Inferring and anticipation of genetic networks based on experimental data and environmental measurements is a challenging research problem of mathematical modeling. In this thesis, we discuss gene-environment network models whose dynamics are represented by a class of time-continuous systems of ordinary differential equations containing unknown parameters to be optimized. Accordingly, time-discrete version of that model class is studied and improved by using different numerical methods. In this aspect, 3rd-order Heun&rsquo / s method and 4th-order classical Runge-Kutta method are newly introduced, iteration formulas are derived and corresponding matrix algebras are newly obtained. We use nonlinear mixed-integer programming for the parameter estimation and present the solution of a constrained and regularized given mixed-integer problem. By using this solution and applying the 3rd-order Heun&rsquo / s and 4th-order classical Runge-Kutta methods in the timediscretized model, we generate corresponding time-series of gene-expressions by this thesis. Two illustrative numerical examples are studied newly with an artificial data set and a realworld data set which expresses a real phenomenon. All the obtained approximate results are compared to see the goodness of the new schemes. Different step-size analysis and sensitivity tests are also investigated to obtain more accurate and stable predictions of time-series results for a better service in the real-world application areas. The presented time-continuous and time-discrete dynamical models are identified based on given data, and studied by means of an analytical theory and stability theories of rarefication, regularization and robustification.

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Background: Meat consumption is associated with an elevated risk of colorectal cancer (CRC); exposure to heterocyclic aromatic amines (HAAs), carcinogens produced when meat is cooked at high temperatures, is one hypothesized explanation for this relationship. HAAs form adducts with DNA; left unrepaired, DNA adducts can induce mutations which may initiate and/or promote the development of colorectal adenomas, precursors to the vast majority of CRCs. Along this continuum, genetic differences in the ability to biotransform or metabolize HAAs and repair DNA is postulated to modify the HAA-CRC relationship. Methods: This thesis examined the HAA-CRC relationship in two studies (Phase 1 and 2). In a cross-sectional study of 99 healthy volunteers, Phase 1 investigated the relationship between dietary exposure to HAAs and the levels of bulky DNA adducts in blood leukocytes. In Phase 2, a cross-sectional study examined the relationships between dietary exposures to: a) HAAs and; b) meat mutagenicity, and the prevalence of colorectal adenomas among 342 patients undergoing a screening colonoscopy. Both Phase 1 and 2 examined potential gene-diet interactions between dietary HAAs and genetic factors relevant to the biotransformation of HAAs and DNA repair. Results: In Phase 1, an interaction was observed for dietary HAAs and NAT1 polymorphisms where a positive association between HAA intakes and bulky DNA adduct levels was found among those with the NAT1 slow acetylator genotype, hypothesized to confer a lower ability to biotransform HAAs. In Phase 2, polymorphisms in genes involved in the biotransformation of HAAs (CYP1B1 rs10012 and rs1056827) and DNA repair (XPC rs2228001) were found to determine colorectal adenoma risk. As well, gene-diet interactions were observed for dietary HAAs/meat mutagenicity exposures and polymorphisms in CYP1B1 and XPD (rs13181 and rs1799793). Overall, a higher risk of colorectal adenoma was observed with higher HAA and/or meat mutagenicity exposures among those with polymorphisms which confer a greater activity to biotransform HAAs and/or a lower ability to repair DNA. Conclusion: This research supports the contribution of dietary HAAs and genetic susceptibility to the risk of developing colorectal adenomas and highlighted bulky DNA adduct formation as a potential biologic pathway through which HAAs may influence cancer risk. / Thesis (Ph.D, Community Health & Epidemiology) -- Queen's University, 2014-04-25 11:32:30.392

