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1
WOO, DANIEL. "GENETIC EPIDEMIOLOGY OF INTRACEREBRAL HEMORRHAGE". University of Cincinnati / OhioLINK, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1099665780.
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Ahmadipour, Nooshin. "Genetic epidemiology of tuberculosis". Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=78234.
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Background. Susceptibility to a complex disease such as tuberculosis generally involves interactions among several genes and environmental factors. Several association studies have been conducted to examine the association between candidate genes and tuberculosis. However, the genetic risk factors are not fully understood.Objective. To examine the effect of several candidate genes, including natural resistance associated macrophage protein 1 (NRAMP1), vitamin D receptor (VDR), surfactant proteins (SFTPA1), and mannose-binding lectin (MBL), and also to assess the effect of several risk factors on their association with tuberculosis. The other objectives were to test for mode of inheritance and also to estimate the relative risks of disease for different genotypes.
Methods. A prospective case-parental control study was conducted. Ninety-five nuclear families were selected from an existing database of families with tuberculosis in Ethiopia. Each family consisted of one affected child and two parents. The primary outcome was transmission/nontransmission of alleles from parents to affected offspring.
Results. The transmission disequilibrium test showed that marker SFTPA1-294 was significantly associated with the outcome (chi 2 = 4.297; p = 0.038). When other risk factors such as age, sex, ethnicity, certain symptoms or other genes were allowed to modify the transmission probabilities in a logistic regression model, several other markers were found to be significantly associated with the outcome.
Conclusions. Despite the limitations of this study, this thesis provided evidence for inheritance of susceptibility to tuberculosis in Hadiayan families in Ethiopia. To confirm the findings in this thesis, it would be useful to conduct similar research in populations with different ethnic origins, where genetic and environmental exposures can be examined and compared.
3
Rahman, Al-Amin Proton. "Genetic epidemiology of psoriatic arthritis". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0004/MQ46117.pdf.
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Wiklund, Fredrik. "Genetic epidemiology of prostate cancer". Doctoral thesis, Umeå : Univ, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-281.
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Keen, Richard William. "Genetic epidemiology of postmenopausal osteoporosis". Thesis, King's College London (University of London), 2000. https://kclpure.kcl.ac.uk/portal/en/theses/genetic-epidemiology-of-postmenopausal-osteoporosis(15d66e32-f0bb-4b51-9e82-60646699d319).html.
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Whong-Barr, Michael. "Biomedical ethics and genetic epidemiology". Thesis, Durham University, 2004. http://etheses.dur.ac.uk/2817/.
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Biomedical ethics developed in the late twentieth century as a challenge to the self- regulatory ethic that previously governed medical practice. Yet in recent years bioethics has come under scrutiny from the social sciences, which claim that the field relies upon an idealised notion of moral agency and fails to consider the extent to which ethical discourse is embedded in a wider societal context. In addition, bioethical concepts such as patient autonomy and informed consent have also recently been challenged by the rise of genetic medicine. After evaluating debates in the historical and philosophical development of biomedical ethics, this thesis uses a case study in genetic epidemiology (commonly referred to as biobanking) to examine competing normative and empirical claims made by bioethicists and social scientists. The study investigates the views and experiences of potential donors to a biobank in north-west England. Data analysis gives particular emphasis to socio-ethical issues such as consent, genetic donation, altruism, and benefit-sharing. Evidence from the case study illustrates that bioethics is susceptible to many of the charges levelled against it - namely that it lacks proper understanding of the processes by which moral concepts and categories are embedded in ongoing forms of social practice and experience. The thesis concludes with suggestions as to how bioethics may better combine philosophical and sociological methods.
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Holberg, Catharine Jean 1944. "Genetic epidemiology of asthma phenotypes". Diss., The University of Arizona, 1998. http://hdl.handle.net/10150/565581.
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Kho, Pik Fang. "Genetic epidemiology of endometrial cancer". Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/211383/1/Pik%20Fang_Kho_Thesis.pdf.
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Endometrial cancer is the fifth most common cancer diagnosed in women in developed countries. This research used genetics to assess relationships between endometrial cancer and, previously identified and novel, risk factors. This work brings new insights by providing evidence that HDL and LDL cholesterol levels are linked to endometrial cancer risk. Further, I have shown that two gynaecological diseases, which are comorbid with endometrial cancer, also share genetic risk architecture with endometrial cancer. This work also advances the understanding of biological mechanisms of endometrial cancer by identifying candidate susceptibility genes.
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Medland, Sarah. "The genetic epidemiology of behavioural laterality /". [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe19204.pdf.
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Spinka, Christine Marie. "Gene-environment interactions in genetic epidemiology". Texas A&M University, 2004. http://hdl.handle.net/1969.1/1399.
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Gene-environment interactions are an area of increasing interest in complex hu-
man diseases. The first step in any study of the interactions between genes and the
environment involves identifying genes which influence the trait of interest. In this
dissertation, a new method for using the information in complex pedigrees to per-
form a joint linkage disequilibrium and linkage mapping of quantitative trait loci is
developed. Subsequently, methods are needed to determine the interaction, if any,
between these genes and environmental risk factors. Many of these factors, such as
weight or age, are continuous and little is known about their distributions. Thus, we
introduce a new method for estimating the gene-environment interaction parameters
in a logistic regression for the case-control study design. In doing so, we make the
assumption that in the underlying population, the distributions of the genetic factors
and the environmental covariates are independent. Additionally, we treat the envi-
ronmental parameters nonparametricly, utilizing the profile likelihood. Furthermore,
the methodology we develop is also general enough to be used on many different types
of genetic information, including haplotypes, and can accommodate missing genotype
data. The method is also extended to allow analysis in the presence of population
stratification or genotype misclassification. We show that the standard errors of pa-
rameter estimates using our method are smaller than those found using complete data
only. These methods are illustrated using simulations and are applied to a real data
set exploring the interaction between genotype and environment in disease risk.
