Mémoire (M.Sc.)-- Université du Québec à Chicoutimi, 1992. / Ce mémoire a été réalisé à l'UQAC dans le cadre du programme de maîtrise en médecine expérimentale (volet génétique) extensionné de l'Université Laval à l'UQAC. CaQCU Bibliogr.: f. 71-75. Document électronique également accessible en format PDF. CaQCU

Orientador: Ana Carla Pereira [UNESP[ Latini / Resumo: A hanseníase é causada pelo Mycobacterium leprae, que infecta macrófagos e células de Schwann, gerando lesões cutâneas e comprometendo nervos periféricos. A doença se apresenta sob diferentes formas clínicas, fortemente determinadas pela resposta imune do hospedeiro, podendo ser classificada como multibacilar (MB) e paucibacilar (PB). Trata-se de uma doença complexa e estudos voltados para a relação genótipo/fenótipo têm evidenciado a participação do componente genético humano nos desfechos da doença. O gene IL2RA está localizado na região cromossômica 10p15, próximo à região 10p13 que foi previamente associada à forma PB da doença, sendo um candidato posicional e funcional para estudos de associação genética com a forma clínica da hanseníase. Este receptor, também denominado CD25, tem papel fundamental na atividade imunorregulatória exercida pelas células Tregs. O TGF-β1 é uma das principais citocinas efetoras da atividade imunorreugulatória das Tregs e está presente em maior quantidade na forma MB. O objetivo do presente trabalho é investigar a associação dos genes IL2RA e TGFB1com as formas clínicas da hanseníase. Para tanto, conduzimos um estudo de associação baseado em duas amostras caso-controles incluindo 885 casos de hanseníase: 406 casos de Rondonópolis-MT como população primária; 479 casos provenientes do Estado de São Paulo como população de replicação. Os dados de frequências nos grupos de pacientes MB e PB foram comparados por modelo de regressão logística univar... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Leprosy is an infectious chronic disease compromising skin and peripheral nerves. There is a spectrum encompassing the clinical forms of leprosy, directed by host immune response. Leprosy has been classified as multibacillary (MB) and paucibacillary (PB), in accord to number of lesions and bacillary burden. Here we have conducted a genetic association study to clinical forms of leprosy based on two case-control samples from Brazil. We have investigated the association of the IL2RA and TGFB1 genes with clinical forms of leprosy. These genes codify important molecules to immunosuppressive activity of the Treg cells, and present differential expressions in accord to the clinical forms of leprosy. A total of 885 leprosy cases were included in the study: 406 cases from Rondonópolis municipality as start population, and 479 cases from the State of São Paulo as a replication population. The AA genotype of the rs2386841 polymorphism in the IL2RA gene was associated to PB form in the start population (OR: 4.29; p-value = 0.0043), but this was not confirmed for the replication population. The C allele of the rs1800470 marker at the TGFB1 gene was associated to MB form in the start population (OR: 2.36; p-value = 0.0238). This association was replicated for the replication population (OR: 2.10; p-value = 0.0300). In a combined analysis joining both populations the association of the rs1800470 was confirmed (OR: 1.81; p-value = 0.0475). We have demonstrated, for the first time, an associ... (Complete abstract click electronic access below) / Mestre

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Yes / PURPOSE. To test the hypothesis that emmetropization buffers against genetic and environmental risk factors for myopia by investigating whether risk factor effect sizes vary depending on children’s position in the refractive error distribution. METHODS. Refractive error was assessed in participants from two birth cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) (noncycloplegic autorefraction) and Generation R (cycloplegic autorefraction). A genetic risk score for myopia was calculated from genotypes at 146 loci. Time spent reading, time outdoors, and parental myopia were ascertained from parent-completed questionnaires. Risk factors were coded as binary variables (0 = low, 1 = high risk). Associations between refractive error and each risk factor were estimated using either ordinary least squares (OLS) regression or quantile regression. RESULTS. Quantile regression: effects associated with all risk factors (genetic risk, parental myopia, high time spent reading, low time outdoors) were larger for children in the extremes of the refractive error distribution than for emmetropes and low ametropes in the center of the distribution. For example, the effect associated with having a myopic parent for children in quantile 0.05 vs. 0.50 was as follows: ALSPAC: age 15, –1.19 D (95% CI –1.75 to –0.63) vs. –0.13 D (–0.19 to –0.06), P = 0.001; Generation R: age 9, –1.31 D (–1.80 to –0.82) vs. –0.19 D (–0.26 to –0.11), P < 0.001. Effect sizes for OLS regression were intermediate to those for quantiles 0.05 and 0.50. CONCLUSIONS. Risk factors for myopia were associated with much larger effects in children in the extremes of the refractive error distribution, providing indirect evidence that emmetropization buffers against both genetic and environmental risk factors. / UK Medical Research Council and Wellcome (grant ref: 102215/2/13/2), and the University of Bristol provided core support for ALSPAC. This research was specifically funded by the UK National Eye Research Centre (grant SAC015), the Global Education Program of the Russian Federation government, a PhD studentship grant from the UK College of Optometrists (“Genetic Prediction of Individuals At-Risk for Myopia Development”), and an NIHR Senior Research Fellowship award SRF-2015-08-005. The Generation R study is supported by the Erasmus Medical Center, Rotterdam, Erasmus University, Rotterdam, the Netherlands; the Netherlands Organization of Scientific Research (NWO); Netherlands Organization for the Health Research and Development (ZonMw); the Ministry of Education, Culture and Science; the Ministry for Health,Welfare and Sports; the European Commission (DG XII); European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant 648268); the Netherlands Organization for Scientific Research (NWO, grant 91815655); and Oogfonds, ODAS, Uitzicht 2017-28 (LSBS, MaculaFonds, Oogfonds).