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Background: Parkinson’s disease (PD) is a complex disease with a multi-factorial aetiology, comprising both genetic and environmental risk factors. The disease pathology is progressive and neurodegenerative where dopaminergic nerve cell death occurs predominantly in the substantia nigra pars compacta (SNpc) with the subsequent loss of the dopamine neurotransmitter in the basal ganglia. The most significant risk factors for PD include an advancing age and a family history of the disease, while environmental and lifestyle risk factors such as pesticide exposure and smoking are widely accepted as risk altering exposures. Currently up to 10% of PD is attributed to Mendelian inherited PD at one of 13 PARK loci in 9 genes. The pursuit of common susceptibility alleles for idiopathic PD has proven challenging with only a few loci reproducibility associated with an altered risk. The aim of this thesis is to study, using a candidate gene case-control design, the potential role of genetic variants in PD. The APOE candidate gene was hypothesized to modify the risk of PD as it is a proven modifier of Alzheimer’s disease (AD). The common pathological finding in PD of elevated levels of iron within the SNpc is proposed to increase the oxidative state of the nerve cells and predispose the dopaminergic neurons to apoptosis. Therefore, susceptibility alleles within the candidate genes that regulate iron metabolism and homeostasis are hypothesized to alter iron metabolism and predispose to iron-induced neurodegeneration in PD. Missense variants and common “tagging” SNPs with the HFE, Transferrin and Transferrin Receptor genes are investigated extensively in this thesis. Finally, autosomal recessively inherited PD can result from mutations in the parkin gene at the PARK2 locus. The final hypothesis explored in this thesis suggests that non-deleterious missense variants in the parkin gene modify the risk for developing sporadic PD. Further genetic variation in the parkin gene such as exon rearrangements is a frequently reported mutation where heterozygosity for these rearrangements may increase the risk of PD. Heterozygous deletions or duplications of exons in the parkin gene provide technical challenges for their detection. In this thesis a novel assay for the detection of these mutations is investigated. Methods: Genotyping was performed using PCR-RFLP for genetic variants in the APOE (E2 and E4 alleles), HFE (C282Y, H63D and S65C), Transferrin receptor (TfR; S142G), Transferrin (Tfn; P570S and G258S), IREB2 genes (L159V) and the parkin gene (S167N, R366W and V380L) in a cohort of 425 PD cases and 387 controls recruited from throughout Queensland, Australia. A tagged SNP high-throughput genotyping approach was then employed to try to replicate single SNP associations in 6 iron-related genes using a cohort of 1034 PD cases and 774 controls. These genetic variants were analysed for direct association with PD risk, age of onset effects as well as potential gene x gene (GxG) and gene x environment (GxE) interactions. Additionally, a quantitative PCR assay was developed to detect heterozygous deletions and duplications within the parkin gene and utilised to screen 43 YOPD cases for these mutations. Results: The initial study of the HFE C282Y variant revealed a significant protective association with PD in the two independent cohorts studied. Further study did not reveal significant associations with PD for the other HFE variants or missense variants within the Tfn and TfR genes. When analysed for GxE interactions, the C282Y, P589S and G277S variants showed evidence for an increased risk of PD in synergy with pesticide and herbicide exposure. Carriers of the risk variant and with toxin exposure were at two-fold increased risk of PD, although the number of individuals in this category was small. A further investigation of the role of common genetic polymorphisms in iron genes revealed only one of the 20 SNPs genotyped using high-throughput multiplex methods, remained significantly associated with PD after correction for age and sex. The rs198855 SNP is downstream of the HFE gene and further implicates a role for HFE in PD. The APOE E4 allele demonstrated modifying effects for the age of PD onset, restricted to the female cases. Analysis of the parkin missense variants also demonstrated a modifying effect on the age of PD onset in carriers of the S167N variant, with putative interactions between the APOE E4 allele, a family history of PD and toxin exposure that further reduced the age of onset. Twenty individuals of the 43 YOPD cases screened demonstrated heterozygous parkin exon rearrangements using the novel qPCR method. Conclusions: Non-synonymous variants within iron-related genes or the parkin gene putatively interact with herbicide and pesticide exposure to increase the risk of PD or modify the phenotype, highlighting the need for future studies to address the multi-factorial aetiology of PD in their study design and analysis. This thesis provides evidence for the association between genetic variation within the HFE locus and PD and for the APOE E4 allele as a modifier of PD.