11
Floßmann, Enrico. "Clinical and genetic epidemiology of stroke". Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441305.
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Wan, Yize Isalina. "Genetic epidemiology of atopy and asthma". Thesis, University of Nottingham, 2011. http://eprints.nottingham.ac.uk/12224/.
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The evidence for genetic contributions to the development of asthma and atopy has been well established. Refining the major genetic factors underlying these contributions will lead to a greater understanding of the pathophysiology of these conditions and potentially identify novel therapeutic targets. This thesis describes a series of studies designed primarily using genome-wide association (GWA) approaches to examine common single nucleotide polymorphisms (SNPs) contributing to these phenotypes in the Caucasian population. Susceptibility to atopy was assessed using both non-parametric association tests of SNPs across the genome and focused analysis of two regions on chromosomes 3p22.1-q22.1 and 17p12-q24.3 previously identified through a meta-analysis of genome-wide linkage studies (GSMA). The discovery cohort consisted of 1,083 cases and 2,770 controls, replication analyses were undertaken in four independent population cohorts. A GWA study of severe asthma was carried out in 933 cases and 3,346 controls with replication in a further 231 cases and 1,345 controls. The contribution of SNPs within all previously reported asthma susceptibility loci identified using a comprehensive literature search was also evaluated. Overall, there is evidence for a large number of loci influencing both atopy and severe asthma, each harbouring modest effects. A number of potentially novel loci meeting nominal significance in both GWA studies have been identified requiring further work. Strong evidence was found to support the IL1RL1-IL33 signalling pathway in asthma pathogenesis. Molecular characterisation of the 5’ untranslated regions of IL1RL1 and IL33 suggest a complex regulatory role of identified common variants involving multiple promoters for IL1RL1. A number of asthma specific variants within the chromosome 2q12 and 9p24.1 regions were detected using next generation re-sequencing in homogenised pools of cases and controls warranting further analyses. This work has identified a potentially important pathway in which to focus the development of effective asthma therapies. Future directions will include functional analysis of replicated variants and tests of interactions between the multiple genetic and environmental factors likely to be involved in disease.
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Lubbe, Steven John. "The genetic epidemiology of colorectal cancer". Thesis, Institute of Cancer Research (University Of London), 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.538696.
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Al, Arrayed Shaikha Salim. "Epidemiology of genetic disease in Bahrain". Thesis, University of Aberdeen, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.259653.
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Bahrain was and still is an important communication and commercial centre between the east and the west. The infiltration of foreign cultures and civilization through time give a cosmopolitan genetic base mingling with the local population. For the first time an attempt has been made to explore the prevalence of the genetic problem among Bahraini. In a study covering 1500 families we found that the consanguinity rate among Bahraini is high. 39.4% among the recent generation, but less than the previous generation (Grandparents) (45%). The high consanguinity rate has left behind its genetic footprint in the form of a high frequency of autosomal recessive diseases e.g. haemoglobinopathies and metabolic diseases. The genetic disorders of haemoglobin are prevalent in Bahrain. We found in our study on the Hospital population which covers 56,198 Bahraini, that 2% of the newborn have sickle cell disease (SCD), and 18% have sickle cell trait, while 24% are carrier for the Alpha thalassaemia gene. The study of the nature of SCD among Bahraini is divided into two parts. The first is community based and the second hospital based. From these we found that the mild form of the disease predominates but a wide clinical variability is apparent.
15
Roxburgh, Richard Hugh Stephen Richards. "The genetic epidemiology of multiple sclerosis". Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.614977.
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Svensson, Kerstin. "Genetic genealogy and epidemiology of Francisella". Doctoral thesis, Umeå universitet, Infektionssjukdomar, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-22452.
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This thesis is about analyzing genetic differences among isolates of Francisella tularensis – the tularemia-causing bacterium. To elucidate how these bacterial isolates are related, and their geographical and genetic origins, I have developed typing assays for Francisella and used them to study the epidemiology of tularemia. Tularemia is an infectious disease of humans and other mammals found throughout the Northern Hemisphere. The severity of the disease depends on the type of F. tularensis causing the infection. In Sweden, as in other countries of Europe and Eurasia, tularemia is caused by F. tularensis subsp. holarctica, while other varieties of the bacterium occur in Middle Asia and North America. It is important to identify a tularemia infection promptly in order to initiate the correct antibiotic treatment. A rapid identification of the causative F. tularensis variety gives additional clinical information. In recent years, several genomes of various Francisella strains have been sequenced, and in this thesis, I have utilized these genomes to identify genetic markers. In studies reported in the first paper (I) appended to the thesis, we identified and analyzed insertion/deletion mutations (INDELs) inferred to have resulted from a sequence repeat-mediated excision mechanism. We found eight new Regions of Difference (RDs) among Francisella strains. Using RDs together with single nucleotide polymorphisms (SNPs), we were able to predict an evolutionary scenario for F. tularensis in which Francisella novicida was the oldest variety while F. tularensis subsp. holarctica was the youngest. We also found that all virulence-attenuated isolates analyzed had deletions at two specific genetic regions - denoted RD18 and RD19 – suggesting that repeat-mediated excision is a mechanism of attenuation in F. tularensis. In subsequent studies (presented in paper II), we developed a combined analysis of INDELs lacking flanking repeats and variable number of tandem repeats (VNTRs). Both markers could be assayed using the same analytical equipment. The inclusion of INDELs provided increased phylogenetic robustness compared with the use of VNTRs alone, while still maintaining a high level of genetic resolution. In analyses described in the next paper (III), we selected INDELs from paper (II) and discovered novel SNPs by DNA comparisons of multiple Francisella strains. Thirty-four phylogenetically informative genetic markers were included in a hierarchical real-time PCR array for rapid and robust characterization of Francisella. We successfully used the assay to genotype 14 F. tularensis isolates from tularemia patients and DNA in six clinical ulcer specimens. Finally, in paper (IV) we demonstrated a strategy to enhance epidemiological investigations of tularemia by combining GIS-mapping of disease-transmission place collected from patient interviews, with high-resolution genotyping of F. tularensis subsp. holarctica isolates recovered from tularemia patients. We found the geographic distributions of specific F. tularensis subsp. holarctica sub-populations to be highly localized during outbreaks (infections by some genotypes being restricted to areas as small as 2 km2), indicative of a landscape epidemiology of tularemia with distinct point sources of infection. In conclusion, the results acquired during the studies underlying this thesis contribute to our understanding of the genetic genealogy of tularemia at both global and local outbreak scales.
