A genetic variant of the clock gene Period2, in an interaction with sleep problems, was studied in relation to alcohol consumption among adolescents. High alcohol consumption was associated with the AA genotype of the PER2 SNP10870 polymorphism, in an interaction with several and frequent sleep problems, among adolescent boys. A genetic variant in the opioid µ receptor 1 gene, in an interaction with alcohol consumption, was studied in relation to depressive symptoms. Depressive symptoms were predicted by the G allele of the OPRM1 A118G polymorphism, in an interaction with high alcohol consumption, among adolescent girls. Additionally, the PER2 SNP10870 and the OPRM1 A118G polymorphisms were studied in a sample of severely alcoholic females. Furthermore, alcohol consumption was assessed by using different instruments, such as biomarkers and surveys. Comparisons were carried out to identify the most suitable method to assess alcohol consumption among adolescents. Questionnaire and interview seemed more suitable tools than biomarkers in this regard.The results eventually support the importance of psychosocial and genetic influences, and their interaction effect on alcohol consumption among adolescents.