abstract: The main objective of this study was to use a genetically-informative design to examine the putative influences of maternal perceived prenatal stress, obstetrical complications, and gestational age on infant dysregulation, competence, and developmental maturity. Specifically, whether or not prenatal and obstetrical environmental conditions modified the heritability of infant outcomes was examined. A total of 291 mothers were interviewed when their twin infants were 12 months of age. Pregnancy and twin birth medical records were obtained to code obstetrical data. Utilizing behavioral genetic models, results indicated maternal perceived prenatal stress moderated genetic and environmental influences on developmental maturity whereas obstetrical complications moderated shared environmental influences on infant competence and nonshared environmental influences on developmental maturity. Gestational age moderated the heritability and nonshared environment of infant dysregulation, shared and nonshared environmental influences on competence, and nonshared environmental influences on developmental maturity. Taken together, prenatal and obstetric conditions were important nonlinear influences on infant outcomes. An evolutionary perspective may provide a framework for these findings, such that the prenatal environment programs the fetus to be adaptive to current environmental contexts. Specifically, prenatal stress governs gene expression through epigenetic processes. Findings highlight the utility of a genetically informative design for elucidating the role of prenatal and obstetric conditions in the etiology of infant developmental outcomes. / Dissertation/Thesis / Ph.D. Psychology 2011

Made available in DSpace on 2014-08-20T13:32:47Z (GMT). No. of bitstreams: 1 dissertacao_liziane_pereira_da_silva.pdf: 573482 bytes, checksum: c057ff271e09c08ae99425d3f04b49da (MD5) Previous issue date: 2013-02-28 / Methylenetetrahydrofolate Reductase (MTHFR) gene polymorphisms are related to low activity of the enzyme increasing homocysteine (Hcy) plasma levels. Hyperhomocysteinemia (HHcy) is a risk factor for several pathological processes including atherosclerosis. The aim of the present study was to evaluate the effect of MTHFR C677T and A1298C polymorphisms and behavioral factors on Hcy levels in 3831 biological samples from 1982 Pelotas Birth Cohort individuals. The Hcy levels were measured in serum samples using chemiluminescence immunoassay. The genotyping was performed by allelic discrimination technique using pre-designed TaqMan® assays in the ABI7500 Fast Real-Time PCR System. The mean levels of Hcy were higher (p<0.001) in homozygous TT variant of MTHFR C677T than in CT and CC genotypes independently of sex, alcohol consumption, smoking and physical activity during leisure time. However it was demonstrated a higher MTHFR 677TT effect in smokers compared to non-smokers, as well as, in alcohol consumers than in non-consumers and in active individuals than in less active ones (p for interaction <0.001, respectively). For the MTHFR A1298C, the Hcy levels were higher in AA genotype than AC and CC genotypes, independently of behavioral factors. Men genotyped as MTHFR 1298AA showed 14% increasing on Hcy levels compared to 4% increase observed in women (p for interaction <0.001). No interactions were demonstrated between this polymorphism and the other behavioral factors analyzed. In conclusion, in young adult from 1982 cohort it was observed an interaction effect between the MTHFR C677T polymorphism and lifestyle on Hcy levels, contributing to an increased risk for cardiovascular chronic diseases in the future. / Os polimorfismos do gene Metilenotetrahidrofolato Redutase (MTHFR) estão relacionados com a baixa atividade da enzima e aumento dos níveis plasmáticos de homocisteína (Hcy). A hiper-homocisteinemia (HHcy) é um fator de risco para vários processos patológicos incluindo a aterosclerose. O objetivo do estudo foi avaliar o efeito do MTHFR C677T e A1298C e fatores comportamentais sobre os níveis de homocisteína em 3.831 amostras biológicas coletadas de indivíduos pertencentes à coorte de nascidos em Pelotas no ano de 1982. Os níveis de homocisteína foram medidos no soro por imunoensaio quimioluminescente. A genotipagem foi realizada pela técnica de discriminação alélica através do uso de sondas pré-desenhadas TaqMan® no equipamento ABI7500 Fast Real-Time PCR System. Os níveis médios de Hcy foram maiores (p <0,001) em indivíduos apresentando a variante MTHFR 677T em homozigose do que em indivíduos com genótipos CT e CC, independentemente de sexo, consumo de álcool, tabagismo e atividade física no lazer. No entanto, foi demonstrado um efeito maior em MTHFR 677TT fumantes em comparação aos não-fumantes, bem como, em consumidores de álcool do que em não-consumidores, e em indivíduos ativos do que em outros menos ativos (p de interação <0,001, respectivamente). Para MTHFR A1298C, os níveis de homocisteína foram maiores no genótipo AA do que nos genótipos AC e CC independente de fatores comportamentais. Homens genotipados como MTHFR 1298AA apresentaram aumento de 14% sobre os níveis de homocisteína em relação ao aumento de 4% observado em mulheres (p de interação <0,001). Não houve interação demonstrada entre este polimorfismo e os outros fatores comportamentais analisados. Em conclusão, em adultos jovens da coorte de 1982 foi observado um efeito de interação entre o polimorfismo MTHFR C677T com estilo de vida na determinação dos níveis de Hcy, contribuindo para um aumento do risco de doenças crônicas cardiovasculares no futuro.