Mémoire (M.Med.Exp.)--Université du Québec à Chicoutimi, 2000. / Document électronique également accessible en format PDF. CaQCU

Although a variety of factors influence the development of eating disorders, genetic factors contribute notably to their etiology. Understanding genetic factors associated with eating disorders is important, as they can influence how these disorders are recognized, researched, and treated. This dissertation included two studies addressing important questions within the fields of eating disorders and genetics; specifically, Study 1 addressed the prevalence and heritability of purging and purging disorder in a population-based sample of female twins from the United States; and Study 2 investigated the nature of the co-morbidity between anorexia nervosa and obsessive compulsive personality disorder in a population-based sample of female twins from Norway. Twin methodology was applied for both studies. Univariate analyses, a bivariate Cholesky decomposition, and an item-factor modeling approach were used. Results from Study 1 revealed estimates of 3.0%, 3.4%, 3.7%, and 11.5% for self-induced vomiting, laxative and diuretic abuse, and excessive exercise, respectively. Laxative abuse was more strongly influenced by common environmental effects, while liability to excessive exercise was more strongly influenced by common genetic factors. Due to insufficient data, an item-factor model of purging disorder did not yield conclusive results. In Study 2, the phenotypic correlation between anorexia nervosa and obsessive compulsive personality disorder was 0.08. A bivariate Cholesky decomposition revealed that an AE-AEre model best fit the data, indicating that additive genetic effects moderately contribute to both anorexia nervosa and obsessive compulsive personality disorder individually but that these genetic influences are not shared between the two disorders. In addition, this model suggests that the slight overlap in liability between the two disorders is entirely accounted for by unique environmental effects and error. These results provide preliminary findings on important topics within the field of eating disorders and genetics research. Further study of the heritability of purging and purging disorder, as well as the nature of the co-morbidity between anorexia nervosa and obsessive compulsive personality disorder, is needed in large population-based samples. Better understanding the etiology of disordered eating and frequently co-occurring diagnoses, both at the diagnosis and symptom level, might have the potential to inform classification and treatment.

During the last two decades, genotyping technology has advanced rapidly, which enabled the tremendous success of genome-wide association studies (GWAS) in the search of disease susceptibility loci (DSLs). However, only a small fraction of the overall predicted heritability can be explained by the DSLs discovered. One possible explanation for this ”missing heritability” phenomenon is that many causal variants are rare. The recent development of high-throughput next-generation sequencing (NGS) technology provides the instrument to look closely at these rare variants with precision and efficiency. However, new approaches for both the storage and analysis of sequencing data are in imminent needs. In this thesis, we introduce three methods that could be utilized in the management and analysis of sequencing data. In Chapter 1, we propose a novel and simple algorithm for compressing sequencing data that leverages on the scarcity of rare variant data, which enables the storage and analysis of sequencing data efficiently in current hardware environment. We also provide a C++ implementation that supports direct and parallel loading of the compressed format without requiring extra time for decompression. Chapter 2 and 3 focus on the association analysis of sequencing data in population-based design. In Chapter 2, we present a statistical methodology that allows the identification of genetic outliers to obtain a genetically homogeneous subpopulation, which reduces the false positives due to population substructure. Our approach is computationally efficient that can be applied to all the genetic loci in the data and does not require pruning of variants in linkage disequilibrium (LD). In Chapter 3, we propose a general analysis framework in which thousands of genetic loci can be tested simultaneously for association with complex phenotypes. The approach is built on spatial-clustering methodology, assuming that genetic loci that are associated with the target phenotype cluster in certain genomic regions. In contrast to standard methodology for multi-loci analysis, which has focused on the dimension reduction of data, the proposed approach profits from the availability of large numbers of genetic loci. Thus it will be especially relevant for whole-genome sequencing studies which commonly record several thousand loci per gene.

