Global ETD Search

1	Maternal and Parent-of-Origin Effects on the Etiology of Orofacial Clefting Rasevic, Nikola 08 September 2021 (has links) Objective: To investigate the association of previously reported single nucleotide polymorphisms (SNPs) in relation to orofacial clefts and assess their interaction with environmental factors. Methods: Genome-wide SNP genotypes were obtained for case-parent triads from the EUROCRAN and ITALCLEFT studies. Candidate SNPs were selected from a previous genome-wide association study (Shi et al., 2012) along with surrounding SNPS for a total of 2142 genotyped and imputed SNPs. A total of 411 case-parent triads and 25 case-parent dyads were analyzed using log-linear models to test for maternal and parent-of-origin effects along with their interaction with maternal smoking and maternal folic acid consumption. Results: A significant association (q = 0.025) was detected for a region in the ATXN3 gene. This significance refers to the interaction between maternal periconceptional smoking and maternal genetic effects. Nominally significant associations in genes relating to the brain were also detected. Conclusion: SNPs in the ATXN3 region warrant further investigation. Orofacial clefts Maternal genetic effects Parent-of-origin genetic effects Gene-environment interaction Case-parent trios
2	Familial amyloidosis with polyneuropathy : studies of genetic factors modifying the phenotype of the disease / Familjär amyloidos med polyneuropati : studier av genetiska faktorer som modifierar sjukdomsfeneotypen Olsson, Malin January 2010 (has links) Background. Familial Amyloidosis with Polyneuropathy (FAP) is an autosomal dominantly inherited systemic amyloid disease. The disease is caused by mutations in the transthyretin (TTR) gene, where close to 100 different amyloidogenic mutations have been identified. FAP is found worldwide, but endemic areas with a high frequency of patients are found in Portugal, Japan and northern Sweden. Cases from these endemic areas all share the same TTR c.148G>A, p.V50M ("V30M") mutation, but the phenotype of the disease varies between the areas, and also within the endemic areas. The mean onset of the disease is two decades earlier in Portugal and Japan compared to Sweden, but late as well as early age at onset cases occur within all the populations. Interestingly, the different populations all display a maternal anticipation, where an earlier onset is observed for those individuals who inherit the trait from their mother. Since substantial variation in the phenotype is observed for different populations, epigenetic/genetic and/or environmental factors must exert a significant impact on the penetrance of the disease. Amyloid formation is caused by conformational changes of proteins, which facilitates their assembly into fibrils, amyloid. Oxidative stress can mediate conformational changes of proteins and since the mitochondria regulate oxidative processes within the cell, mitochondrial function may affect amyloid formation. The mitochondrial DNA is a non-nuclear DNA, which is entirely maternally inherited, and therefore could be related to the observed maternal anticipation of the disease. In addition, differences within the surrounding regions of the TTR gene may have an impact on the transcription of the gene and thereby on the expression of the different alleles. Material and methods. DNA from early and late onset V30M cases and from non-carriers (the latter utilised as controls) from Swedish, French, Japanese and Portuguese populations were analysed. In addition, DNA from healthy Swedish V30M carriers was analysed. Conventional analytical methods were employed, such as PCR, sequencing and genotyping. Conventional statistical methods used were t-test, Chi-squared test and maximum likelihood. Results. The study of V30M carrier frequency in two counties (Lycksele and Skellefteå) within the Swedish endemic area revealed a carrier frequency of 2.14% and 2.54%, respectively. The mitochondrial haplogroup analysis showed that in populations with generally late onset (French and Swedish), the haplogroup distribution of late onset cases resembled that of the controls derived from the same area, whereas haplogroup distribution for early onset patients was significantly different. The most pronounced difference was for the rare haplogroup K, of which early onset cases had a higher frequency than the controls. Analysis of the Portuguese population, with predominantly early onset, showed that haplogroup distribution for early onset cases were similar to the Portuguese control group, which had a different distribution than the Swedish control group. By analysis of pedigrees from Swedish and Portuguese patients it could be shown that mitochondrial genetic variation entirely could explain maternal anticipation in the Portuguese patients, whereas for Swedish patients, an additional parent of origin effect is present. Our analysis of the TTR gene disclosed a polymorphism (rs62093482) in the 3'UTR region of the Swedish patients. This polymorphism was found in all V30M carriers, irrespective of symptoms. In addition, homozygous TTR V30M carriers were homozygous also for the polymorphism. Since Swedish patients share a common founder this polymorphism thus is localised on the V30M allele. This polymorphism was found in only 4% of the Swedish controls. French controls showed the same frequency, but none of the French V30M patients displayed the polymorphism. In the Japanese population the