Introduction – Animal studies suggested that NFKB1, SOCS3 and IKBKB genes could be involved in the association between overnutrition and obesity. This study aims to investigate interactions involving these genes and nutrition affecting obesity-related phenotypes. Methods – We used multifactor dimensionality reduction (MDR) and penalized logistic regression (PLR) to better detect gene/environment interactions in data from the Toronto Nutrigenomics and Health Study (n=1639) using dichotomized body mass index (BMI) and waist circumference (WC) as obesity-related phenotypes. Exposure variables included genotypes on 54 single nucleotide polymorphisms, dietary factors and ethnicity. Results – MDR identified interactions between SOCS3 rs6501199 and rs4969172, and IKBKB rs3747811 affecting BMI in whites; SOCS3 rs6501199 and NFKB1 rs1609798 affecting WC in whites; and SOCS3 rs4436839 and IKBKB rs3747811 affecting WC in South Asians. PLR found a main effect of SOCS3 rs12944581 on BMI among South Asians. Conclusion – MDR and PLR gave different results, but support some results from previous studies.

Genetic association studies have successfully identified many genetic markers associated with complex human diseases and related quantitative traits. However, for most complex diseases and quantitative traits, all associated genetic markers identified to date only explain a small proportion of heritability. Thus, exploring the unexplained heritability in these traits will help us discover novel genetic determinants for these traits and better understand disease etiology and pathophysiology. Due to limited sample size, a single cohort study may not have sufficient power to identify novel genetic association with a small effect size, and meta-analysis approaches have been proposed and applied to combine results from multiple cohorts in large consortia, increasing the sample size and statistical power. Rare genetic variants and gene by environment interaction may both play a role in genetic association studies. In this dissertation, we develop statistical methods in meta-analysis, rare genetic variants analysis and gene by environment interaction analysis, conduct extensive simulation studies, and apply these methods in real data examples. First, we develop a method of moments estimator for the between-study covariance matrix in random effects model multivariate meta-analysis. Our estimator is the first such estimator in matrix form, and holds the invariance property to linear transformations. It has similar performance with existing methods in simulation studies and real data analysis. Next, we extend the Sequence Kernel Association Test (SKAT), a rare genetic variants analysis approach for unrelated individuals, to be applicable in family samples for quantitative traits. The extension is necessary, as the original test has inflated type I error when directly applied to related individuals, and selecting an unrelated subset from family samples reduces the sample size and power. Finally, we derive methods for rare genetic variants analysis in detecting gene by environment interaction on quantitative traits, in the context of univariate test on the interaction term parameter. We develop statistical tests in the settings of both burden test and SKAT, for both unrelated and related individuals. Our methods are relevant to genetic association studies, and we hope that they can facilitate research in this field and beyond.

A multitude of factors, that either singly, interactively, or sequentially influence the gene-environment interplay in affective and dementia states, include several phases of neurodevelopmental liability in both humans and laboratory animals. Genetic vulnerability for both affective disorders and dementia describes a scenario distinguished by progressive need for concern, particularly in view of the interplay between these areas of ill-health. The contribution of emotional and cognitive expression to personal outcomes, e.g., as a function of affective personality type, a state-dependent analysis of personality characteristics, appears to pervade both the individual's experience of social and physical environments and the performance of cognitive tasks. The role of the endocannabinoids in mental health may offer insights for the psychopharmacology of both cognition and affect. Maladaptive emotional reactions and a defective cognitive ability will contribution to unsatisfactory/maladaptive coping strategies, in turn, leading to further complications of an affective and dysfunctional nature, eventually with a clinical psychopathological outcome. These considerations impinge upon critical issues concerning predisposition and vulnerability. Classical eye-blink conditioning provides a highly established procedure for assessment of defective physiology in models of Alzheimer's dementia. In order to develop a consideration of the array of situations presenting the variation of outcome due to type of affective personality, the role of fear and anxiety and stress in affective states influencing cognition are examined and the critical role of brain circuits mediating emotions influencing cognitive outcomes is discussed.