Dissertations / Theses: 'Genomic Wide Association Study (GWAS)'

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Kaplan, Abdullah. "Genomic Selection and Genome-Wide Association Study in Populus trichocarpa and Pinus taeda." Thesis, Virginia Tech, 2016. http://hdl.handle.net/10919/82501.

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Forest tree breeding methods rank among the most efficient ways to increase productivity and quality of forests. With the advent of high-throughput genotyping technology, genome-enabled breeding has started to gain importance and may overcome some weaknesses of traditional tree breeding. Genomic Selection (GS), which involves using genome-wide markers to predict breeding values of individuals in a population, has been proposed for animal and plant breeding programs. GS enables very accurate selection decisions through estimation of genomic estimated breeding values (GEBVs). While the goal of GS is to predict phenotype from genotype, it does not identify the underlying genes that have important roles in a trait. Genome-Wide Association Studies (GWAS) approaches are therefore complementary to GS, enabling identification of these genes, which may be useful for marker-assisted selection in some traits. In this study, we first estimated heritability for several adaptive traits (cold hardiness, dbh, bud flush, height, and bud set) in a population of Populus trichocarpa and for height, diameter, and stem straightness in Pinus taeda. GEBVs accuracies were estimated using a ridge regression–best linear unbiased prediction (rrBLUP) model, and these accuracies were compared with estimated heritabilities. GWAS was also performed for the both imputed and non–imputed data of P. taeda population using TASSEL (Trait Analysis by aSSociation Evolution and Linkage) software, as well as rrBLUP and FFBSKAT (Fast Family-Based Sequence Kernel Association Test) packages in R. Heritabilities ranged from 0.34 to 0.56 for P. trichocarpa and 0.14 to 0.37 for P.taeda. GWAS identified 3244 associations for dbh, 4077 associations for stem straightness, and 5280 SNPs for height (p≤0.05) in TASSEL using the reduced model (marker data only), whereas 2729, 3272 and 3531 associations were found with the full model where we also included population structure as a covariate. FFBSKAT showed a similar number of SNP associations (2989, 3046 and 3058). There was an inflation of SNP associations (~20k) found in rrBLUP, which suggests population structure was not effectively controlled. The GEBVs accuracies ranged from 0.09 and 0.22 for P.trichocarpa and 0.09 to 0.23 for P.taeda using rrBLUP method. Testing the effect of repetation on the accuracy of GEBV for poplar showed that there was no significant difference between the number of cycles. Also, there was no significant difference the accuracy of GEBVs in pine between two different imputation methods, the marker mean value and Beagle software.
Master of Science

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Ghaffar, Ammarah. "Identifying and understanding the molecular mechanisms of migraine via functional interpretation of genome-wide association study (GWAS) data." Thesis, Queensland University of Technology, 2022. https://eprints.qut.edu.au/236251/7/Ammarah_Ghaffar_Thesis_2_.pdf.

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Migraine is the most common brain disorder, affecting almost 14% of the adult population, yet its molecular mechanisms and pathogenic tissue(s) remain unclear. In this thesis, I have developed a novel approach that uses genome-wide association study (GWAS) summary statistics and expression quantitative trait loci (eQTL) data to impute genetically regulated tissue-specific gene expression and prioritise disease-relevant pathogenic tissues. In subsequent studies, I compared three transcriptome imputation models to characterise genome-wide significant migraine GWAS risk loci and identified 14 novel migraine risk loci that were confirmed to be true risk loci in a recent larger migraine GWAS.

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Trivedi, Sapna. "A genetic association study in ANCA associated vasculitis." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607655.

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Risslén, Rebecca. "Genome-wide association study to find SNPs associated with circulating levels of the protein FGF-21." Thesis, Umeå universitet, Institutionen för fysik, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-173011.

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Colorectal cancer (CRC) is one of the most common types of cancer globally. In Sweden, every year over 6000 individuals are diagnosed with CRC making it the fourth most common form of cancer in the country. The symptoms of the disease occur late in its development, therefore diagnosis is often delayed, which has a negative effect on mortality. Once an individual starts to experience symptoms, a colonoscopy is performed to examine the colon and set a diagnosis. However, colonoscopy is straining for the individual and costly for the health care system. Therefore, a complementary risk screening method is needed to help identify high-risk individuals. Two separate studies have shown that individuals who develop CRC also have increased levels of the fibroblast protein (FGF-21). Thus, there is an interest in potentially using FGF-21 as a risk screening marker in a blood test for filtering out the high-risk individuals of colorectal cancer. However, it is not known whether FGF-21 is part of the causal pathway leading to CRC development or only a marker of increased risk. Therefore, more work is needed to better understand the role of FGF-21 in CRC disease. This study represents the first step in identifying if FGF-21 has any causal role in CRC. To do this I have tried to identify single genetic variants (so-called SNPs) in the human DNA that are associated with circulating levels of FGF-21 by conducting a genome-wide association study (GWAS). The genome and protein data used in the GWAS originated from 131 individuals participating in the Västerbotten Intervention Programme. Preliminary results showed no significant SNPs among the study subjects when correcting for multiple tests at a significance level of 5%. Although there were no significant findings I did find several indications of potential associations and the small size of the dataset might explain why they did not reach significance. The analytical pipeline I have created as part of this project will be used in a larger dataset where it will be possible to both verify potential associations from this study and hopefully identify other interesting SNPs. Any confirmed findings will in the future be used in a Mendelian Randomization study where the association between having SNPs that increase your levels of FGF-21 and the risk of CRC will be assessed. If such an association could be confirmed it would indicate that FGF-21 plays a causal role in CRC development.

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Floyd, James A. B. "Analysis of high-density SNP data from complex populations." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/4926.

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Data from a Croatian isolate population are analysed in a genome-wide association study (GWAS) for a variety of disease-related quantitative traits. A novel genomewide approach to analysing pedigree-based association data called GRAMMAR is utilised. One of the significant findings, for uric acid, is followed up in greater detail, and is replicated in another isolate population, from Orkney. The associated SNPs are located in the SLC2A9 gene, coding for a known glucose transporter, which leads to identification of SLC2A9 as a urate transporter too (Vitart et al., 2008). These SNPs are later implicated in affecting gout, a disease known to be linked with high serum uric acid levels, in an independent study (Dehghan et al., 2008). Subsequently, investigation into different ways in which to use SNP data to identify quantitative trait loci (QTL) for genome-wide association (GWA) studies is performed. Several multi-marker approaches are compared to single SNP analysis using simulated phenotypes and real genotype data, and results show that for rare variants haplotype analysis is the most effective method of detection. Finally, the multi-marker methods are compared with single SNP analysis on the real uric acid data. Interpretation of real data results was complicated due to low sample size, since only founder and unrelated individuals may be used for population-based haplotype analysis, nonetheless, results of the prior analyses of simulated data indicate that multi-marker methods, in particular haplotypes, may greatly facilitate detection of QTL with low minor allele frequency in GWA studies.

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Fatima, Fizza. "Genome-Wide Association Study for Disease Traits In Wheat and Its Wild Relatives." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/40900.

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Wheat is the most widely grown crop in the world and as such, is an essential source of energy and nutrition. The challenges that breeders presently face is to increase production to feed the rising population of the world, while also accounting for climate change, pollution, water and environmental stresses. As genetic uniformity of modern cultivars has increased vulnerability to pests and diseases, the wild relatives of wheat offer a rich source of genetic diversity and stress tolerance traits, that can be harnessed and transferred in to modern wheat. In this study, we used array-based genotyping to explore genetic diversity in 385 domesticated and non-domesticated lines of wheat and their wild relatives. Genetic characterization using the wheat 90K array, and subsequent filtering and validation mapped 9,570 single nucleotide polymorphic markers onto the wheat reference genome. Phylogenetic analyses illustrated four major clades, clearly separating the wild species from the domesticated, and the ancient Triticum turgidum species from modern T. turgidum cultivars. Using this diverse germplasm, a genome-wide association study (GWAS) was performed for leaf rust, the most widespread rust disease of wheat. Identification of novel sources of resistance is necessary to maintain disease resistance and stay ahead in the plant-pathogen evolutionary arms race. GWAS was conducted using eight statistical models for infection types against six leaf rust isolates and leaf rust severity rated in field trials for 3-4 years at 2-3 locations in Canada. Functional annotation of genes containing significant quantitative trait nucleotides (QTNs) identified 96 disease-related nucleotide associated with leaf rust resistance. A total of 21 QTNs were in haplotype blocks or within flanking markers of at least 16 known leaf rust (Lr) resistance genes. The remaining significant QTNs were considered loci that putatively harbor new Lr resistance genes. Future efforts to validate these loci will help understand their role in disease resistance and promote their utility for marker-assisted selection in pre-breeding.

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Pooler, Tammy. "Genome-Wide Association Study on the Sleep Symptom of Post Traumatic Stress Disorder." ScholarWorks, 2015. https://scholarworks.waldenu.edu/dissertations/1273.

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Posttraumatic stress disorder (PTSD) is a psychiatric condition that presents with 3 main symptoms're-experiencing, avoidance/numbing, and hyper arousal'after an individual experiences a traumatic event. Recent evidence suggests a potential genetic basis for PTSD and a sub symptom of hyper arousal, sleep, as a potential pathway for PTSD development, but no study has identified candidate genes associated with specific symptoms such as sleep difficulty. Based on a conceptual framework in which specific genes are associated with the onset of PTSD, this study used a genome-wide association study (GWAS) method with a case control study design to compare the genomes of individuals with and without PTSD. A secondary GWAS dataset from a study on alcohol dependence in European and African Americans was obtained from the National Center for Biotechnology Information. PTSD cases and controls were analyzed using PLINK software. Signals from 2 single nucleotide polymorphisms (SNPs), which have not been previously associated with PTSD, exceeded the established genome-wide threshold: SNP rs13160949 on chromosome 5 (p = 7.33x10-9, OR: 1.565) and SNP rs2283877 on chromosome 22 (p = 2.55x10-8, OR: 1.748). Neither SNP, though, maintained genomewide significance following corrected tests for multiple testing, population stratification, and false discovery, so the planned analysis for possible associations with PTSD by symptom category then by the sub symptom of sleep could not be completed. The results of this study suggest that PTSD may be the result of polygenic SNPs with weak effects, which supports a recent study indicating the disease may be highly polygenic. Positive social change implications include bringing attention to the clinical and research community that PTSD may involve complex polygenic factors in need of further study.

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Aterido, Ballonga Adrià 1990. "Identification of clinically relevant genetic variation in immune-mediated inflammatory diseases using genome-wide approaches." Doctoral thesis, Universitat Pompeu Fabra, 2019. http://hdl.handle.net/10803/666363.

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Rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus, Crohn’s disease and ulcerative colitis are six of the most prevalent immune-mediated inflammatory diseases (IMIDs) and are associated with a high socio-economic impact. There is compelling evidence that IMIDs are genetically complex diseases. To date, however, the genetic component of IMIDs has been only partially explained. Identifying new clinically relevant variation is therefore of major clinical interest. The objective of the present thesis was to identify new genetic variation underlying IMIDs. The research activity here presented is the result of analyzing high-throughput genomic data from a large cohort of IMID patients collected by the IMID Consortium. Using genome-wide approaches and functional analyses, we have identified new genetic variants associated to IMID susceptibility, IMID clinical phenotypes and specific treatment outcomes. Taken together, these findings contribute to better understanding the genetic basis of IMIDs and suggest more specific and preventive therapeutic strategies.
L’artritis reumatoide, la psoriasis, l’artritis psoriàsica, el lupus eritematós sistèmic, la malaltia de Crohn i la colitis ulcerosa són sis malalties inflamatòries mediades per immunitat (IMIDs) d’elevada prevalença i amb un fort impacte socioeconòmic. Totes elles comparteixen un component genètic important. No obstant, a dia d’avui, només s’ha caracteritzat una part dels factors genètics de les IMIDs. La identificació de factors genètics clínicament rellevants presenta doncs un gran interès clínic per tal d’incorporar la informació genètica a la pràctica mèdica. L’objectiu d’aquesta tesi és identificar noves variants genètiques associades a les IMIDs. La recerca que es presenta és el resultat d’analitzar dades genòmiques d’una gran cohort de pacients amb IMIDs, els quals es van obtenir a través del consorci IMID Consortium. Mitjançant estratègies d’anàlisi de genoma complet i estudis funcionals, en aquesta tesi s’han identificat noves variants genètiques associades al risc de desenvolupar IMIDs així com als seus fenotips clínics i tractament. Aquesta tesi contribueix significativament a la caracterització del component genètic de les IMIDs i, des d’un punt de vista clínic, suggereix noves estratègies terapèutiques.