17
Dubé, Marie-Pierre. "New approaches in human genetic analysis". Thesis, McGill University, 1999. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=36581.
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The present thesis covers two aspects of statistical analysis applied to the genetics of human diseases. First, the significance of LOD-score results for the confirmation of linkage is addressed, with special emphasis on small pedigrees. A new analytical approach is presented for the linkage analysis of heterogenetic traits, using hereditary spastic paraplegia as a model, a disease well suited for the analyses. The critical significance values for confirmation of linkage are evaluated using Bayesian statistics, and empirical P-values for LOD score results are calculated using computer simulation methods. The presented analytical approach resulted in conclusive linkage analyses on small to medium-size families, under the restrictions of genetic heterogeneity.The second part addresses linkage-disequilibrium based fine mapping in the French Canadian population. The performance of five linkage-disequilibrium based fine-mapping methods is evaluated using French Canadian chromosomes with one of three diseases found in this population: oculopharyngeal muscular dystrophy (OPMD), hidrotic ectodermal dysplasia (HED), and sensorimotor polyneuropathy with or without agenesis of the corpus callosum (ACCPN). The gene for OPMD was recently mapped and cloned, allowing us to evaluate the performance of the methods with the OPMD results, and to make predictions about the ACCPN and HED putative gene positions. In addition, a new approach to linkage-disequilibrium based fine mapping is presented using FrenchCanadian ascending genealogies. The method involves two steps. First, the likely founding couple of a mutation-bearing chromosome is identified using a computerised randomisation statistic. Then, using a delete-d jackknife resampling scheme, the distribution of gene mapping estimates is calculated from the count of ancestral recombinants and ancestral meioses joining the identified founding couple to the disease gene carriers. Gene mapping estimates are calculated from each marker individually, and confidence intervals of the estimates are derived from the jackknife distributions. The method, when applied to French Canadian families with OPMD, successfully confirmed the localisation of PABP2 responsible for OPMD and performed better than other linkage disequilibrium-based mapping models.
18
Lambert, Deborah M. "The genetic epidemiology of hyperphenylalaninemia in Québec /". Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=55505.
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The province of Quebec screens for autosomal recessive phenylketonuria (PKU) and other forms of hyperphenylalaninemia due to phenylalanine hydroxylase deficiency and tetrahydrobiopterin variants in newborns. A review of the annual reports of the Quebec Newborn Screening Program and of the clinical files of individuals with hyperphenylalaninemia born in Quebec since 1970 was undertaken. The Newborn Screening Program was evaluated for its ability to detect and identify individuals with hyperphenylalaninemia, to characterize their phenotype, and to continue surveillance. Less than universal participation in the screening (98.6%) and loss to follow-up of individuals not on treatment are causes for concern in the context of maternal hyperphenylalaninemia. Characteristics of individuals with PKU or non-PKU HPA including ethnicity, age at screening test, administrative region of birth, and month of birth were analyzed.
19
Cantelmo, Jill Love. "The genetic epidemiology of asthma and allergy". Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.434855.
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Ford, Deborah. "Genetic epidemiology of breast and ovarian cancer". Thesis, Institute of Cancer Research (University Of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367527.
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Gregory, Wendy L. "The genetic epidemiology of primary biliary cirrhosis". Thesis, University of Newcastle Upon Tyne, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.359212.
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Ennis, Sarah. "Genetic epidemiology of the fragile X region". Thesis, University of Southampton, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273869.
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Bolton, Kelly. "The genetic epidemiology of ovarian cancer survival". Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610071.
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Dunn, Steven J. "Genetic epidemiology and heterogeneity of Campylobacter spp". Thesis, Nottingham Trent University, 2017. http://irep.ntu.ac.uk/id/eprint/32176/.