polymorphism was not present at all. Interestingly, this polymorphism generates a potential binding site for microRNA and thereby possibly could down-regulate the expression of the mutated TTR allele. Conclusions. The carrier frequency in the endemic area is remarkably high, above 2% in the Lycksele and Skellefteå areas. The prevailing haplogroup distributions in the different endemic areas are consistent between the general population and the patient group with the predominant phenotype of that area. Mitochondrial genetic differences may explain maternal anticipation in Portuguese patients, and have an influence in Swedish patients. A polymorphism in the 3'UTR regulatory region of the mutated TTR allele is found in all Swedish patients. This polymorphism may down-regulate TTR V30M expression and thereby contribute to the late onset of the disease noted in the Swedish population. Mitochondria parent-of-origin MicroRNA Single Nucleotide Polymorphism 3' Untranslated Regions/genetics Medical genetics Medicinsk genetik Clinical genetics Klinisk genetik
3	A Novel Approach to Identify Candidate Imprinted Genes in Humans Shapiro, Jonathan 21 March 2012 (has links) Many imprinted genes are necessary for normal human development. Approximately 70 imprinted genes have been identified in humans. I developed a novel approach to identify candidate imprinted genes in humans using the premise that imprinted genes are often associated with nearby parent-of-origin-specific DNA differentially methylated regions (DMRs). I identified parent-of-origin-specific DMRs using sodium bisulfite-based DNA (CpG) methylation profiling of uniparental tissues, mature cystic ovarian teratoma (MCT) and androgenetic complete hydatidiform mole (AnCHM), and biparental tissues, blood and placenta. In support of this approach, the CpG methylation profiling led to the identification of parent-of-origin-specific differentially methylated CpG sites (DMCpGs) in known parent-of-origin-specific DMRs. I found new DMRs for known imprinted genes NAP1L5 and ZNF597. Most importantly, I discovered many new DMCpGs, which were associated with nearby genes, i.e., candidate imprinted genes. Allelic expression analyses of one candidate imprinted gene, AXL, suggested polymorphic imprinting of AXL in human blood. Allele Allele-specific DNA Methylation Allele-specific Gene Expression Allele-specific Expression Allele-specific Methylation AnCHM Androgenetic Androgenetic Mole Mole Complete Mole Hydatidiform Mole Complete Hydatidiform Mole Androgenetic Hydatidiform Mole Androgenetic Complete Hydatidiform Mole Biparental Tissue Bisulfite Bisulphite Blood Blood DNA Computational Biology DNA Methylation DNA Methylation Profiling Epigenetic Epi-genetic Epigenomic Epi-genomic Expression Expression Regulation Gene Expression Gene Expression Regulation Genetic Genetic Imprint Genetic Imprinting Genomic Genomic DNA Genomic Imprint Genomic Imprinting Human Imprint Imprinting Teratoma Ovarian Teratoma Cystic Teratoma Mature Teratoma Mature Cystic Teratoma Mature Ovarian Teratoma Cystic Ovarian Teratoma Mature Cystic Ovarian Teratoma MCT Methylation Cytosine Methylation Microarray Neoplasm Ovarian Neoplasm Placenta Profiling Promoter Promoter Region Sodium Bisulfite Sodium Bisulphite Uniparental Tissue WB WBC Imprinted Gene Polymorphic Imprinting Parent-of-origin Parent-of-origin-specific Methylation Parent-of-origin-specific Expression 0369 0307
4	A Novel Approach to Identify Candidate Imprinted Genes in Humans Shapiro, Jonathan 21 March 2012 (has links) Many imprinted genes are necessary for normal human development. Approximately 70 imprinted genes have been identified in humans. I developed a novel approach to identify candidate imprinted genes in humans using the premise that imprinted genes are often associated with nearby parent-of-origin-specific DNA differentially methylated regions (DMRs). I identified parent-of-origin-specific DMRs using sodium bisulfite-based DNA (CpG) methylation profiling of uniparental tissues, mature cystic ovarian teratoma (MCT) and androgenetic complete hydatidiform mole (AnCHM), and biparental tissues, blood and placenta. In support of this approach, the CpG methylation profiling led to the identification of parent-of-origin-specific differentially methylated CpG sites (DMCpGs) in known parent-of-origin-specific DMRs. I found new DMRs for known imprinted genes NAP1L5 and ZNF597. Most importantly, I discovered many new DMCpGs, which were associated with nearby genes, i.e., candidate imprinted genes. Allelic expression analyses of one candidate imprinted gene, AXL, suggested polymorphic imprinting of AXL in human blood. Allele Allele-specific DNA Methylation Allele-specific Gene Expression Allele-specific Expression Allele-specific Methylation AnCHM Androgenetic Androgenetic Mole Mole Complete Mole Hydatidiform Mole Complete Hydatidiform Mole Androgenetic Hydatidiform Mole Androgenetic Complete Hydatidiform Mole Biparental Tissue Bisulfite Bisulphite Blood Blood DNA Computational Biology DNA Methylation DNA Methylation Profiling Epigenetic Epi-genetic Epigenomic Epi-genomic Expression Expression Regulation Gene Expression Gene Expression Regulation Genetic Genetic Imprint Genetic Imprinting Genomic Genomic DNA Genomic Imprint Genomic Imprinting Human Imprint Imprinting Teratoma Ovarian Teratoma Cystic Teratoma Mature Teratoma Mature Cystic Teratoma Mature Ovarian Teratoma Cystic Ovarian Teratoma Mature Cystic Ovarian Teratoma MCT Methylation Cytosine Methylation Microarray Neoplasm Ovarian Neoplasm Placenta Profiling Promoter Promoter Region Sodium Bisulfite Sodium Bisulphite Uniparental Tissue WB WBC Imprinted Gene Polymorphic Imprinting Parent-of-origin Parent-of-origin-specific Methylation Parent-of-origin-specific Expression 0369 0307