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Thompson, Katherine L. "Using ancestral information to search for quantitative trait loci in genome-wide association studies." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1372410951.

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Shen, Hanyang, Bizu Gelaye, Hailiang Huang, Marta B. Rondon, Sixto Sanchez, and Laramie E. Duncan. "Polygenic prediction and GWAS of depression, PTSD, and suicidal ideation/self-harm in a Peruvian cohort." Springer Nature, 2020. http://hdl.handle.net/10757/652459.

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Genome-wide approaches including polygenic risk scores (PRSs) are now widely used in medical research; however, few studies have been conducted in low- and middle-income countries (LMICs), especially in South America. This study was designed to test the transferability of psychiatric PRSs to individuals with different ancestral and cultural backgrounds and to provide genome-wide association study (GWAS) results for psychiatric outcomes in this sample. The PrOMIS cohort (N = 3308) was recruited from prenatal care clinics at the Instituto Nacional Materno Perinatal (INMP) in Lima, Peru. Three major psychiatric outcomes (depression, PTSD, and suicidal ideation and/or self-harm) were scored by interviewers using valid Spanish questionnaires. Illumina Multi-Ethnic Global chip was used for genotyping. Standard procedures for PRSs and GWAS were used along with extra steps to rule out confounding due to ancestry. Depression PRSs significantly predicted depression, PTSD, and suicidal ideation/self-harm and explained up to 0.6% of phenotypic variation (minimum p = 3.9 × 10−6). The associations were robust to sensitivity analyses using more homogeneous subgroups of participants and alternative choices of principal components. Successful polygenic prediction of three psychiatric phenotypes in this Peruvian cohort suggests that genetic influences on depression, PTSD, and suicidal ideation/self-harm are at least partially shared across global populations. These PRS and GWAS results from this large Peruvian cohort advance genetic research (and the potential for improved treatments) for diverse global populations.
National Institutes of Health
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Richter, Annett Verfasser], Jörg [Akademischer Betreuer] Degenhardt, Gunter [Akademischer Betreuer] Reuter, and Jonathan [Akademischer Betreuer] [Gershenzon. "Identifizierung von QTLs der Terpenbiosynthese mittels „Nested Association Mapping“ (NAM) und „Genome Wide Association Study“ (GWAS) / Annett Richter. Betreuer: Jörg Degenhardt ; Gunter Reuter ; Jonathan Gershenzon." Halle, Saale : Universitäts- und Landesbibliothek Sachsen-Anhalt, 2014. http://d-nb.info/1068208147/34.

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PESENTI, MICHELE. "GERMPLASM EVALUATION FOR SALT TOLERANCE IN JAPONICA RICE." Doctoral thesis, Università degli Studi di Milano, 2020. http://hdl.handle.net/2434/707844.

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Soil salinity is one of the environmental constraints that affect crop cultivation worldwide. Among cereals, rice (Oryza sativa L.) is one of the most salt-sensitive although cultivars can differ in their response to salt stress. In European coastal rice areas, the salt wedge intrusion phenomenon caused by the rise in the sea levels consequent to the ongoing climate changes is provoking a tendency toward salinization in the adjacent paddy fields and coastal areas where rice is grown. Thus, the identification of rice cultivars tolerant to salt stress and the dissection of salt stress tolerance mechanisms are of high interest for European rice breeding. Plant responses to salt stress are complex depending on the combination of the activity of many metabolic pathways and of the several involved genes, and thus they are difficult to control and/or engineer. Exploiting natural variation that occurs in worldwide genotypes may be a powerful approach to discover new genes and/or alleles involved in salt tolerance. Since salinity has many different effects on plants, several different tolerance mechanisms (osmotic tolerance, ion exclusion and/or tissue tolerance) exist. The predominance of a specific tolerance mechanism over others depends on salt stress intensity (severity x duration) and plant developmental stage. Concerning indica rice subspecies, several QTLs and some genes involved in the phenotypic variability in response to salt stress have been identified and exploited in breeding programs for genetic improvement of élite varieties. On the contrary, in the case of japonica subspecies, far fewer information are available. General objective of this work is the discovery of novel molecular variability at different developmental stages in japonica rice cultivars resulting in tolerance to the mild salt stress conditionsreported for some European rice areas. In major detail, possible research deliverables are the identification of QTLs, alleles and/or molecular markers exploitable in future genetic improvement programs. The stated goal was pursued by a Genome Wide Association Study (GWAS) using a panel of 277 accessions of japonica rice already genotyped-by-sequencing producing 31,421 SNPs. The accession panel was subjected to a two-year phenotyping through the evaluation, at different growth stages, of traits [leaf visual injuries score (SES), tillering rate, plant height, flowering time, flag leaf chlorophyll index, and flowering time] sensitive to salt stress. For these activities, plants were grown in greenhouse environment, in pots filled with paddy soil maintained submerged and, starting from the 4th leaf stage, subjected to about 5 dSm-1soil electric conductivity (ECe) by the addition of adequate NaCl amounts.For all the measurements obtained from the two-years data, the Least Mean Square (LMS) were calculated. To be able to compare two-year data and different parameters with different range amplitudes, all data were standardized by Z-score transformation, and subjected to two-step cluster analysis, achieving a Core Collection of the 5 most tolerant and the 5 most susceptible varieties in response to salt stress. Moreover, the seed germination dynamics and the seedling emergence rate were analyzed under high salt environment (150 mM NaCl for germination, and about 10 dSm-1 soil ECe for emergence) in a single-year experiment. For each of the 277 rice accessions the effect of salt on each trait was evaluated in terms of Stress Susceptibility Index (SSI) evaluating the performance of a single accession in relation to the whole collection. An association analysis between the phenotyping and the GBS results was carried out using Tassel 3.0 to calculate a Mixed Linear Model (MLM). The critical p-values for assessing the significance of SNPs were calculated based on a False Discovery Rate (FDR) separately for each trait; a FDR cut-off of α 0.05 was used for determining significance. Currently, a total of 33 Marker-Trait Associations (MTAs) between SNPs and the analyzed salt stress-related traits have been identified. Several loci were subsequently identified by intersecting the MTAs with the genes annotated on the Nipponbare reference genome. GWAS analysis carried out on germination and emergence parameters highlighted the presence of interesting associations between two markers and two loci in linkage disequilibrium with them: Os09g0369400 and Os07g0485000, coding for a Trehalose 6-Phosphate Phosphatase 7 (OsTPP7) and a Trehalose 6-Phosphate Phosphatase 10 (OsTPP10), respectively, known to be involved in anoxia and salt stress response. Members of the OsTPPs family playing a role in the Trehalose-6P (T6P)/SnRK1 system that regulates the C-metabolism under stress conditions. Indeed, high levels of T6P inhibit the cell energetic metabolism that is, on the contrary, stimulated when T6P is dephosphorylated by TPPs activities. The possible involvement of OsTPP7/10 in this regulative network and in the different salt sensitiveness of the different rice accessions has been investigated in two japonica accessions Olcenengo and SR113, salt tolerant and sensitive, respectively. The results obtained indicate that under salt condition (NaCl 150 mM) the coleoptile growth rate is less affected in Olcenengo where the T6P levels are quite lower than in SR113. The rate of growth in the controls appeared after 24 h from sowing and it was greater in Olcenengo than in SR113. Salt stress reduces coleoptile growth rate in each genotype but in SR113 the effect was more marked. In salt condition, Olcenengo showed a higher and earlier OsTPP10 expression than SR113; this could trigger SnRK1 activity and thus the mobilization of starch (α-amylase activity), supporting the energy needed for seed germination and coleoptile elongation under salt stress. The data confirmed that in the general framework of stress tolerance, members of the OsTPPs family play a key role to overcome saline stress during the first stages of germination. Moreover, on the basis of GWAS carried out on SES parameter, a QTL including a few genes that in the indica rice genome are localized within the major salinity tolerance-related QTL ‘SalTol’ have been identified. Among them, the gene encoding the vacuolar H+-pyrophosphatase 6 (OsOVP6) is present. Since OsOVP6 activity is suggested to be important in the network of the transport activities concerning Na+ and K+ transmembrane movement related to plant salt stress susceptibility/tolerance, an in depth physiological approach evaluating this possibility has been conducted. Two japonica salt-tolerant varieties (Galileo and Virgo), one japonica rice variety (PL12) known to be salt-susceptible, and the salt-tolerant indica genotype FL478 (containing the ‘SalTol’ QTL) have been considered. The Na+/K+ ratio, Na+ influx and K+ efflux, H+ extrusion, cytosolic and vacuolar pH by in vivo 31P-NMR techniques were evaluated in roots. The results obtained, together with the electrophysiological evaluation of the whole root Na+ conductance, allow to define a picture that may explain the different salt tolerance observed among the genotypes analyzed. In this picture, OsOVP6 plays a central role. In general, good variability within the population was observed for all the analyzed parameters. Salt stress tolerance is a multi-genic complex trait, and GWAS has proven to be a powerful tool for detecting natural variation underlying complex traits in crops. Through association analysis, several MTAs have been highlighted, with the identification of interesting loci, involved in the salt stress response. In particular, the idea of the function of two genes belonging to the OsTPPs family has been reinforced, confirming that in the general framework of salt tolerance, OsTPPs play a key role to overcome the stress during the germination stages. In this context, two varieties with contrasting behavior have been identified within the collection, Olcenengo and SR113, very tolerant and susceptible, respectively. Moreover, the idea of the vacuolar H+-pyrophosphatase function has been reinforced, too, since OsOVP6 activity is suggested to be important in the network of the transport activities concerning Na+ and K+ transmembrane movement related to plant salt stress tolerance. Finally, by evaluating the overall performance of each genotype of the population in relation to each parameter measured along the two-years experiment, a "core collection" of the 5 most tolerant and the 5 most susceptible varieties has been identified.

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Milet, Jacqueline. "Étude de la composante génétique de la variabilité des infections palustres simples : Approche génome entier dans deux cohortes de jeunes enfants au Bénin First Genome-Wide Association Study of Non-Severe Malaria in Two Birth Cohorts in Benin Mixed logistic regression in Genome-Wide Association Studies." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASR013.