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Initially, this work examines clinical Campylobacter isolates obtained from a single health trust site in Nottingham. These results reveal novel sequence types, and identified a previously undescribed peak in incidence that is observable across national data. By utilising a read mapping approach in combination with existing comparative methods, the first instance of case linkage between sporadic clinical isolates was demonstrated. This dataset also revealed an instance of repeat patient sampling, with the resulting isolates showing a marked level of diversity. This generated questions as to whether the diversity that Campylobacter exhibits can be resolved to an intra-population level. To study this further, isolates from the dominant clinical lineage – C. jejuni ST-21 – were analysed using a deep sequencing methodology. These results reveal a number of minor allele variations in chemotaxis, membrane and flagellar associated loci, which are hypothesised to undergo variation in response to selective pressures in the human gut. In an expansion of this work, additional datasets were generated to include other clinically relevant CC's, including the C. coli lineage ST-828. These results revealed a similar pattern of diversity, with common loci identified as undergoing variation in multiple samples, and in some instances the same amino acid residue. In general, ST-21 isolates exhibited more non-synonymous mutations, distributed across fewer loci, suggesting that this lineage may have a repertoire of alleles that ismore adapted to the human host. To investigate whether the observed diversity is generated during infection, or is maintained from a diverse infectious source, isolates from fresh retail chicken were analysed. These samples revealed a marked decrease in overall diversity, as well as differences in the functions of variable loci. These results show that infections occurring from the consumption of retail chicken (the largest single source of campylobacteriosis) arise from genetically uniform populations, and that the diversity observed in clinical cases is generated within - and furthermore may be specific to - the human host.
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Hudson, Julie. "Maternal Gene-Environment Effects: An Evaluation of Statistical Approaches to Detect Effects and an Investigation of the Effect of Violations of Model Assumptions". Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39637.
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Discovering the associations between genetic variables and disease status can help reduce the burden of disease on society. This thesis focuses on the methods required to detect maternal genetic effects (an effect where the genes of the mother affect the disease risk of the child) and interaction effects between these maternal genes and environmental variables in trio data consisting of parents and an affected child. A simulation study was conducted to determine the extent to which testing for these effects is affected by violations to the mating symmetry assumption required for two current methods when control parents are not available.. This study showed that methods for maternal effect estimation are not robust to these violations; however, the interaction test is robust to the violation. Finally, a candidate gene study on orofacial clefts was conducted to evaluate maternal gene-environment interactions in international consortium data. Significant effects were found but the large magnitude of the effect estimates raises concerns about the validity of the results. This thesis tries also discusses the lack of methods and software available to estimate maternal gene environment interactions.
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Davis, Patricia. "The molecular evolution and genetic epidemiology of lyssaviruses". Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433259.
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Mahmoud, Medhat [Verfasser]. "Genetic epidemiology of bovine infectious diseases / Medhat Mahmoud". Gießen : Universitätsbibliothek, 2019. http://d-nb.info/1188195239/34.
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Ishihara, Lianna Shizuko. "The genetic and environmental epidemiology of Parkinson's disease". Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612856.
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Deshmukh, Harshal. "Genetic epidemiology studies of aspects of diabetic complications". Thesis, University of Dundee, 2014. https://discovery.dundee.ac.uk/en/studentTheses/bdbeee0f-7507-411f-914f-95a889afa6d0.
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Introduction Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), present in approximately 25%-40% of patients with long-standing diabetes and conferring additional risk of cardiovascular disease and mortality. Variations in the clinical presentations of DKD, heritability estimates from family-based studies and, more recently, the results from Genome-wide Association Studies (GWAS) demonstrate a heritable component of DKD. However, as is the case with the most of complex disorders, identifying causal genetic variants contributing to DKD has proven difficult. An important step in identifying variants associated with DKD in diabetes will involve integration of patient populations across multiple DKD cohorts, investigating rarer variants and by addressing the heterogeneity in DKD disease phenotypes in diabetes. Methods In this thesis, I reviewed the existing literature in genetic epidemiology in diabetic kidney disease. I then estimate chip-based heritability of DKD sub-phenotypes and replicated the association of known SNPS associated with renal function and upstream risk factors for diabetic kidney disease (BP, HbA1c) in patients with Type 2 Diabetes. I performed first GWAS for soluble receptor for advanced glycation products (sRAGE) a biomarker implicated in the pathogenesis of DKD. Finally, I performed GWAS for various DKD phenotypes on Type 1 Diabetes cohort (EURODIAB) and Type 2 Diabetes cohort (Go-DARTS) and helped with joint metaanalysis with DKD cohorts in SUMMIT consortium investigating genetic determinants of DKD. Results First, I showed that some DKD sub-phenotypes (like macro-albuminuria and ESRD) might be more heritable than others are and demonstrate that usefulness of estimation of chip-based heritability for complex trait by GCTA can be limited in the absence of large sample sizes. Second, I investigated the known genes for renal function (eGFR) and upstream risk factors for diabetic kidney disease (BP, HbA1c) in patients with Type 2 diabetes and showed that cumulative genetic risk for BP and HbA1c is associated with DKD. Third, I replicated the association of known loci associated with eGFR (UMOD GCKR and SHROOM3) in patients with Type 2 diabetes and showed that albuminuria affects the association of these variants with renal function. Fourth, I conducted a GWAS for sRAGE, an important biomarker associated with DKD, and identified novel variants in ITGA1 and HLA-DQA1 associated with circulating sRAGE levels. Finally, I performed GWAS for various DKD sub-phenotypes, and assisted in GWAS meta-analysis with SUMMIT consortium and identified potential novel genetic determinants for diabetic kidney diseases. Conclusion In conclusion this thesis has shown that a) estimation of chip based heritability of various DKD sub-phenotypes using GCTA has limited utility and requires GWAS studies with extremely large sample sizes b) the genetic determinants of renal function (eGFR) can interact with albuminuria in patients with T2D c) there are yet unidentified genetic markers associated with DKD and have identified potentially novel genetic markers associated with sRAGE (an important biomarker for DKD) and DKD itself which can be investigated in future studies for their reproducibility and functional consequences.