5	Etudes d'association prenant en compte des mécanismes complexes : application à l'asthme / Genetic Association Studies Taking Into Account Complex Mechanisms In The Context Of Asthma Sarnowski, Chloé 18 December 2015 (has links) L’asthme est une maladie inflammatoire chronique des voies respiratoires. C’est une maladie complexe et hétérogène, présentant un large spectre de manifestations cliniques dans lequel l’âge de début joue un rôle important. L’asthme résulte de nombreux facteurs génétiques et environnementaux et des interactions entre ces facteurs.Afin d’identifier de nouveaux gènes de susceptibilité à l’asthme et aux maladies allergiques, nous avons réalisé des études d’association pan-génomiques et de clonage positionnel en prenant en compte des mécanismes complexes : 1) empreinte parentale, 2) hétérogénéité de la maladie et 3) interactions gène-environnement.Nous avons tout d’abord réalisé une étude de clonage positionnel pour le phénotype asthme-plus-rhinite dans des familles d’origine européenne de quatre études indépendantes (770 familles recensées par un asthmatique et incluant 3200 sujets) en prenant en compte l'effet de l'origine parentale. L’intégration de données génétiques et épigénétiques, nous a permis d’identifier un mécanisme de médiation de l’effet d’un variant génétique transmis par le père sur le phénotype combiné asthme-plus-rhinite, par une méthylation différentielle d’un site CpG localisé dans le gène MTNR1A.Nous avons ensuite pris en compte la variabilité de l’âge de début de l'asthme dans la modélisation de la maladie par des méthodes d’analyse de survie et avons réalisé une méta-analyse d’études d'association pan-génomiques du délai de survenue de l’asthme dans neuf populations d’origine européenne (5462 asthmatiques et 8424 non asthmatiques). Nous avons ainsi identifié un nouveau locus de susceptibilité à l’asthme localisé dans la région 16q12. Nous avons également mis en évidence que les variants génétiques des régions 9p24 et 17q12-q21 étaient associés à un asthme précoce alors que les variants en 16q12 étaient associés à un asthme plus tardif. Enfin, nous avons réalisé une méta-analyse de cinq études d’interaction pan-génomiques du délai de survenue de l’asthme avec l’exposition au tabagisme passif dans l’enfance (3643 exposés et 5275 non-exposés). Nous avons montré que l’effet des variants génétiques des régions 9p24 et 17q12-q21 sur le délai de survenue de l’asthme était augmenté par l’exposition au tabagisme parental dans l’enfance.La prise en compte de mécanismes complexes dans les études génétiques, nous a permis d’identifier de nouveaux gènes de susceptibilité à l’asthme et de mieux comprendre les mécanismes physiopathologiques à l'origine de l’asthme et de son expression variable au cours de la vie. / Asthma is a chronic airway inflammatory disease. It is a complex and heterogeneous disease with a wide spectrum of clinical manifestations in which the age of onset plays an important role. Asthma results from many genetic and environmental factors and from interactions between these factors.To identify new susceptibility genes to asthma and allergic diseases, we performed genome-wide association studies and positional cloning studies, while taking into account complex mechanisms: 1) parental imprinting, 2) heterogeneity of the disease and 3) gene-by-environment interactions.We first conducted a positional cloning study for asthma-plus-rhinitis in European families of four independent studies (770 families ascertained through an asthmatic and including 3200 subjects) while taking into account parent-of-origin effects. The integration of genetic and epigenetic data enabled us to identify that the effect of a paternally inherited genetic variant on the combined phenotype asthma-plus-rhinitis was mediated by a differentially methylated CpG site within MTNR1A gene. We then took into account the variability of age-of-asthma onset in the disease modeling using survival analysis methods and conducted a meta-analysis of genome-wide association studies of time-to-asthma onset in nine European populations (5,462 asthmatics and 8,424 non-asthmatics). We identified a new asthma susceptibility locus in 16q12. We also showed that genetic variants of 9p24 and 17q12-q21 regions were associated with early-onset asthma while 16q12 variants were associated with later-onset asthma. Finally, we performed a meta-analysis of five genome-wide interaction studies of time-to-asthma onset with early-life tobacco smoke exposure (3,643 exposed and 5,275 unexposed). We showed that the effect of genetic variants of 9p24 and 17q12-q21 regions on time-to-asthma onset was increased by early-life tobacco smoke exposure.Studying complex mechanisms in genetic studies led to identify new asthma susceptibility genes and to better understand the pathophysiological mechanisms underlying asthma and its variable expression throughout life. Asthme Etudes d'association génétiques Effet de l'origine parentale Méthylation de l'ADN Age de début de l'asthme Interaction gène-Environnement Asthma Genetic association studies Parent-Of-Origin effect DNA methylation Asthma age-Of-Onset Gene-By-Environment interaction

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