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Malgré les moyens importants de prévention et de lutte mis en place ces dernières années, le paludisme reste dévastateur avec près d’un demi-million de décès par an (405 000 en 2018, d'après le dernier rapport de l'OMS). Le rôle clé joué par les facteurs génétiques de l’hôte dans la susceptibilité et la sévérité de la maladie est admis aujourd'hui. Cependant, les bases moléculaires de la sensibilité/résistance au paludisme restent encore mal connues. Ces dix dernières années, les efforts de recherches pour l’identification de gènes impliqués dans la sensibilité au paludisme à P. falciparum se sont concentrés sur les formes graves de paludisme, avec plusieurs plusieurs études d’association sur l’ensemble du génome (Genome-Wide Association Study ou GWAS) publiées. Ce manuscrit porte sur l’extension de cette approche aux formes simples du paludisme, au travers de l’étude d’association génome entier de deux cohortes de nouveau-nés au Sud Bénin (au total 800 enfants), suivis pendant 18-24 mois par l’UMR261 (MERIT IRD/Université de Paris). Dans une première partie nous présentons les résultats de la première GWAS réalisée sur les formes simples de paludisme dans ces deux cohortes. L’association a été testée avec la récurrence des accès palustres et la récurrence de l’ensemble des infections (incluant les accès palustres et les infections asymptomatiques) en prenant en compte un risque environnemental estimé au niveau individuel. Elle met en évidence plusieurs signaux d’association forts, en lien avec des gènes dont la fonction biologique est pertinente pour le paludisme (notamment PTPRT, MYLK4, UROC1 et ACER3). La forte variabilité génétique présente au sein des populations africaines a nécessité de prendre en compte l’effet de confusion potentiel de la structure de population. Dans l’étude les formes simples de paludisme, une approche en deux étapes a été utilisée, le modèle de Cox mixte, utilisé pour l’analyse des données longitudinales, n’étant pas applicable à l’ensemble du génome du fait du temps de calcul nécessaire. Un modèle de Cox mixte a été appliqué pour construire un « effet individuel » ajusté sur les covariables, puis un modèle mixte linéaire pour tester l’association avec les polymorphismes du génome. Ceci nous a conduits à nous intéresser plus généralement aux modèles mixtes non-linéaires. Deux méthodes permettant l’estimation de l’effet des polymorphismes avec le modèle logistique mixte sont proposées, qui pourront être dans le futur généralisé à d’autres modèles, dont le modèle de Cox. Dans une dernière partie, le paludisme ayant constitué une des plus fortes pressions de sélection que l’homme ait connue dans son histoire récente, nous explorons la possibilité d’exploiter l’information de sélection naturelle pour augmenter la puissance de l’analyse, et améliorer la détection des signaux d’association. L’analyse des signaux de sélection positive récente sur l’ensemble du génome a été réalisée avec plusieurs méthodes basées sur les haplotypes longs ((iHS, nsL and XP-EHH). Celle-ci met en évidence plusieurs régions chromosomiques d’intérêt potentiel où les signaux d’association et de sélection co-localisent ; mais confirme également la difficulté à mettre en évidence les signaux de sélection liés au paludisme avec les outils disponibles actuellement
In spite of numerous prevention and control efforts in recent years, malaria remains a major global public health problem with nearly half a million deaths per year (405,000 in 2018). The key role played by genetic factors of the host in the susceptibility and severity of the disease is is admitted nowadays. However, the molecular basis of susceptibility / resistance to malaria has not been elucidated to date. Over the past decade, research efforts to identify genes involved in malaria susceptibility have focused on severe malaria, with several genome-wide association studies (GWAS) published. This manuscript concerns the extension of this approach to uncomplicated forms of malaria, through the genome wide association study of two birth cohorts in South Benin (800 children), followed for 18-24 months by UMR261 (MERIT IRD / University of Paris).In the first part, we present the results of the first GWAS performed on simple forms of malaria in these two cohorts. The association was tested with the recurrence of malaria attacks and the recurrence of all infections (including malaria attacks and asymptomatic infections) taking into account an environmental risk estimated at the individual level. It highlights several strong association signals, linked to genes whose biological function is relevant for malaria (in particular PTPRT, MYLK4, UROC1 and ACER3). The high genetic diversity within African populations has made it necessary to take into account the potential confounding effect of population structure. In this study we proceeded with a two-step strategy as the Cox mixed model, used for the analysis of longitudinal data, is not applicable to the whole genome due to computational burden. In a first step, an analysis was performed with a Cox mixed model to build an "individual effect" fitted on the covariates, then a linear mixed model were used to test the association with genome polymorphisms. This led us to focus more generally on non-linear mixed models. Two methods allowing the estimation of the effect of polymorphisms with the mixed logistic model are proposed, which may in the future be generalized to other models, including the Cox model.In a final part, malaria having been one of the strongest selection pressures that man has known in recent history, we explore the possibility of exploiting natural selection information to increase the power of analysis, and improve the detection of association signals. The analysis of recent positive selection signals were performed using several genome-scan methods focusing on patterns of long-range haplotype homozygosity (iHS, nsL and XP-EHH). This analysis revealed several chromosomic region of potential interest, where the signals of association and selection co-localized but confirms also the difficulty of highlighting the selection signals linked to malaria with tools currently available

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Garcia, Neto Baltasar Fernandes. "Power of QTL mapping of different genome-wide association methods for traits under different genetic structures : a simulation study /." Universidade Estadual Paulista (UNESP), 2018. http://hdl.handle.net/11449/152982.

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A complexidade das características que podem apresentar diferentes estruturas de ação gênica como, por exemplo, poligênicas ou afetadas por genes de efeito maior, aliado a diferentes herdabilidades, entre outros fatores, tornam a detecção de QTLs desafiadora. Diversos métodos têm sido empregados com o intuito de realizar estudos de associação ampla do genoma (GWAS), objetivando o mapeamento de QTL. A metodologia weighted single-step GBLUP (wssGBLUP), por exemplo, é uma alternativa para a realização de GWAS, que permite o uso simultâneo de informações genotípicas, de pedigree e fenotípicas, mesmo de animais não genotipados. Métodos Bayesianos também são utilizados para a realização de GWAS, partindo da premissa básica de que a variância observada pode variar em cada locus em uma distribuição a priori específica. O objetivo do presente estudo foi avaliar, por meio de simulações, quais métodos, dentre os avaliados, mais auxiliaria na identificação de QTLs para características poligênicas e afetadas por genes de efeito maior, apresentando diferentes herdabilidades. Utilizamos os métodos: wssGBLUP, com a inclusão ou não de informação adicional fenotípica de animais não genotipados e dois distintos ponderadores para os marcadores, onde w1 representou a mesma ponderação (w1=1) e w2 a ponderação calculada de acordo com o processo de iteração anterior (w1) ; Bayes C, assumindo dois valores para π (π=0.99 and π=0.999), onde π é a proporção de SNPs não incluída no modelo, além do LASSO Bayesiano. Os resultados mostraram que para cenários poligênicos o poder de detecção é menor e o uso adicional de fenótipos de animais não genotipados pode ajudar na detecção, ainda que com pouca intensidade. Para cenários com característica sob efeito maior, houve maior poder na detecção de QTL pelos diferentes métodos em comparação aos cenários poligênicos com destaque para a leve vantagem do método Bayes C. A inclusão de informação fenotípica adicional, entretanto, causou viés nas estimativas e atrapalhou o desempenho do wssGBLUP na presença de QTL com efeito maior. O aumento da v herdabilidade para ambas as estruturas melhorou o desempenho dos métodos e o poder de mapeamento. O método mais adequado para a detecção de QTL depende da estrutura genética e da herdabilidade da característica, não existindo um método que seja superior para todos os cenários.
The complexity of the traits that can present different genetic structures, such as polygenic or affected by genes of major effect, in addition to different heritabilities, among other factors, make the detection of QTLs challenging. Several methods have been employed with the purpose of performing genome wide association studies (GWAS), aiming the mapping of QTL. The single-step weighted GBLUP (wssGBLUP) method, for example, is an alternative to GWAS, which allows the simultaneous use of genotypic, pedigree and phenotypic information, even from non-genotyped animals. Bayesian methods are also used to perform GWAS, starting from the basic premise that the observed variance can vary at each locus with a specific priori distribution. The objective of the present study was to evaluate, through simulation, which methods, among the evaluated ones, more assist in the identification of QTLs for polygenic and major gene affected traits, presenting different heritabilities. We used the following methods: wssGBLUP, with or without additional phenotypic information from non-genotyped animals and two different weights for markers, where w1 represented the same weight (w1=1) and w2 the weight calculated according to the previous iteration process (w1); Bayes C, assuming two values for π (π = 0.99 and π = 0.999), where π is the proportion of SNPs not included in the model, and Bayesian LASSO. The results showed that for polygenic scenarios the detection power is lower and the additional use of phenotypes from non-genotyped animals may help in the detection, yet with low intensity. For scenarios with major effect, there was greater power in the detection of QTL by all different methods with slighter superior performance for the Bayes C method. However, the inclusion of additional phenotypic information caused bias in the estimates and harmed the performance of the wssGBLUP in the presence of major QTL. The increase in heritability for both structures improved the performance of the methods and the power of mapping. The most suitable method for the iii detection of QTL is dependent on the genetic structure and the heritability of the trait, and there is not a superior method for all scenarios.

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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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16

Mgonja, Emmanuel Mohamed. "Molecular Analysis of Host Resistance and Pathogenicity of Rice Blast in East Africa." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1471537840.

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Maupetit, Agathe. "Potentiel évolutif et déterminisme génétique de caractères d’agressivité et morphologiques de l’agent de la rouille du peuplier, Melampsora larici-populina." Thesis, Université de Lorraine, 2018. http://www.theses.fr/2018LORR0202/document.

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Pour lutter contre les agents phytopathogènes, la sélection de plantes résistantes est la stratégie la plus rentable et la plus écologique. Les résistances quantitatives, basées sur des mécanismes de résistances complexes, sont connues pour être sujettes à l’érosion, en cas d’évolution de l’agressivité des agents pathogènes. L’objectif de ce travail basé sur le pathosystème peuplier – rouille du peuplier (Melampsora larici-populina) est d’évaluer le potentiel évolutif des caractères d’agressivité et morphologiques du parasite par des approches de génétique quantitative et d'identifier les bases génétiques par génétique d'association. Pour estimer la plasticité, l’héritabilité et les compromis évolutifs d’un ensemble de caractères quantitatifs, nous avons précisément mesuré leurs variations dans quatre populations contrastées du champignon. Nous avons montré que le volume des spores est un caractère héritable qui évolue rapidement. La quantité de mycélium in planta est aussi héritable mais très conservée car sous sélection stabilisante dans les populations étudiées. Le temps de latence, la taille des lésions et le taux de sporulation présentent une héritabilité faible, ce qui explique l’absence d’évolution observées au cours du temps pour ces trois caractères. Les caractères liés à la fonction de sporulation semblent être les plus plastiques le long d’un gradient de maturité foliaire. Cependant, l’absence de mise en évidence de compromis évolutifs ne nous a pas permis d’identifier des caractères d’agressivité qui seraient les meilleures cibles pour les résistances quantitatives chez le peuplier. Si aucune base génétique de ces caractères quantitatifs n’a été mise en évidence, nous avons localisé un locus d’avirulence potentiel (Avr7) sur lequel une caractérisation fonctionnelle est envisagée
To control plant pathogens, breeding resistant plants is the most cost-effective and ecological strategy. Quantitative resistances, which are based on complex plant mechanisms, are known to be exposed to erosion through an increase of pathogens aggressiveness. Through the study the poplar – poplar rust (Melampsora larici-populina) pathosystem, this work aims to estimate the evolutionary potential of aggressiveness and morphological traits using quantitative genetic approaches and to identify molecular bases through genome-wide association study. To estimate plasticity, heritability, and trade-offs for a set of quantitative traits, we precisely measured their variation in four contrasted pathogen populations. It appeared that spore volume is highly heritable and evolved rapidly. In planta mycelium quantity is also heritable but constant because of stabilizing selection occurring in the studied populations. Latent period, lesion size and sporulation rate exhibit low heritability, which explains the absence of evolution during the studied time period. Traits involved in the sporulating function seem to be the most plastic ones along a leaf maturity gradient. However, the lack of evidence of trade-offs did not allow us to identify aggressiveness traits that would be the best targets for the construction of durable resistance in poplar. No genetic underpinning has been found for quantitative traits, but we have identified a potential avirulence locus (Avr7), opening the way for its functional characterization

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Janes, Jennifer Gail. "THE ROLES OF ORTHOPAEDIC PATHOLOGY AND GENETIC DETERMINANTS IN EQUINE CERVICAL STENOTIC MYELOPATHY." UKnowledge, 2014. http://uknowledge.uky.edu/gluck_etds/16.