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Marcão, Ana Maria Lopes. "Arylsulfatase A : Genetic epidemiology and structure/ function studies". Doctoral thesis, Universidade do Porto. Reitoria, 2003. http://hdl.handle.net/10216/9650.
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Badin, Sevil. "Genetic epidemiology of allergy to beta-lactam antibiotics". Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/genetic-epidemiology-of-allergy-to-betalactam-antibiotics(c6571b05-3322-4662-88c4-88b300c96c9d).html.
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Background: Immediate antibiotic allergic response is an important public health problem. Genetic and molecular characterization will improve treatment outcomes for truly allergic patients, and also reduce the use (and risk of evolution of pathogen resistance) of second-line antibiotics given to patients who incorrectly believe themselves to be allergic to first-line antibiotics. Objective: To identify genetic and metabolic factors associated with allergic responses to beta-lactam antibiotics using the TwinsUK cohort and recruited participants from the Guy’s allergy clinic. Methods: The TwinsUK cohort is the largest registry of adult twins in the UK, and the Guy’s allergy clinic is an outsized clinic covering a large area of the UK. The TwinsUK cohort has been extensively molecularly characterized. After characterising the heritability, we conducted the first high-coverage genomewide association study (GWAS) between 211 self-reported cases in the TwinsUK cohort with questionnaire-defined beta-lactam allergic status and over 1000 individuals without self-reported allergic reaction to any substances. Approximately 2.1 million imputed and genotyped single nucleotide polymorphisms were investigated. A second GWAS was conducted on 48 clinically proven cases from the Guy’s Hospital allergy clinic and ~6000 population controls. In addition a metabolome-wide association study (MWAS) was conducted on the same TwinsUK registry individuals, scanning 510 different metabolites. Results: Following refinement of the self-reported beta-lactam allergy phenotype via the application of a more detailed questionnaire, we estimated a heritability of 21%. The heritability estimates provided positive evidence for a genetic component for beta-lactam allergy. A single hit from the TwinsUK GWAS at the MTHFS/BCL2A1 locus was found (p < 5x10-8 ), indicating a provisional “genomewide significant” hit. Results from the TwinsUK MWAS demonstrated that all metabolites responded as a correlated system to the differences among twins in their allergy status. There were also 4 distinct “metabolome-wide significant” hits, of which two corresponded to known metabolites, suggesting that people who had penicillin allergy had less piperine in their system in comparison with our control group and had higher amounts of 4-vinylphenol-sulfate metabolite. Conclusion: This study demonstrated a genetic component to beta-lactam allergy, and in particular provided evidence for a genetic signal at the MTFHS/BCL2A1 locus. Although the MWAS study showed that there was a metabolomic difference between the allergic and non-allergic individuals. These findings may lead to new personalised treatments based on a combination of genotyping and metabolic characterization. The findings of our studies need verification in independent cohorts.
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Wolber, Lisa Eleni. "The genetic epidemiology of age-related hearing impairment". Thesis, King's College London (University of London), 2015. http://kclpure.kcl.ac.uk/portal/en/theses/the-genetic-epidemiology-of-agerelated-hearing-impairment(97622e04-21fe-4cc6-aee1-145bee728af5).html.
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Age-related hearing impairment (ARHI) affects 46% of the population over the age of 48 and with increasing life expectancy in Western nations, this incidence is likely to rise. The causes for this disorder are still poorly understood but there is known to be a heritable component of around 65%. In addition, epigenetic regulation of gene expression changes over time and may explain many age-related traits. The basis of this research was to explore genetic and epigenetic factors in ARHI to understand better the mechanisms involved in its pathology. Hearing data were obtained from female volunteers of the TwinsUK register using the gold standard measure, air-conduction pure-tone audiometry and a web-based speechin-noise perception test. The prevalence of ARHI in TwinsUK was comparable to previous reports. Heritability estimates based on the classical twin model confirmed a moderate heritability of hearing ability in TwinsUK, supporting the use of this sample in genetic association studies. Genome-wide association with hearing ability was performed in TwinsUK but no genome-wide significant polymorphisms were identified possibly due to inadequate sample size. Accordingly, the data were combined with existing genome-wide association studies (GWAS) of hearing function from the G-EAR consortium. This meta-analysis resulted in a genome-wide significant association with an exonic SNP of the SIK3 gene encoding salt-inducible kinase 3, a novel gene reported to regulate metabolism and skeletal development via HDAC4. Immunohistochemistry of sik3 in mouse models confirmed striking expression profiles A small epigenome-wide association study of hearing ability in TwinsUK (n=115) revealed an epigenome-wide significant association with a probe in the promoter region of TCF25. Epigenome-wide associations at two highly associated probes (TCF25 and POLE) were replicated in an independent sample from TwinsUK (n=203). DNA methylation at these genes was negatively correlated with expression of the same, indicating gene expression repression by DNA methylation. Furthermore, using identical twins discordant for hearing loss, differentially methylated regions were found at genes ACP6 and CCNDBP1. This research supports a role of common genetic variants in ARHI, including the novel association with SIK3, which may be essential for healthy hair cell development and maintenance of spiral ganglion cells with increased age. Differentially methylated in hair cells and spiral ganglion cells of mouse cochlea, validating a putative function of SIK3 in hearing ability. regions were significantly associated with ARHI and showed an effect on gene expression despite small sample size, supporting a role of epigenetic modifications in ARHI. This research is the first to report genome-wide significant association with SIK3 and epigenome-wide significant associations at TCF25 with ARHI, which may shed light on the pathways involved in this disabling condition.