Alcohol use (AU) and alcohol use disorder (AUD) are leading causes of morbidity, premature death, and economic burden. They are also associated with high levels of disability and many other negative outcomes. Twin and family studies have consistently shown that AU and AUD are complex traits influenced by both genetic and environmental factors. Although much has been learned about the genetic and environmental etiology of AU and AUD, significant gaps remain. These include the need for a more comprehensive understanding of the roles of risk and protective factors, and the nature of developmental trajectories underpinning the progression from AU to AUD. The aims of this dissertation are: (1) to examine the roles of resilience and personality disorders in the etiology of AU and AUD; (2) to investigate the nature of longitudinal changes in genetic and environmental risk factors responsible for individual differences in AU; and (3) to determine the moderating roles of key environmental risk factors on the impact of aggregate molecular, or polygenic, risk for AU during adolescence. Using both biometrical behavioral genetic and molecular genetic methodologies, five key findings were observed: (1) Resilience is strongly associated with a reduction in risk for AUD, and this relationship appears to be the result of overlapping genetic and shared environmental influences; (2) Borderline and antisocial personality disorders are the strongest and most stable personality pathology predictors of the phenotypic and genotypic liability to AU and AUD across time; (3) Genetic influences on the development of AUD from early adulthood to mid-adulthood are dynamic, whereby two sets of genetic risk factors contribute to AUD risk; (4) The specific genetic influences on AU follow an unfolding pattern of growth over time, whereas unique environmental risk factors are consistent with an accumulation of environmental impacts and risks across time; and (5) High peer group deviance and low parental monitoring are associated with increased AU, while early parental monitoring moderates the polygenic risk for AU at age 20. The implications of these results with regard to prevention and intervention efforts are discussed.

Abstract Mitochondrial DNA (mtDNA) is a maternally inherited 16.6 kbp circular genome that codes for 13 subunits of the mitochondrial respiratory chain, 2 rRNAs and 22 tRNAs. The mutation rate in mtDNA is high and therefore, mutations have accumulated sequentially to lineages that have diverged tens of thousands of years ago. The neutral theory predicts that a proportion of these variations may be slightly deleterious, associated with diseases and selected against, but the issue is still controversial. This study reports an analysis of selection against mutations in mtDNA. First, the population prevalence of one of the most pathogenic mtDNA mutations, the common MELAS mutation (3243A>G), was determined in a population-based screening setting in Northern Ostrobothnia, and the reproductive capacity, or genetic fitness, of women with the mutation was estimated in order to measure for the first time the degree of host-level selection against this highly pathogenic mutation. The frequency of 3243A>G was high, as the minimum estimate for the prevalence was 10.2/100,000, and this together with the geographical distribution of maternal ancestors of the mutation carriers suggested that nuclear genes may be involved in the population history of the mutation. Surprisingly, the genetic fitness of mutation carriers was not reduced, suggesting that the average host-level selection against carriers is not strong. Second, all available complete human mtDNA sequences worldwide (N=847) were collected into a database and analysed for evidence to support the hypothesis concerning slightly deleterious mutations and selective constraints imposed by lineage-specific interactions. 465 distinct missense and 6 nonsense mutations were identified. 48% of the amino acid replacements changed the polarity, 44% hydropathy, 32% aliphaticity, 26% size, 13% aromaticity, and 8% charge. Nonconservative amino acid replacements were found to be more common among the evolutionarily recent mutations than among the older ones, and mutations that have arisen more than once during human evolution showed different properties from the remaining ones. The major continent-specific mtDNA lineages were analysed in terms of nucleotide diversity indices, neutrality tests and nonsynonymous/synonymous rate ratios, and patterns suggesting selective constraints possibly due to lineage-specific interactions were identified. Moreover, a general correlation between nucleotide position and nucleotide polymorphism was identified in the mtDNA. The results are compatible with the assumption that selection has a marked role in human mtDNA evolution and that selective constraints may vary between populations, so that the pathogenic potential of a given mutation may depend markedly on the presence of other, interacting mutations.