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Cervical stenotic myelopathy (CSM) is an important musculoskeletal and neurologic disease of the horse. Clinical disease occurs due to malformations of the vertebrae in the neck causing stenosis of the cervical vertebral canal and subsequent spinal cord compression. The disease is multifactorial in nature, therefore a clearer understanding of the etiology and pathogenesis of CSM will allow for improved management and therapeutic practices. This thesis examines issues of equine CSM diagnosis, skeletal tissue pathology, and inherited genetic determinants utilizing advances in biomedical imaging technologies and equine genomics. Magnetic resonance imaging (MRI) data provided a more complete assessment of the cervical column through image acquisition in multiple planes. First, MRI was compared to standing cervical radiographs for detection of stenosis. Using canal area or the cord canal area ratio, MRI more accurately predicted sites of compression in CSM cases. Secondly, articular process skeletal pathology localized on MRI was found to be more frequent and severe in CSM horses compared to controls. In addition, lesions were generalized throughout the cervical column and not limited to the spinal cord compression sites. A subset of lesions identified on MRI was evaluated using micro-CT and histopathology. Osteochondrosis, osseous cyst-like structures, fibrous tissue replacement of bone, and osteosclerosis were observed. These lesions support likely developmental aberrations of vertebral bone and cartilage maturation with secondary biomechanical influences. Bone cyst-like structures are a novel finding in this disease. Finally, the long-standing question of the contribution of genetic determinants to CSM was investigated using a genome wide association study (GWAS). Multiple significant loci were identified supporting the influence of a complex genetic trait in clinical disease. A simple Mendelian trait controlled by one gene is unlikely given the detection of variants across multiple chromosomes. Major contributions from this research include documentation of articular process bone and cartilage pathology in horses with CSM, support for abnormal cervical vertebrae development being an important contributing factor in the etiology and/or pathogenesis of equine CSM, and evidence that multiple genetic loci contribute to the CSM disease phenotype.

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Gosseau, Florie. "Développement de nouveaux idéotypes de tournesol par une approche associant génétique quantitative et modélisation du couvert végétal." Thesis, Toulouse 3, 2019. http://www.theses.fr/2019TOU30267.

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L’évaluation des performances et des caractéristiques des nouvelles variétés produites est une étape clef de l’amélioration des performances d’une culture. Cependant, le processus d’évaluation des variétés est actuellement principalement basé sur des expérimentations en champs. Cela réduit le nombre et la diversité des conditions pédologiques, climatiques et les pratiques culturales évaluées et bien sûr rend impossible l’évaluation dans des conditions climatiques futures induites par le changement climatique. Evaluer, comprendre génétiquement et prédire la plasticité de la performance des variétés est donc un enjeu de recherche fondamentale et appliquée pour adapter les variétés aux conditions climatiques et aux systèmes de culture futurs. Notre objectif général est de construire des outils qui permettent de tirer parti de la plasticité phénotypique pour utiliser plus efficacement les ressources génétiques et environnementales afin de réduire les écarts de rendement actuellement observés entre le progrès génétique (rendement potentiel) et la production agricole. Pour parvenir à cet objectif, nous avons développé deux approches pour contribuer à l’identification de marqueurs génétiques impliqués dans la performance et la stabilité des variétés dans des environnements de culture variés. Les deux approches utilisent à la fois des modèles de génétique quantitative et un modèle écophysiologique pour tenir compte de l’interaction entre les variétés et l’environnement. La première approche ("plasticité") se base sur l’identification des bases génétiques de la plasticité du rendement et la seconde ("optimisation") sur l’identification des bases génétiques des caractéristiques d’hybrides optimaux pour le niveau et la stabilité du rendement dans une population d’environnement de cultureélargie. Dans la première approche "plasticité", le modèle écophysiologique nous a permis de caractériser les niveaux de stress abiotiques des environnements du réseau d’essais. Nous avons ensuite pu estimer la plasticité des performances d’un panel d’hybride vis-à-vis de ces stress. L’intégration avec les données de génotypage a permis ensuite d’en identifier le contrôle génétique et de prédire ces caractéristiques chez des hybrides apparentés. Dans la seconde approche "optimisation", la conception d’un modèle multi-échelle génétique et écophysiologique est un élément central pour prédire la performance d’hybrides non observés en champ dans des conditions de culture variées. Nous avons procédé en deux étapes : (1) utiliser des modèles de prédiction génomique pour prédire un ensemble de paramètres phénotypiques caractérisant un hybride en fonction de son génotype, puis (2) utiliser un modèle de simulation pour prédire le rendement de l’hybride en fonction de l’environnement, de la conduite de culture et de ses paramètres phénotypiques. La performance de ce modèle couplé s’est révélée inférieure à une approche de prédiction génomique seule et nous a permis d’identifier des verrous méthodologiques pour cette problématique. Nous avons mis en oeuvre de manière exploratoire ce modèle dans une approche d’optimisation par simulation qui nous a permis d’identifier des combinaisons de caractères physiologiques et développementaux associés à des performances plus élevées ainsi que d’en identifier le contrôle génétique. Dans les deux approches menées, les analyses de génétique d’association ont permis de la complexité du contrôle génétique des différents caractères, les informations relatives à aux marqueurs associés sont disponibles pour développer des variétés qui seront adaptées à des conditions de culture de plus en plus variables, du fait du changement climatique et de la nécessité de développer des pratiques agricoles plus durables
Assessing the performance and the characteristics (e.g. yield, quality, disease resistance, abiotic stress tolerance) of new varieties is a key component of crop performance improvement. However, the variety testing process is presently exclusively based on experimental field approaches. This reduces the number and the diversity of experienced combinations of varieties x environment x management conditions and of course testing in future climatic conditions generated by climate change. Testing, understanding genetically and predicting phenotyic plasticity of crop performance constitutes therefore a challenge for basic and applied research in order to adapt varieties to future climatic conditions and technical practices. Our aim is to design tools to leverage phenotypic plasticity and better use genetic and environmental resources to reduce yield gaps currently observed between the genotypic potential and the agricultural production. We developed two approaches to identify genetic markers associated to yield and its stability in various production situations. Both approaches are based on the combination of quantitative genetics models and crop simulation models to capture phenotypic plasticity. The first approach ("plasticity") aims to identify the genetic architecture of yield plasticity in a multi-environment trial, while the second ("optimization") rather focus of the genetic architecture of plant traits that are optimal for yield and its variance in specific growing conditions. In the first "plasticity" approach, the crop simulation model allowed assessing abiotic stress levels occurring in a multi environment trial. We then calculated yield plasticity for each genotype in a hybrid panel as the regression of the yield of the hybrid against the stress level in the environment (reaction norms). Finally, a genome-wide association study (GWAS) identified genetic markers linked to yield plasticity. In the second "optimization" approach, the key step was to design a multiscale model to predict the performance of new hybrids in new environments. We proceed in two steps: (1) build whole genome prediction models to predict a set of component traits as a function of allelic combination of genotypes and (2) use a crop simulation model to predict the hybrid yield as a function of component traits, environmental variables and management practices. We found that the accuracy of our multi-scale model was worse than the accuracy of a sole genome prediction model directly predicting crop yield, but we identified new bottlenecks related to the design of such models. We nevertheless used this model in an experimental simulation-based optimisation method, which allowed identifying plant traits associated to high yield level and stability in specific growing conditions and we discussed their genetic architecture. In both approaches, association studies identified numerous genomic regions controlling yield plasticity in responses to abiotic stresses and highlighted its complexity. Such information is available to plant breeders to develop new genotypes adapted to increasingly variable cropping conditions drived by climate change to fulfill the societal need to switch to more sustainable agricultural management

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O’Mara, Tracy Ann-Maria. "The association of single nucleotide polymorphisms with endometrial cancer risk and prognosis." Thesis, Queensland University of Technology, 2013. https://eprints.qut.edu.au/63648/1/Tracy_O%E2%80%99Mara_Thesis.pdf.

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Endometrial cancer is one of the most common female diseases in developed nations and is the most commonly diagnosed gynaecological cancer in Australia. The disease is commonly classified by histology: endometrioid or non-endometrioid endometrial cancer. While non-endometrioid endometrial cancers are accepted to be high-grade, aggressive cancers, endometrioid cancers (comprising 80% of all endometrial cancers diagnosed) generally carry a favourable patient prognosis. However, endometrioid endometrial cancer patients endure significant morbidity due to surgery and radiotherapy used for disease treatment, and patients with recurrent disease have a 5-year survival rate of less than 50%. Genetic analysis of women with endometrial cancer could uncover novel markers associated with disease risk and/or prognosis, which could then be used to identify women at high risk and for the use of specialised treatments. Proteases are widely accepted to play an important role in the development and progression of cancer. This PhD project hypothesised that SNPs from two protease gene families, the matrix metalloproteases (MMPs, including their tissue inhibitors, TIMPs) and the tissue kallikrein-related peptidases (KLKs) would be associated with endometrial cancer susceptibility and/or prognosis. In the first part of this study, optimisation of the genotyping techniques was performed. Results from previously published endometrial cancer genetic association studies were attempted to be validated in a large, multicentre replication set (maximum cases n = 2,888, controls n = 4,483, 3 studies). The rs11224561 progesterone receptor SNP (PGR, A/G) was observed to be associated with increased endometrial cancer risk (per A allele OR 1.31, 95% CI 1.12-1.53; p-trend = 0.001), a result which was initially reported among a Chinese sample set. Previously reported associations for the remaining 8 SNPs investigated for this section of the PhD study were not confirmed, thereby reinforcing the importance of validation of genetic association studies. To examine the effect of SNPs from the MMP and KLK families on endometrial cancer risk, we selected the most significantly associated MMP and KLK SNPs from genome-wide association study analysis (GWAS) to be genotyped in the GWAS replication set (cases n = 4,725, controls n = 9,803, 13 studies). The significance of the MMP24 rs932562 SNP was unchanged after incorporation of the stage 2 samples (Stage 1 per allele OR 1.18, p = 0.002; Combined Stage 1 and 2 OR 1.09, p = 0.002). The rs10426 SNP, located 3' to KLK10 was predicted by bioinformatic analysis to effect miRNA binding. This SNP was observed in the GWAS stage 1 result to exhibit a recessive effect on endometrial cancer risk, a result which was not validated in the stage 2 sample set (Stage 1 OR 1.44, p = 0.007; Combined Stage 1 and 2 OR 1.14, p = 0.08). Investigation of the regions imputed surrounding the MMP, TIMP and KLK genes did not reveal any significant targets for further analysis. Analysis of the case data from the endometrial cancer GWAS to identify genetic variation associated with cancer grade did not reveal SNPs from the MMP, TIMP or KLK genes to be statistically significant. However, the representation of SNPs from the MMP, TIMP and KLK families by the GWAS genotyping platform used in this PhD project was examined and observed to be very low, with the genetic variation of four genes (MMP23A, MMP23B, MMP28 and TIMP1) not captured at all by this technique. This suggests that comprehensive candidate gene association studies will be required to assess the role of SNPs from these genes with endometrial cancer risk and prognosis. Meta-analysis of gene expression microarray datasets curated as part of this PhD study identified a number of MMP, TIMP and KLK genes to display differential expression by endometrial cancer status (MMP2, MMP10, MMP11, MMP13, MMP19, MMP25 and KLK1) and histology (MMP2, MMP11, MMP12, MMP26, MMP28, TIMP2, TIMP3, KLK6, KLK7, KLK11 and KLK12). In light of these findings these genes should be prioritised for future targeted genetic association studies. Two SNPs located 43.5 Mb apart on chromosome 15 were observed from the GWAS analysis to be associated with increased endometrial cancer grade, results that were validated in silico in two independent datasets. One of these SNPs, rs8035725 is located in the 5' untranslated region of a MYC promoter binding protein DENND4A (Stage 1 OR 1.15, p = 9.85 x 10P -5 P, combined Stage 1 and in silico validation OR 1.13, p = 5.24 x 10P -6 P). This SNP has previously been reported to alter the expression of PTPLAD1, a gene involved in the synthesis of very long fatty acid chains and in the Rac1 signaling pathway. Meta-analysis of gene expression microarray data found PTPLAD1 to display increased expression in the aggressive non-endometrioid histology compared with endometrioid endometrial cancer, suggesting that the causal SNP underlying the observed genetic association may influence expression of this gene. Neither rs8035725 nor significant SNPs identified by imputation were predicted bioinformatically to affect transcription factor binding sites, indicating that further studies are required to assess their potential effect on other regulatory elements. The other grade- associated SNP, rs6606792, is located upstream of an inferred pseudogene, ELMO2P1 (Stage 1 OR 1.12, p = 5 x 10P -5 P; combined Stage 1 and in silico validation OR 1.09, p = 3.56 x 10P -5 P). Imputation of the ±1 Mb region surrounding this SNP revealed a cluster of significantly associated variants which are predicted to abolish various transcription factor binding sites, and would be expected to decrease gene expression. ELMO2P1 was not included on the microarray platforms collected for this PhD, and so its expression could not be investigated. However, the high sequence homology of ELMO2P1 with ELMO2, a gene important to cell motility, indicates that ELMO2 could be the parent gene for ELMO2P1 and as such, ELMO2P1 could function to regulate the expression of ELMO2. Increased expression of ELMO2 was seen to be associated with increasing endometrial cancer grade, as well as with aggressive endometrial cancer histological subtypes by microarray meta-analysis. Thus, it is hypothesised that SNPs in linkage disequilibrium with rs6606792 decrease the transcription of ELMO2P1, reducing the regulatory effect of ELMO2P1 on ELMO2 expression. Consequently, ELMO2 expression is increased, cell motility is enhanced leading to an aggressive endometrial cancer phenotype. In summary, these findings have identified several areas of research for further study. The results presented in this thesis provide evidence that a SNP in PGR is associated with risk of developing endometrial cancer. This PhD study also reports two independent loci on chromosome 15 to be associated with increased endometrial cancer grade, and furthermore, genes associated with these SNPs to be differentially expressed according in aggressive subtypes and/or by grade. The studies reported in this thesis support the need for comprehensive SNP association studies on prioritised MMP, TIMP and KLK genes in large sample sets. Until these studies are performed, the role of MMP, TIMP and KLK genetic variation remains unclear. Overall, this PhD study has contributed to the understanding of genetic variation involvement in endometrial cancer susceptibility and prognosis. Importantly, the genetic regions highlighted in this study could lead to the identification of novel gene targets to better understand the biology of endometrial cancer and also aid in the development of therapeutics directed at treating this disease.