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Marcão, Ana Maria Lopes. "Arylsulfatase A : Genetic epidemiology and structure/ function studies". Tese, Universidade do Porto. Reitoria, 2003. http://hdl.handle.net/10216/9650.
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Risso, Davide <1989>. "Genetic Epidemiology of Taste Perception and Cigarette Use". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2017. http://amsdottorato.unibo.it/7902/1/PhD_Thesis_RissoDavide.pdf.
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Cigarettes and other tobacco products contain bitter compounds including nicotine, which contribute to the chemosensory properties of tobacco and stimulate multiple sensory systems, including taste transduction pathways. Since bitter taste has evolved to identify potentially toxic compounds, and thus protect against harmful foods, our hypothesis is that aversion to this taste may prevent smoking and nicotine dependence. The goal of this research was to investigate the role of inherited differences in taste perception in smoking behaviors. We sought to determine whether such genetic variation could account for the well-known differences in flavored tobacco use among different U.S. ethnic groups. For example, around 80% of African-American smokers report that they prefer menthol cigarettes, compared to only 30% of European-American smokers who express this preference. We recruited subjects from four different populations, comprising a total of 9871 individuals, purified DNA’s from some saliva or blood samples and used a candidate gene approach to sequence taste-related genes. We identified several genetic associations between polymorphisms in taste-related genes and different smoking behaviors. We have shown that the frequency of the TAS2R38 taster haplotype differs between smokers and non-smokers in European-American populations. In addition, we identified two SNPs, one located in the menthol receptor TRPM8 and one in the menthol reactive gene TRPA1, that are strongly associated with menthol smoking in a study group of African-Americans. Moreover, we found that the taster haplotype of the TAS2R38 bitter taste receptor gene is less common in European-American smokers and that the non-taster haplotype of this gene is significantly lower in menthol smokers compared to non-menthol smokers. Overall, these findings support the hypothesis that variations in taste-related genes play a role in the choice of cigarettes when smoking. Understanding genetic differences in taste perception in tobacco use could help inform the development of more effective tobacco control policies.
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Shetty, Priya Bhatia. "Genetic Epidemiology of Hypertension in Populations: Applications of Modified Methods". Case Western Reserve University School of Graduate Studies / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1385562333.
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Miller, P. W. "The genetic epidemiology of tardive dyskinesia in Northern Ireland". Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.446126.
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Gao, P. "Epidemiology of asthma and atopy : environmental and genetic factors". Thesis, Swansea University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.637026.
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Lin, Xinyi (Cindy). "Statistical Methods for High-Dimensional Data in Genetic Epidemiology". Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11326.
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Recent technological advancements have enabled us to collect an unprecedented amount of genetic epidemiological data. The overarching goal of these genetic epidemiology studies is to uncover the underlying biological mechanisms so that improved strategies for disease prevention and management can be developed. To efficiently analyze and interpret high-dimensional biological data, it is imperative to develop novel statistical methods as conventional statistical methods are generally not applicable or are inefficient. In this dissertation, we introduce three novel, powerful and computationally efficient kernel machine set-based association tests for analyzing high-throughput genetic epidemiological data. In the first chapter, we construct a test for identifying common genetic variants that are predictive of a time-to-event outcome. In the second chapter, we develop a test for identifying gene-environment interactions for common genetic variants. In the third chapter, we propose a test for identifying gene-environment interactions for rare genetic variants.
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Li, Qiao. "Data mining and statistical techniques applied to genetic epidemiology". Thesis, University of East Anglia, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.533716.
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Genetic epidemiology is the study of the joint action of genes and environmental factors in determining the phenotypes of diseases. The twin study is a classic and important epidemiological tool, which can help to separate the underlying effects of genes and environment on phenotypes. Twin data have been widely examined using traditional methods to genetic epidemiological research. However, they provide a rich sources information related to many complex phenotypes that has the potential to be further explored and exploited. This thesis focuses on two major genetic epidemiological approaches: familial aggregation analysis and linkage analysis, using twin data from TwinsUK Registry. Structural equation modelling (SEM) is a conventional method used in familial aggregation analysis, and is applied in this research to discover the underlying genetic and environmental influences on two complex phenotypes: coping strategies and osteoarthritis. However, SEM is a confirmatory method and relies on prior biomedical hypotheses. A new exploratory method, named MDS-C, combining multidimensional scaling and clustering method is developed in this thesis. It does not rely on using prior hypothetical models and is applied to uncover underlying genetic determinants of bone mineral density (BMD). The results suggest that the genetic influence on BMD is site-specific. Haseman-Elston (H-E) regression is a conventional linkage analysis approach using the identity by descent (IBD) information between twins to detect quantitative trait loci (QTLs) which regulate the quantitative phenotype. However, it only considers the genetic effect from individual loci. Two new approaches including a pair-wise H-E regression (PWH-E) and a feature screening approach (FSA) are proposed in this research to detect QTLs allowing gene-gene interaction. Simulation studies demonstrate that PWH-E and FSA have greater power to detect QTLs with interactions. Application to real-world BMD data results in identifying a set of potential QTLs, including 7 chromosomal loci consistent with previous genome-wide studies.
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Baksh, Mohamed Fazilluddeen. "Sequential tests of association with applications in genetic epidemiology". Thesis, University of Reading, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250735.
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Hammond, Christopher John. "Genetic epidemiology of common eye diseases : a twin study". Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272510.
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Mitry, Danny. "Primary rhegmatogenous retinal detachment : clinical epidemiology and genetic aetiology". Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/8923.
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Primary rhegmatogenous retinal detachment (RRD) is one of the most common ophthalmic emergencies. RRD is caused by a full thickness break in the retina which initiates separation of the neurosensory retina from the underlying retinal pigment epithelium. The subsequent accumulation of fluid within this potential space extends the area of detachment and causes visual loss. Previous assessments of RRD incidence have demonstrated large differences in case definition and methodology, with incidence estimates varying 3-fold geographically and in different time periods. To date there have been no systematic or prospective incidence estimates of primary RRD in the U.K. In this thesis I present the findings of a 2-year epidemiology study that prospectively aimed to recruit all incident cases of primary RRD diagnosed in Scotland. Case recruitment from consenting participants comprised a detailed questionnaire and a blood sample. In this thesis, I present the findings of the Scottish retinal detachment study that examined the incidence, demographic features, temporal incidence trends, as well as clinical and socio-economic associations of primary RRD in Scotland. From the clinical and genetic resource I assembled, I calculated the first population based estimate of the sibling recurrence risk ratio for RRD and designed and assisted in the analysis of the first case-control genome wide association study of this condition. Results from this study have estimated the annual incidence of primary RRD in Scotland to be 12.05 per 100,000 population. Based on this estimate, there are approximately 7,300 new cases annually in the United Kingdom. RRD incidence increases with age, is more common in men and right eyes, and is strongly associated with socio-economic affluence. In addition, using hospital episode data, the overall age-standardised incidence of RRD in Scotland was shown to be steadily increasing since 1987 with an average annual increase of 1.9%. Analysis of the clinical findings highlighted that the majority of RRD cases are caused by more than one retinal break; an important consideration for appropriate surgical management. Ocular trauma, previous cataract surgery, family history, and retinal degeneration are important predisposing features. In addition, over a 2 year period approximately 7% of individuals will suffer a RRD in the fellow eye representing an important risk of bilateral visual loss. Furthermore, I demonstrate that the risk of having an affected sibling with RRD is increased 2-fold given that one sibling has had the condition, substantiating a genetic component to the pathogenesis of this condition. In the final aspect of this thesis I will present the design and analysis of a two stage case-control genome-wide association study examining the role of common genetic variants and selected candidate genes in predisposing to RRD development.
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Tobin, Martin Damian. "The genetic epidemiology of blood pressure in human populations". Thesis, University of Leicester, 2004. http://hdl.handle.net/2381/30481.
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Yonova-Doing, Ekaterina. "The genetic epidemiology and omics of age-related cataract". Thesis, King's College London (University of London), 2018. https://kclpure.kcl.ac.uk/portal/en/theses/the-genetic-epidemiology-and-omics-of-agerelated-cataract(ea655b39-6da1-45d4-866b-7b29dfa12a23).html.
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Age-related cataract is the leading cause of blindness worldwide and a major public health problem. The two most common types of age-related cataract are nuclear and cortical cataract. Nuclear and cortical cataracts are complex diseases, meaning both genetic and environmental factors play a role in their pathogenesis. In addition, it is increasingly clear that pathogenesis of age-related cataracts is intertwined with systemic factors related to ageing. Holistic approaches taking into account the systemic nature of the cataract risk factors are needed. High-throughput technologies have enabled detailed studies of the molecular changes and biological pathways underlying a variety of complex traits but their use in age-related cataract research is long overdue. The current thesis describes the implementation of various “omics” platforms to answer questions related to genetic and environmental risks such as: 1) What are the genetic variants (both common and rare) that underlie the pathogenesis of the common forms of age-related cataract: nuclear and cortical cataract?; 2) Do nuclear and cortical share genetic risk factors?; 3) What are the effects of diet on cataract formation and progression and are these effects mediated through circulating metabolites or the gut microbiome? The work presented in this thesis resulted in, among others: the identification of six new genetic loci for age-related nuclear cataract; determining that dietary vitamin C protects not only against cataract formation but also against cataract progression; and suggesting that gut bacteria may play a role in the pathogenesis of cataract. Omics data can be useful for elucidating the biological pathways underling cataract. However, various factors that lead to reduction in power to identify effects, such as mismatches between dates of phenotyping and sample collection, may limit their potential.
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Burrows, Kimberley. "Molecular genetic epidemiology studies of quantitative nucleic acid markers". Thesis, University of Bristol, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.761240.
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Porter, Daniel Edward. "Studies on the genetic epidemiology of heritable breast cancer". Thesis, University of Edinburgh, 1995. http://hdl.handle.net/1842/21467.
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Pedigrees with two or more cases of breast cancer were collected from southeast Scotland. Data were corroborated from the Registrar General for Scotland's records. Constitutional DNA from members of 15 pedigrees, each containing between 3 and 8 cases of breast cancer, was extracted from blood lymphocytes and paraffin-embedded material. Polymorphic markers on chromosome 17 were screened to locate a putative breast cancer susceptibility gene by means of linkage analysis in these families. Pairwise Lod scores were calculated at 5 loci. The maximal summated Lod was +5.62 at hypothetical genetic distance theta = 2.5cM from marker 42D6. A genetic exclusion map of critical recombinants in five linked pedigrees suggested that the susceptibility gene (BRCA1) could be flanked by markers 42D6 and MFD188 (D17S579); a region 5 - 10 cM in length mapping to chrosome 17q12-21. In eight pedigrees a posterior probability of linkage to BRCA1 was calculated as greater than 75% (range 79.2% - 99.9%) and a total of 102 female relatives from these families were typed with one or both of adjacent markers 42D6 and MFD188. Lifetime disease penetrance of BRCA1 gene mutation was calculated to be 88%. The survival curve in probable BRCA1 mutation carriers who developed breast cancer appeared to be less steep than in the general population. Two breast cancer pedigrees were found to contain individuals in which specific p53 point mutations could be identified as important heritable susceptibility factors for breast and other tumours. These studies have enabled high-risk women from both BRCA1 and p53 gene mutation carrying families to be identified and discriminated from their low-risk, non-gene carrying relatives; an important prerequisite for improved survival in familial breast cancer.