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Kraatari, M. (Minna). "The heritability and genetic risk factors of Modic changes." Doctoral thesis, Oulun yliopisto, 2018. http://urn.fi/urn:isbn:9789526220550.

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Abstract Low back pain (LBP) is a highly prevalent musculoskeletal condition and the leading cause for workplace absenteeism. Lumbar disc degeneration (DD) is considered as a contributing factor to LBP. The role of genetic factors in the development of lumbar DD has been demonstrated to be significant, with heritability estimates ranging from 64% to 81%. Modic change (MC), a distinct phenotype of lumbar DD, is a subchondral and vertebral bone marrow change revealed only by magnetic resonance imaging (MRI). MC has been associated with LBP in both clinical samples and the general population. The genetic background of MC is largely unknown, and the heritability of MC has not previously been assessed. The aim of this study was to assess the heritability of MC using a twin study, identify predisposing genetic factors for MC in a family-based design using whole-exome sequencing and to identify genetic loci associated with MC using genome-wide association study (GWAS) meta-analysis. An additional aim was to study the prevalence, incidence and morphology of MC. The data consisted of two general population samples, the Northern Finland Birth Cohort 1966 (NFBC1966) and TwinsUK from the United Kingdom, as well as two Finnish families from the Oulu region. MC was found to be partly heritable with a heritability estimate of 30%. Two novel candidate genes, HSPG2 and MAML1, were found co-segregating with MC in two Finnish families. Both genes are important in the growth and differentiation of chondrocytes. Finally, a genetic locus on chromosome 9 was found to be significantly associated with MC using genome-wide meta-analysis of NFBC1966 and TwinsUK. These results showed that genetic factors play a role in the development of MC. In conclusion, this thesis increased the knowledge on the genetics of MC. However, the specific roles of these genes need to be studied further
Tiivistelmä Alaselkäkivun kansaterveydellinen merkitys on suuri, sillä jopa 84% aikuisista kärsii siitä elämänsä aikana. Selkäkivun vuoksi Suomessa kertyy yli 2 miljoona sairauslomapäivää vuodessa. Välilevyrappeumaa pidetään merkittävänä tekijänä alaselkäkivun synnyssä ja perinnölliset tekijät selittävät välilevyrappeuman synnystä jopa 74%. Modic-muutokset ovat selkärangan välilevyjen päätelevyjen ja subkondraalisen luun muutoksia, jotka voidaan havaita ainoastaan magneettikuvauksella. Niitä pidetään välilevyrappeuman alatyyppinä. Modic-muutosten on osoitettu olevan yhteydessä alaselkäkipuun, mutta etiologia tunnetaan huonosti. Perinnöllisyyden osuutta Modic-muutoksien synnyssä ei ole aiemmin tutkittu ja niiden taustalla vaikuttavat geneettiset tekijät ovat pääasiassa tuntemattomia. Tämän tutkimuksen tavoitteena oli arvioida perinnöllisyyden osuutta Modic-muutoksissa kaksoisaineistossa, tunnistaa Modic-muutoksille altistavia geneettisiä muutoksia perheaineistossa käyttäen eksomisekvensointia ja tunnistaa genomin alueita, jotka assosioituvat Modic-muutoksiin. Tutkimus perustui kahteen väestöperäiseen aineistoon: Pohjois-Suomen Syntymäkohorttiin 1966 ja TwinsUK-kaksosaineistoon Yhdistyneistä kuningaskunnista sekä kahteen pohjois-suomalaiseen perheeseen. Tutkimuksessa osoitettiin, että Modic-muutokset ovat perinnöllisiä ja, että perinnölliset tekijät selittävät noin 30% niiden ilmenemisestä. Lisäksi tutkimuksessa tunnistettiin kaksi uutta alttiusgeeniä; HSPG2- ja MAML1-geenit. Molemmilla geeneillä on tärkeä rooli rustosolujen kasvamisessa ja erilaistumisessa. Tutkimuksessa myös tunnistettiin kromosomista 9 genomin alue, joka assosioituu Modic-muutoksiin. Väitöskirjassani osoitettiin, että perinnöllisillä tekijöillä on merkitystä Modic-muutosten synnyssä. Kokonaisuudessaan tämä väitöskirja kasvattaa ymmärrystä Modic-muutoksista, mutta lisätutkimusta aiheesta tarvitaan

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Catoia, Vitor. "Mineração de genes em regiões genômicas bovinas associadas à resistência ao carrapato Rhipicephalus (Boophilus) microplus." Universidade Federal de São Carlos, 2014. https://repositorio.ufscar.br/handle/ufscar/5556.

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The Brazilian cattle industry is presented as highlighted on the world stage and the significant participation of this productive sector in the economy means that there is concern with production losses, among which stands out those caused by infestation of Rhipicephalus (Boophilus) microplus, main ectoparasite vector cattle and various diseases. The genetic variability for resistance to the cattle tick shows that this trait can be genetically improved. For the execution of this work, it was used a study of genome wide association (GWAS) for resistance to Rhipicephalus (Boophilus) microplus, performed by Dr. Fernando Flores Cardoso, with 260 Hereford and 500 Braford animals. The monitoring of the infestation was accomplished by counting tick females larger than 4.5 mm from one of the animal's body side, and the degree of infestation was evaluated for each animal by averaging at least two consecutive counts, with intervals of approximately thirty days, in the months of highest incidence of the parasite. The animals were genotyped using a 50K SNP chip, and it was found a total of 37,346 SNPs that passed in quality test. Among these markers, 178 showed significant effects and allowed the mining of 175 genes in these regions, at an interval of 200 Kb (100 Kb for each side of each marker). Most of these polymorphisms associated with the trait is located in regions without defined functions (intronic and intergenic), and only one of them is located in the splicing region. The most significant regions of the GWAS were identified on chromosomes 7, 21 and 23, which were found 72 genes in linkage disequilibrium with the molecular markers. Therefore, a functional annotation of the genes on these 3 chromosomes was performed, allowing the choice of 11 candidate genes for the study of various metabolic pathways in which they are inserted. Among these pathways, the most important are those related to immune responses, secretion and intracellular transport, calcium influx and epidermal growth and differentiation.
A bovinocultura brasileira apresenta-se como destaque no cenário mundial e a expressiva participação deste setor produtivo na economia faz com que haja preocupação com as perdas produtivas, dentre as quais destaca-se aquelas causadas pela infestação do carrapato Rhipicephalus (Boophilus) microplus, principal ectoparasita de bovinos e vetor de diversas doenças. A variabilidade genética observada para a resistência dos bovinos ao carrapato permite que essa característica seja melhorada geneticamente, como forma alternativa de controle desses ectoparasitos. Para a execução do presente trabalho, foi utilizado um estudo de associação genômica ampla (GWAS) para a resistência ao carrapato R. microplus, o qual foi realizado pela equipe do Dr. Fernando Flores Cardoso (Embrapa Pecuária Sul), com 260 animais da raça Hereford e 500 animais da raça Braford. O monitoramento das infestações foi realizado por meio da contagem de fêmeas do carrapato com tamanho superior a 4,5 mm em um dos lados do corpo do animal, e o grau de infestação de cada animal foi avaliado pela média de pelo menos duas contagens consecutivas, com intervalos de aproximadamente trinta dias, conduzidas no sobreano, nos meses de maior incidência do parasito. Os animais foram genotipados com utilização de um chip de SNPs de 50 K e, após a realização do GWAS, verificou-se que um total de 37.346 SNPs passou nos teste de qualidade. Dentre esses marcadores, 178 SNPs apresentaram efeitos significativos e permitiram a mineração de 175 genes nessas regiões, em um intervalo de 200 Kb (100 Kb para cada lado de cada marcador). A maioria dos polimorfismos associados com a característica está localizada em regiões sem funções determinadas (intergênicas e intrônicas), apenas um deles encontra-se em região de splicing. Sendo assim, estes marcadores podem constituir mutações não causais que se encontram em desequilíbrio de ligação com mutações funcionais. As regiões mais significativas do GWAS foram identificadas nos cromossomos 7, 21 e 23, onde foram identificados 72 genes em desequilíbrio de ligação com os marcadores moleculares. Portanto, foi realizada uma anotação funcional dos genes localizados nesses 3 cromossomos, o que permitiu a seleção de 11 genes candidatos para um estudo mais aprofundado das vias metabólicas nas quais eles estão inseridos. Verificou-se que esses genes participam de processos importantes em vias já relacionadas com a resistência a carrapatos, tais como apresentação de antígenos, transporte e secreção intracelular e diferenciação da epiderme.

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Ndiaye, Fatou Kiné. "Étude post-GWAS des gènes de susceptibilité au diabète de type 2 : rôle phare dans la fonction de la cellule β pancréatique." Thesis, Lille 2, 2017. http://www.theses.fr/2017LIL2S039/document.