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Prosser, Christiane. "Genetic surveillance and molecular epidemiology of human malaria parasites". Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/27226.
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This study investigates P. falciparum adaption to human activities to control malaria. Patient data analysis, genetic screening and molecular phylogeny were used to understand the drug resistance and diagnostic test-evasion profiles of P. falciparum imported to NSW and collected in Thailand.
Artemisinin resistance (ART Rx) markers were found, including from PNG (resistance not previously reported). A geographically informative barcoding protocol was developed to identify evolutionary origins. Findings support the hypothesis that genetic background is crucial to the (ART Rx) phenotype. Putative P. vivax drug resistance markers (Pvmdr, Pvcrt-o, Pvdfr, and Pvdhps) and P. falciparum ART Rx markers (Pfkelch13) were analysed from samples collected in four provinces of South Thailand. Numerous P. vivax chloroquine and antifolate Rx-associated mutations were observed. The C580Y coding mutation was detected in 60-100% of P. falciparum samples originating from Ranong and Yala - the first reports of ART Rx genotypes south of the Rx perimeter in Southeast Asia.
This study determined the pfhrp2/pfhrp3 deletion status of imported P. falciparum (genes underlying the protein detected by HPR2-based Rapid Diagnostic Tests). The study detected gene-deleted parasites from several African countries without reported data, with >10% from Sudan, South Sudan, and Nigeria, posing a risk of false-negative HRP2-RDT results. Microsatellite analysis was used to investigate genetic diversity and relatedness. Country cohorts were compared to Eritrean parasites, which have undergone selection for gene-deleted lineages. Selection signatures were not observed.
The surprising diversity (including Rx genotypes) from populations lacking genetic data redefined ongoing surveillance targets. We conclude that malaria surveillance in Australia is a valuable global data gathering tool and necessary to pre-empt treatment failure and modify diagnostic testing algorithms in light of the genetic changes detected.
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Feizabadi, Mohammad Mehdi. "Genetic relationships, subspecific differentiation and molecular epidemiology of mycobacteria". Thesis, Feizabadi, Mohammad Mehdi (1996) Genetic relationships, subspecific differentiation and molecular epidemiology of mycobacteria. PhD thesis, Murdoch University, 1996. https://researchrepository.murdoch.edu.au/id/eprint/51843/.
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In this study genetic relationships amongst and between isolates belonging to the Mycobacterium avium complex (MAC) and the M. tuberculosis complex, as well as other mycobacteria which are genetically and phenotypically related to the MAC including M. paratuberculosis, M. scrofulaceum and “X” Mycobacteria, were examined. For this purpose multilocus enzyme electrophoresis (MEE) and pulsed field gel electrophoresis (PFGE) were standardised for mycobacteria, and then used to compare isolates of these bacteria.
Isolates of the M. tuberculosis complex and isolates of M. paratuberculosis each were closely related, and each are likely to represent a single species. Isolates of M. avium and M. intracellulare were different from each other and from the other mycobacterial species examined. While isolates of M. avium were clustered in several sub-groups by MEE, most of the isolates of M. intracellulare were differentiated and represented a heterogeneous group. Similarly M. scrofulaceum and “X” mycobacteria were found to be heterogeneous and it is likely that each of these groups contains several species.
Most isolates of M. avium cultured from chickens in Australia belonged to a few closely related electrophoretic types (ET). As isolates from pigs from Tasmania also were located in some of these ETs, it is likely that transmission of infection between the two species has occurred. Conversely in other states of Australia no evidence of this cross-species transmission was evident. All isolates of M. avium cultured from animals were found to have different DNA banding patterns from isolates cultured from humans. Patients with Acquired Immunodeficiency Syndrome (AIDS) and those without AIDS were found to be infected with genetically diverse isolates of M. avium suggesting that infection occurred from the environment.
Isolates of M. bovis were homogeneous, and as only a few specific strains were detected on numerous Western Australian farms it is likely that spread of the infection was primarily due to movement of infected stock. In contrast, in Canada outbreaks of bovine and cervine tuberculosis were found to have occurred independently of each other.
Isolates of M. paratuberculosis were divided into nine PFGE patterns, and movement of infected livestock appeared to be the major factor influencing the spread of this disease in Australia. Evidence of cross-species transmission between sheep and goats and between cattle and alpacas was detected.
Australian residents who were born overseas were found to be infected with a more diverse group of M. tuberculosis isolates than were Australian born patients. Infection in Australia is most likely to be as a result of reactivation of a previous infection. Hence it is predicted that infection with M. tuberculosis in Australians in the future will increasingly be with strains that are now common in young migrants.
The population genetics of mycobacteria differed widely for each species, despite the similarity of clinical signs induced by infection. It is concluded that MEE and PFGE are useful tools for investigating genetic relationships between mycobacteria, and for studying their epidemiology. The speciation of some organisms in this genus needs to be reconsidered.
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McHenry, Michael Lyon. "Genomic and Co-Evolutionary Determinants of Clinical Severity in Active Tuberculosis Patients". Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1623754259445275.
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Goode, Ellen Lee. "Epidemiology of hereditary prostate cancer : genetic analysis of susceptibility loci incorporating clinical characteristics /". Thesis, Connect to this title online; UW restricted, 2000. http://hdl.handle.net/1773/10856.
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