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Les études d’association pangénomique (GWAS) ont permis la mise en évidence de nouvelles voies putativement importantes dans la physiopathologie du diabète de type 2, par l’identification de variants génétiques fréquents (SNP) de susceptibilité au diabète de type 2, mais souvent avec peu ou pas d'informations sur le mécanisme sous-jacent expliquant le lien entre ces variants génétiques et le phénotype diabétique. En effet ces SNP sont souvent non codants et ont un effet modeste sur le risque de diabète de type 2, ce qui rend difficile leur étude d’un point de vue fonctionnel. Dès le début des GWAS, il a été suggéré que ces gènes associés au diabète de type 2, étaient des « gènes de la cellule β pancréatique » sans que des études fonctionnelles n’aient été faites de manière systématique. Dans ce contexte, nous avons mené une étude de fishing pour déblayer cette quantité importante de données provenant des GWAS et d’identifier des gènes potentiellement importants, pouvant être de nouvelles cibles thérapeutiques. Le premier objectif de ma thèse a été l’étude de l’expression des gènes de susceptibilité au diabète de type 2 dans un panel de tissus humains comprenant des tissus pancréatiques et des tissus sensibles à l’insuline. Pour cela nous avons utilisé une technique de quantification non biaisée de l’expression génique dans le but de montrer si ces gènes associés au diabète de type 2 avaient une expression enrichie (proportion de gènes de susceptibilité au diabète de type 2 surexprimés dans les cellules β versus les autres tissus) dans les cellules β pancréatiques. Nous avons ensuite réalisé des études fonctionnelles sur la trentaine de gènes de susceptibilité au diabète de type 2 les plus exprimés dans notre modèle cellulaire par des tests de sécrétion d’insuline, des études de la viabilité cellulaire, du séquençage d’ARN (RNA-seq) et du western blotting dans la lignée de cellules β pancréatiques humaines EndoC-βH1. Les EndoC-βH1 sont des cellules en mesure de sécréter de l’insuline en réponse au glucose et à d’autres sécrétagogues. Nous les avons utilisé afin d’étudier le rôle de ces gènes de susceptibilité au diabète de type 2 dans la fonction de la cellule β pancréatique, en particulier dans la sécrétion insulinique. Notre étude d’expression a montré que l’expression des gènes de susceptibilité au diabète de type 2 est enrichie de manière significative dans les cellules β pancréatiques et la lignée EndoC-βH1. Pour cinq gènes du diabète de type 2 (TBC1D4, TCF19, KCNK16, CDKN2A et SLC30A8) ayant une présence et un effet déjà connus dans la fonction des cellules β, nous avons démontré une variation significative de la sécrétion d’insuline après extinction génique, en concordance avec la littérature. Par ailleurs, nous avons pu mettre en évidence quatre gènes de susceptibilité au diabète de type 2 (PRC1, SRR, ZFAND3 et ZFAND6) montrant une baisse significative de la sécrétion d’insuline après extinction génique et dont la présence ou la fonction dans la cellule β était pour l’heure inconnue. Les analyses RNA-seq ont montré une association significative de l’extinction de ces gènes avec des réseaux moléculaires liés à la physiopathologie du diabète de type 2 (par exemple : l’apoptose des cellules pancréatiques, l’insulinémie, la glycolyse, le stress du réticulum endoplasmique…). Et l’évaluation de l’expression de nos quatre gènes dans des îlots de souris obèses (ob/ob) ou traitées à la streptozotocine a montré une corrélation positive de leur expression avec celle de l’insuline. Notre étude a démontré que les études fonctionnelles post-GWAS sont importantes et permettent de définir le lien de causalité des gènes de susceptibilité avec la maladie, et ainsi de mener à des progrès sur la compréhension de la physiopathologie de la maladie [...]
Genome-wide association studies (GWAS) have identified a plethora of single nucleotide polymorphisms (SNPs) associated with the risk of type 2 diabetes, but most often with little information about the mechanism underlying the relationship between these genetic variants associated with type 2 diabetes and the diabetic phenotype. Indeed, these SNPs are often noncoding and have a modest effect on the risk of type 2 diabetes, making difficult their functional study. At the beginning of the GWAS era, it has been suggested that susceptibility genes for type 2 diabetes are strongly involved in pancreatic β cell gene function, while no functional studies had been systematically performed. In this context, we conducted a “fishing” study to decipher this large amount of data generated by GWAS and to pinpoint potentially important genes that may be new therapeutic targets. The first objective of my thesis was to study the expression of type 2 diabetes susceptibility genes in a panel of human tissues comprising pancreatic and insulin-sensitive tissues using an unbiased technique of quantification of genes expression in order to show that these genes associated with type 2 diabetes were enriched in pancreatic β-cells. We then performed functional studies on the thirty mostly expressed genes in our cell model by insulin secretion tests, cell viability test, RNA sequencing (RNA-seq) and Western blotting in the human pancreatic β cell line (EndoC-βH1). These cells are able to secrete insulin in response to glucose and other secretagogues. Our goal was to study the role of these type 2 diabetes susceptibility genes in pancreatic β cell function, particularly in insulin secretion. Our expression study of type 2 diabetes susceptibility genes showed that their expression is significantly enriched in pancreatic β cells and the EndoC-βH1 cell line. For five genes associated with type 2 diabetes (TBC1D4, TCF19, KCNK16, CDKN2A and SLC30A8) with an already known presence and function in pancreatic β cell, we showed a significant variation in glucose-stimulated insulin secretion after gene silencing, in agreement with the literature. In addition, we identified four type 2 diabetes associated genes (PRC1, SRR, ZFAND3 and ZFAND6), with a significant decrease in insulin secretion after gene silencing without already know function in pancreatic β cell. RNA-seq has shown a significant association between the extinction of these genes and molecular networks related to the pathophysiology of type 2 diabetes (e.g. apoptosis of pancreatic cells, insulinemia, glycolysis, endoplasmic reticulum stress response...). The assessment of the expression of our four genes in the islets of obese mice (ob/ob) or treated with streptozotocin shows a positive correlation between their expression and the expression of insulin. Our study has shown that post-GWAS functional studies are important and can help to define the causal link between these genes and the disease, and therefore to make progress in the understanding of the pathophysiology of type 2 diabetes. This study allowed us to identify genes whose function in β cell was not anterior known and which are involved in pancreatic β cell function and the pathophysiology of type 2 diabetes

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Antoni, Guillemette. "Identification de facteurs génétiques modulant deux phénotypes intermédiaires de la maladie thrombo-embolique veineuse : les taux de facteurs VIII et von Willebrand : Intérêt de l’utilisation de différentes approches de recherche pangénomique." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA11T019/document.

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La Maladie Thrombo-Embolique Veineuse (MTEV) est une maladie dont les facteurs de risque sont à la fois environnementaux et génétiques. Les facteurs de risque génétiques bien établis sont les déficits en anti-thrombine, en protéine S, en protéine C, la mutation du Facteur V de Leiden (FVL), la mutation du Facteur (F) II G20210A, ainsi que le gène ABO dont les allèles A1 et B augmentent le risque de MTEV par rapport aux allèles A2 et O. Alors qu’une part importante de l’héritabilité de la MTEV reste inexpliquée, les études contemporaines se heurtent à un manque de puissance pour découvrir de nouveaux facteurs génétiques dont les effets sont de plus en plus faibles. En vue d’augmenter la puissance de détection de nouveaux gènes de susceptibilité à la MTEV, j’ai recherché les déterminismes génétiques de deux de ses phénotypes intermédiaires : les taux d’activité plasmatique du FVIII et les taux d’antigénémie de sa protéine de transport, le Facteur de von Willebrand (vWF). Dans un premier temps, j’ai réalisé une analyse de liaison des taux de FVIII et de vWF à partir d’un échantillon de cinq grandes familles franco-canadiennes (totalisant 255 personnes) recrutées via un cas de MTEV avec mutation FVL. Quatre régions liées aux taux de FVIII et/ou vWF ont été identifiées. L’une de ces régions correspondait au locus du gène ABO déjà connu pour influencer les taux de FVIII et vWF. La recherche de gènes candidats au sein des autres signaux de liaison s’est effectuée par l’étude in silico d’une analyse d’association pangénomique de la MTEV incluant 419 cas et 1228 témoins. Deux gènes candidats ont été identifiés : STAB2 et BAI3. J’ai ensuite réalisé des études d’associations de cinq polymorphismes de BAI3. L’un d’entre eux était d’une part associé à une élévation des taux de vWF (résultat obtenu dans un échantillon de 108 familles nucléaires en bonne santé et reproduit dans un échantillon de 916 patients non apparentés atteints de MTEV), et d’autre part associé au risque de survenue de MTEV parmi les sujets non porteurs de mutations FVL et FII de deux échantillons cas-témoins (respectivement 916 cas et 801 témoins, et 250 cas et 607 témoins). Quant à STAB2, durant le courant de ma thèse, deux de ces polymorphismes ont été décrits comme associés aux taux de FVIII et vWF au cours d’une vaste étude d’association pangénomique (GWAS) menée par le consortium CHARGE rassemblant 23 600 personnes. Dans un second temps, j’ai réalisé une méta-analyse de trois GWAS des taux de FVIII et vWF. Ces analyses avaient été conduites avec l’échantillon des cinq grandes familles franco-canadiennes et deux échantillons de 972 et 570 patients atteints de MTEV. Elles étaient ajustées sur les polymorphismes du gène ABO permettant de distinguer les allèles A1, A2, B et O, dans l’optique d’augmenter la puissance des analyses en diminuant la variance résiduelle des phénotypes. Aucun polymorphisme n’était associé ni aux taux de vWF ni à ceux de FVIII après prise en compte de la correction de Bonferroni pour tests multiples (p<10-7). Cependant, parmi les onze gènes qui présentaient des polymorphismes associés aux taux de vWF ou de FVIII avec une significativité p<10-5, de manière intéressante se trouvait STAB2. Cette étude a de plus permis de confirmer les associations nouvellement découvertes de polymorphismes situés dans les gènes VWF, STXBP5 et STX2
The Venous Thromboembolism (VTE) risk factors are environmental and genetic. The well established risk factors are anti-thrombin, protein C, protein S deficiency, Factor V Leiden and factor II mutation and ABO gene, with A1 and B allele increasing the risk of VTE. While an important part of VTE heritability remains unexplained, contemporary studies fail to discover new susceptibility genes with weaker effects. In order to increase the discovery power, I searched for genetic geterminism of two intermediary phenotypes of VTE : Factor VIII plasmatic activity (FVIII) and von Willebrand factor antigenemia (vWF)First, I performed a linkage study of FVIII and vWF from a sample of 5 large pedigrees (N=255). Four loci have been identified. One included ABO gene. I searched for candidate genes located in the others loci by studying in silico results from o Genome Wide Association Study (GWAS) of the VTE including 419 cases and and 1228 controls. témoins. Two candidate genes were identified : STAB2 et BAI3. Then I performed association studies of five SNPs in BAI3 with FVIII and vWF. One of them was associated to vWF (in a sample of 108 nuclear families and 916 VTE patients), and associated to VTE in two case-controls samples (respectively 916 cases and 801 controls, and 250 cases et 607 controls).Second, I performed a meta-analysis of three GWAS of FVIII and vWF from the same 5 pedigrees and two samples of VTE (N=972 and 570) adjusted on ABO blood group. No polymorphisms were significant after Bonferoni correction (p<10-7). Nevertheless, among 11 genes carrying polymorphisms with a p<10-5, interestingly was STAB2. Futhermore, this study allowed to confirm newly discoverd association with VWF, STXBP5 et STX2

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Yu, Mengyao. "Exploitation des données issues d'études d'association pangénomiques pour caractériser les voies biologiques associées au risque génétique du prolapsus de la valve mitrale GWAS-driven gene-set analyses, genetic and functional follow-up suggest GLIS1 as a susceptibility gene for mitral valve prolapse Up-dated genome-wide association study and functional annotation reveal new risk loci for mitral valve prolapse." Thesis, Sorbonne Paris Cité, 2019. https://wo.app.u-paris.fr/cgi-bin/WebObjects/TheseWeb.woa/wa/show?t=2203&f=17890.

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Le prolapsus de la valve mitrale (MVP) est une valvulopathie fréquente qui touche près de 1 personne sur 40 dans la population générale. Il s'agit de la première indication de réparation et / ou de remplacement de la valve. De nombreux gènes comme FLNA, DCHS1 pour les formes familiales et TNS1 et LMCD1 pour les formes sporadiques ont récemment été décrit comme associés au MVP. Cependant, les défauts génétiques touchant ces gènes n'expliquent pas tous les cas du MVP. De plus, les mécanismes biologiques expliquant la susceptibilité génétique au MVP, notamment pour les formes sporadiques les plus fréquentes restent mal compris. Dans cette thèse, mon objectif était 1) de caractériser globalement les mécanismes biologiques impliqués dans le risque génétique du MVP dans le contexte des études d'association pangénomique (GWAS), et 2) d'améliorer la résolution du génotypage par l'imputation génétique et par l'addition d'une nouvelle étude cas témoins, (UKBioBank) afin de permettre la découverte de nouveaux loci de prédisposition. Dans la première partie, j'ai appliqué des outils d'enrichissement de voies biologiques ou sets de gènes (i-GSEA4GWAS, DEPICT) aux données GWAS. J'ai pu montrer que les gènes présents autour des loci GWAS sont impliqués dans l'organisation des filaments d'actine, l'organisation du cytosquelette et le développement cardiaque. Nous avons également décrits de nombreux régulateurs de la transcription impliqués le développement, la prolifération cellulaire et la migration, comme le gène GLIS1 qui joue un rôle dans les transitions morphologiques cellulaires (EndoMT, MET). Afin de confirmer le rôle de GLIS1 dans l'association avec le MVP, j'ai réalisé une analyse génétique dans UKBiobank et, en combinaison avec les données françaises, l'association a atteint le seuil de significativité génomique. Des expériences d'immunohistochimie ont indiqué que Glis1, la protéine orthologue de la souris est exprimée au cours du développement embryonnaire principalement dans les noyaux des cellules endothéliales et interstitielles des valves mitrales. D'autre part, l'inactivation de Glis1 à l'aide d'oligonucléotides de type Morpholinos ont été l'origine d'une régurgitation atrio-ventriculaire chez le poisson zèbre. Dans la deuxième partie, j'ai généré des données de génotypage plus dense à l'aide d'une imputation basée sur Haplotype Reference Consortium (HRC) et TOPMed. J'ai d'abord comparé la précision d'imputation entre les données utilisant les différents panels et constaté qu'aucun panel n'atteignait une précision optimale pour les variants rares (MAF <0,01) dans nos échantillons. La précision d'imputation s'améliorait pour les variants fréquents (MAF> 0,05), en particulier pour les cohortes dont le génotypage étaient réalisé avec des puces identiques. J'ai pu ainsi cartographier avec plus de précision les loci déjà confirmés (ex. Chr 2 autour de TNS1). J'ai également identifié 6 nouveaux loci associés au MVP prometteurs. Les nouveaux variants associés sont tous fréquents. L'annotation fonctionnelle fine à l'aide de données publiques a indiqué leurs rôles potentiels dans la régulation transcriptionnelle de plusieurs gènes candidats (ex. PDGFD et ACTN4). En résumé, mes travaux de thèse ont apporté des résultats génétiques originaux mettant en lumière de nouveaux mécanismes biologiques en rapport avec la biologie et le développement de la valve. Ces travaux ont fait appel à de nombreuses stratégies génétiques d'association et d'enrichissement, d'imputation haute densité et d'annotations fonctionnelles. Mes travaux ont également été renforcés par des validations dans des modèles animaux en collaboration. Il sera nécessaire toutefois de confirmer par réplication, et potentiellement par des expériences biologiques, les résultats nouveaux issus des travaux d'imputation haute densité afin de déclarer ces nouveaux gènes de prédispositions au MVP
Mitral valve prolapse (MVP) is a common heart valve disease affecting nearly 1 in 40 individuals in the general population. It is the first indication for valve repair and/or replacement and moreover, a risk factor for mitral regurgitation, an established cause of endocarditis and sudden death. MVP is characterized by excess extracellular matrix secretion and cellular disorganization which leads to bulky valves that are unable to coapt correctly during ventricular systole. Even though several genes including FLNA, DCHS1 TNS1, and LMCD1 were reported to be associated with MVP, these explain partially its heritability. However, understanding the biological mechanisms underlying the genetic susceptibility to MVP is necessary to characterize its triggering mechanisms. In this thesis, I aimed 1) to characterize globally the biological mechanisms involved in the genetic risk for MVP in the context of genome-wide association studies (GWAS), and 2) improve the genotyping resolution using genetic imputation, which allowed the discovery of additional risk genes for MVP. In the first part of my study, I applied pathway enrichment tools (i-GSEA4GWAS, DEPICT) to the GWAS data. I was able to show that genes at risk loci are involved in biological functions relevant to actin filament organization, cytoskeleton biology, and cardiac development. The enrichment for positive regulation of transcription, cell proliferation, and migration motivated the follow-up of GLIS1, a transcription factor that regulates Hedgehog signalling. I followed up the association with MVP in a dataset of cases and controls from the UK Biobank and, in combination with previously available data, I found a genome-wide significant association with MVP (OR=1.22, P=4.36 ×10-10). Through collaborative efforts, immunohistochemistry experiments in mouse indicated that Glis1 is expressed during embryonic development predominantly in nuclei of endothelial and interstitial cells of mitral valves, while Glis1 knockdown using morpholinos caused atrioventricular regurgitation in zebrafish. In the second part of my work, I generated larger genotyping datasets using a imputation based on Haplotyp Refernece Consortium and TOPMed, two large and highly dense imputation panels that were recently made available. I first compared the imputation accuracy between data using HRC and TopMED and found that both panels have low imputation accuracy for rare allele (MAF<0.01). However, the imputation accuracy increased with the input sample size for common variants (MAF>0.05), especially when genotyping platforms were harmonised. I was able to fine map established loci (e.g Chr 2) and also able to identify six novel and promising associated loci. All new loci are driven by common variants that I confirmed as high profile regulatory variants through an extensive computationally-based functional annotations at promising loci that pointed at several candidate genes for valve biology and development (e.g PDGFD and ACTN4). In summary, my PhD work applied up-to-data high throughput genetic association methods and functional enrichment and annotation to GWAS data. My results provide novel insights into the genetics, molecular and cellular basis of valve disease. Further genetic confirmation through replication, but also through biological experiments are expected to consolidate these statistically and computationally supported results

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Ulveling, Damien. "Analyse génomique de la coinfection par le virus VIH et VHC." Thesis, Paris, CNAM, 2016. http://www.theses.fr/2016CNAM1066/document.

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Plus de 170 millions d'individus sont infectés par le VHC dans le monde et 37 millions par le VIH. La coinfection VIH/VHC est fréquente et représente un élément clé de la prise en charge des patients infectés par le VIH. Depuis l'arrivée des HAART, les maladies du foie sont devenues la cause principale de mortalité chez les patients coinfectés VIH/VHC. L'évolution naturelle et le pronostic de l'hépatite C sont plus sévères en cas de coinfection par le VIH du fait d'une fibrose accélérée et d'une évolution rapide vers la cirrhose et ses complications. Certains facteurs accélérant la fibrose hépatique sont clairs aujourd'hui comme: l'absence de recours au traitement anti-VHC, la réplication active du VHC et la consommation excessive d'alcool. De plus, il existe de plus en plus de preuves que les variants génétiques contribuent à la fibrose hépatique chez les patients monoinfectés par le VHC, mais cet aspect a été peu étudié dans la coinfection VIH/VHC.Durant ma thèse, j'ai eu accès aux données d'un échantillon de 494 patients coinfectés génotypés issu de la cohorte ANRS CO13 HEPAVIH. L'histoire naturelle du VIH et du VHC y est renseignée de manière très détaillée et le suivi clinique des patients permet d'avoir des informations précises sur l'état de fibrose hépatique. J'ai pu alors réaliser deux études d'association « génome-entier » pour identifier des polymorphismes associés à la sévérité de la fibrose à l'aide de données complètes de 292 patients. La première étude a mis en évidence une association entre la quantification de l'élasticité hépatique par Fibroscan® et un locus, également répliqué dans la monoinfection par le VHC. Cette association a permis d'identifier deux gènes impliqués dans des mécanismes de maintien de structure et de signalisation cellulaire (CAV3) mais aussi dans la réplication du VHC (RAD18). La seconde étude a identifié deux associations significatives en comparant deux groupes de scores METAVIR (F0F1F2 vs F3F4), en particulier dans le gène CTNND2 qui est impliqué dans un réseau d'interaction associé à des mécanismes moléculaires lié à des maladies hépatiques.Ces deux études sont en cours de publication dans des revues scientifiques internationales à comité de lecture. Ces nouvelles perspectives dans la compréhension des mécanismes de fibrose dans le contexte de la coinfection VIH/VHC pourraient aider à l'identification de nouvelles cibles pour la création de médicaments ou de tests diagnostiques afin d'améliorer les soins des patients
Over 170 million people worldwide are infected by HCV and 37 million by HIV. Both viruses share the same modes of transmission, and HIV/HCV coinfection is common and represents a key element in the management of patients infected with HIV. Since the appearance of HAART, liver diseases have become the leading cause of death in HIV/HCV coinfected patients. The natural history and prognosis of hepatitis C are more severe in case of coinfection with HIV due to accelerated rate of fibrosis progression and rapid progression to cirrhosis and its complications. Factors accelerating liver fibrosis are known today such as the lack of recourse to anti-HCV treatment, active HCV replication and excessive alcohol consumption. There is increasing evidence that genetic variants contribute to liver fibrosis in HCV monoinfection, but this aspect has been little studied in HIV/HCV coinfection.I have exploited the genotype information from 494 coinfected patients from the cohort ANRS CO13 HEPAVIH. These patients are very-well documented regarding the history of their HIV/HCV infection and are very carefully followed-up, especially regarding the status of liver fibrosis. I have performed two genome-wide association studies to identify polymorphisms associated with the severity of fibrosis from complete data of 292 patients. The first study has dealt with the quantification of liver stiffness by Fibroscan® and an association with the 3p25 region has been identified, also replicated in monoinfection HCV. Two genes involved in cell signaling and structure of holding mechanisms (CAV3) but also in HCV replication (RAD18) appear as good candidates. The second study has unraveled two significant associations by comparing the METAVIR score group (F0F1F2 vs F3F4), especially in the CTNND2 gene implicated in a network of interactions with molecular mechanisms involved in liver diseases.These results are under publications in peer-review international scientific journals. These new insights into the molecular mechanisms of liver fibrosis in patients with HIV/HCV co- infection may help to define new targets for drug development or new diagnostic tests, to improve patient care

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Corbin, Laura Jayne. "Application of genomic technologies to the horse." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/11808.

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The publication of a draft equine genome sequence and the release by Illumina of a 50,000 marker single-nucleotide polymorphism (SNP) genotyping chip has provided equine researchers with the opportunity to use new approaches to study the relationships between genotype and phenotype. In particular, it is hoped that the use of high-density markers applied to population samples will enable progress to be made with regard to more complex diseases. The first objective of this thesis is to explore the potential for the equine SNP chip to enable such studies to be performed in the horse. The second objective is to investigate the genetic background of osteochondrosis (OC) in the horse. These objectives have been tackled using 348 Thoroughbreds from the US, divided into cases and controls, and a further 836 UK Thoroughbreds, the majority with no phenotype data. All horses had been genotyped with the Illumina Equine SNP50 BeadChip. Linkage disequilibrium (LD) is the non-random association of alleles at neighbouring loci. The reliance of many genomic methodologies on LD between neutral markers and causal variants makes it an important characteristic of genome structure. In this thesis, the genomic data has been used to study the extent of LD in the Thoroughbred and the results considered in terms of genome coverage. Results suggest that the SNP chip offers good coverage of the genome. Published theoretical relationships between LD and historical effective population size (Ne) were exploited to enable accuracy predictions for genome-wide evaluation (GWE) to be made. A subsequent in-depth exploration of this theory cast some doubt on the reliability of this approach in the estimation of Ne, but the general conclusion that the Thoroughbred population has a small Ne which should enable GWE to be carried out efficiently in this population, remains valid. In the course of these studies, possible errors embedded within the current sequence assembly were identified using empirical approaches. Osteochondrosis is a developmental orthopaedic disease which affects the joints of young horses. Osteochondrosis is considered multifactorial in origin with a variety of environmental factors and heredity having been implicated. In this thesis, a genome-wide association study was carried out to identify quantitative trait loci (QTL) associated with OC. A single SNP was found to be significantly associated with OC. The low heritability of OC combined with the apparent lack of major QTL suggests GWE as an alternative approach to tackle this disease. A GWE analysis was carried out on the same dataset but the resulting genomic breeding values had no predictive ability for OC status. This, combined with the small number of significant QTL, indicates a lack of power which could be addressed in the future by increasing sample size. An alternative to genotyping more horses for the 50K SNP chip would be to use a low-density SNP panel and impute remaining genotypes. The final chapter of this thesis examines the feasibility of this approach in the Thoroughbred. Results suggest that genotyping only a subset of samples at high density and the remainder at lower density could be an effective strategy to enable greater progress to be made in the arena of equine genomics. Finally, this thesis provides an outlook on the future for genomics in the horse.

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Torres-Dini, Diego Gabriel [UNESP]. "Detection of QTLs associated to DBH in a Eucalyptus grandis x Eucalyptus Globulus monoprogeny." Universidade Estadual Paulista (UNESP), 2017. http://hdl.handle.net/11449/148905.

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Outra
In Uruguay, reforestation with Eucalyptus sp. is of fundamental importance to produce paper, pulp and wood. The productivity of these continually grows due to application of breeding techniques, such as hybridization. This study aimed to investigate genetic parameters, productivity, stability, adaptability and to identify SNP markers associated with the diameter breast height (DBH) for to select Eucalypts grandis x Eucalyptus globulus full-sibs hybrid clones. The study was conducted in a clonal test, repeated at two different soils, in the state of Rio Negro, Uruguay. The population was phenotypically characterized to the DBH at 48 months of age and cambium tissues of each individual were sampled for genotyping with EuCHIP60K chip. The mean growth in DBH was similar between both places. The genotype-environment interaction was the simple type, with high genotype correlation in clones’ performance between environments (0.708), indicating the possibility of the same clones being selected for both places. Mean heritability between clones (0.724), coefficient of individual genetic variation (10.9%) and relative variation (0.916), showed the possibility of obtaining gains by selecting clones with higher growth, which was estimated in 3.1% for both sites together. A total of 15,196 markers SNPs were used in the genomic selection for the DBH, but after cleaning of SNPs data, the number was reduced for 15,196 (23.5%). The predictive capacity was expected to be low or negative (-0.15) for this population given the population size (78 individuals). We used the model rrBLUP with a validation of Jackknife. The model do not showed precision to predict the DBH. These results were consistent with theoretical expectations, which indicate that it is necessary to have an improvement population of at least 1,000 phenotyped and genotyped individuals. The DBH is the most important trait in the breeding of the genus Eucalyptus. However its quantitative nature added to the time necessary for this phenotype to develop makes the early detection of this trait are difficult. The identification of molecular markers associated with quantitative phenotypes is a good choice for the identification of QTLs that will help the early detection of individuals with high DBH. Significant markers associated to DBH , were indentificated into the chromosome 6, suggesting the presence of a QTL in this chromosome. Since they are clones originated from vegetative propagation and a full-sibs single-progeny, they should preferably be used for reforestation based on their cloning, since mating between clones can generate endogamy by biparental inbreeding. The utilization of SNPs helped to confirm the degree of parentage between the clones as well as clonal identity control.

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Torres-Dini, Diego Gabriel. "Detecção de qtl associado a dap em eucaliptus grandis x eucaliptus globulus monoprogênie /." Ilha Solteira, 2017. http://hdl.handle.net/11449/148905.

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Orientador: Alexandre Magno Sebbenn
Resumo: In Uruguay, reforestation with Eucalyptus sp. is of fundamental importance to produce paper, pulp and wood. The productivity of these continually grows due to application of breeding techniques, such as hybridization. This study aimed to investigate genetic parameters, productivity, stability, adaptability and to identify SNP markers associated with the diameter breast height (DBH) for to select Eucalypts grandis x Eucalyptus globulus full-sibs hybrid clones. The study was conducted in a clonal test, repeated at two different soils, in the state of Rio Negro, Uruguay. The population was phenotypically characterized to the DBH at 48 months of age and cambium tissues of each individual were sampled for genotyping with EuCHIP60K chip. The mean growth in DBH was similar between both places. The genotype-environment interaction was the simple type, with high genotype correlation in clones’ performance between environments (0.708), indicating the possibility of the same clones being selected for both places. Mean heritability between clones (0.724), coefficient of individual genetic variation (10.9%) and relative variation (0.916), showed the possibility of obtaining gains by selecting clones with higher growth, which was estimated in 3.1% for both sites together. A total of 15,196 markers SNPs were used in the genomic selection for the DBH, but after cleaning of SNPs data, the number was reduced for 15,196 (23.5%). The predictive capacity was expected to be low or negative (-0.15)... (Resumo completo, clicar acesso eletrônico abaixo)
Doutor

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Benabou, Marion. "Étude génétique de la voie sérotonine-N-acétylsérotonine-mélatonine et de ses anomalies dans la vulnérabilité aux Troubles du Spectre Autistique (TSA) et dans la prématurité." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB010.

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Des anomalies biochimiques de la voie sérotonine-N-acétylsérotonine-mélatonine ont été observées dans les Troubles du Spectre Autistique (TSA) et la prématurité. Cependant, les mécanismes moléculaires de régulation de cette voie et les causes des anomalies biochimiques observées dans ces maladies sont encore mal connus. Afin de mieux comprendre les bases génétiques de la voie sérotonine-N-acétylsérotonine-mélatonine, nous avons utilisé une approche de génétique quantitative au travers de deux populations d’étude indépendantes, dans lesquelles des paramètres de cette voie ont été mesurés. Ces deux cohortes, composées d’une part de plus de 250 familles avec autisme et plus de 300 témoins et d’autre part, de 183 nouveau-nés dont 93 nés très prématurés, incluent ainsi des individus présentant deux situations pathologiques différentes associées à des anomalies de cette voie. Une première étude de la voie sérotonine-N-acétylsérotonine-mélatonine dans les familles avec TSA a permis d’obtenir des estimations de l’héritabilité au sens strict, allant de 0,22 pour la mélatonine à 0,72 pour la N-acétylsérotonine (NAS). Des études d’association portant dans un premier temps sur une liste de 812 gènes candidats pour la régulation de la voie sérotonine-NAS-mélatonine et dans un second temps sur tout le génome, n’ont pas permis d’identifier des variants significativement associés aux traits biochimiques. Cependant, des études d’association par gènes ont permis d’identifier trois nouveaux gènes candidats (IL21R, JMJD7 et MAPKBP1) pour la régulation de cette voie dans les familles avec TSA ainsi qu’un nouveau gène (RAET1G) dans la cohorte de nouveau-nés prématurés et témoins. Enfin une étude biochimique des phénol-sulfotransférases (PST) dans les familles avec TSA a mis en évidence une faible activité enzymatique chez 29% des patients en comparaison avec les témoins (5ème percentile). Le séquençage et le génotypage du nombre de copies des gènes de la famille SULT1A1 n’ont pas permis d’identifier des variations génétiques associées aux TSA, à l’activité PST, ou aux taux de sérotonine et de mélatonine. En conclusion, ces résultats confirment la complexité de l’architecture génétique de la voie sérotonine-NAS-mélatonine. D’autre part, ils ont permis de mettre en évidence une héritabilité élevée de cette voie et d’identifier de nouveaux gènes candidats pour comprendre la diversité inter-individuelle de cette voie chez les personnes avec TSA, les enfants prématurés et la population générale
Biochemical abnormalities of the serotonin-N-acetylserotonin-melatonin pathway have been reported in many clinical conditions such as Autism Spectrum Disorders and preterm birth. However, molecular mechanisms underlying this pathway regulation, as well as the causes of these biochemical abnormalities remain largely unknown. The aim of this study was thus to characterize the genetic basis of the serotonin-N-acetylserotonin-melatonin pathway. To do so, we used a quantitative genetic approach in two independent populations that were previously biochemically explored for this pathway. One cohort consisted of more than 250 families with ASD and more than 300 controls and the other was composed of 183 infants including 93 very preterm newborns. Both cohorts included individuals with clinical conditions associated with disruptions of the serotonin-N-acetylserotonin-melatonin pathway. Narrow sense heritability analysis of this pathway showed relatively high estimates, ranging from 0.22 for melatonin to 0.72 for N-acetyserotonin (NAS). First, candidate-gene association studies including 812 genes related to the serotonin-NAS-melatonin pathway, then genome-wide association studies were conducted. These analyses did not identify any variant associated at the genome-wide significance level. However, a gene-based approach identified three new candidate genes (IL21R, JMJD7 and MAPKBP1) for the regulation of the pathway in families with ASD as well as one gene (RAET1G) in the cohort of preterm and term newborns. Finally, a biochemical exploration of the phenol-sulfotransferases (PST) in families with ASD revealed a decreased enzyme activity in 29% of patients compared with controls (5th percentile). SULT1A1-4 genes were then sequenced and copy number variants (CNV) were genotyped. No genetic variant could be significantly associated with PST activity, melatonin and serotonin levels, or ASD status. In conclusion, these results confirm the complexity of serotonin-NAS-melatonin pathway genetic architecture. Furthermore, this study revealed high heritability of this pathway and identified new candidate genes to understand the inter-individual variability of this pathway in ASD, preterm birth and the general population

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Vincent, Quentin. "Epidémiologie et génétique humaine de l’ulcère de Buruli." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05S019/document.

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L'ulcère de Buruli (UB), infection à Mycobacterium ulcerans, troisième mycobactériose mondiale, connait une émergence rapide depuis 1980, essentiellement dans les pays d'Afrique subsaharienne. Jusqu’ici, les connaissances épidémiologiques sur l’UB étaient fondées sur des séries de cas cliniques non confirmés par laboratoire. Nous avons constitué la plus grande cohorte de cas confirmés à ce jour rassemblant plus de 1200 patients traités au CDTUB de Pobè au Bénin entre 2005 et 2011, afin de décrire l'épidémiologie clinique de la maladie et d'explorer l’architecture génétique de la susceptibilité à cette maladie. Les patients atteints d’UB sont des enfants (âge médian au diagnostic de 12 ans), présentant une lésion unique (96%), large (plus de 15 cm, 36%), ulcérative (66%) du membre inférieur (60%). Nous rapportons une présentation clinique atypique de l’UB, dans laquelle les patients présentent exclusivement une ostéomyélite à M. ulcerans. Le sex-ratio varie avec l’âge : les garçons sont majoritaires parmi les enfants (57% de patients masculins chez les moins de 15 ans), et les femmes parmi les adultes (33% de patients masculins). La présentation clinique dépend de l’âge et du sexe. 9% des patients masculins ont présenté une ostéomyélite contre 4% des patients féminins. Un an après la fin du traitement, 22% des patients présentent des séquelles fonctionnelles fixées. Une présentation clinique comportant une lésion oedémateuse, osseuse, de grande taille ou plusieurs lésions est significativement associée avec le développement de séquelles fonctionnelles (OR 7.64, IC95% [5.29-11.31]). Les patients coinfectés par le VIH ont un risque significativement plus élevé de développer un UB sévère (OR 2.77, IC95% [1.32-6.33]). Nous avons exploré l’architecture génétique de la susceptibilité à l’UB dans une perspective mendélienne et une perspective complexe. Le cas le plus sévère de la maladie observé dans ce centre appartient à une famille consanguine dans laquelle la ségrégation du phénotype suggère un défaut génétique mendélien récessif. Une analyse de liaison génétique par cartographie d'homozygotie suggère l’implication du locus des béta-défensines sur le chromosome 8 dans la pathogénèse de l'UB, et mène à l’identification d’une délétion homozygote ségrégeant parfaitement avec la maladie. Dans une perspective complexe, une étude d’association pangénomique a été réalisée après génotypage d’une cohorte de 400 cas et 400 témoins exposés sur plus de 2 millions de SNPs par la puce Illumina Omni2.5 et a permis l’identification de nombreux signaux d’intérêt. L’étude de réplication est en cours. La compréhension de la physiopathologie de l'infection à M. ulcerans est cruciale pour générer de nouvelles pistes thérapeutiques et vaccinales. La dissection du contrôle génétique de l'infection par l'hôte est en ce sens indispensable
Buruli ulcer (BU), caused by Mycobacterium ulcerans, is the third most frequent mycobacteriosis worldwide. It has been rapidly emerging in sub-Saharan African countries since 1980. Until now, knowledge of BU epidemiology relied on series of non laboratory-confirmed clinical cases. From 2005-2011, we recruited the current largest cohort of laboratory-confirmed cases (more than 1,200 patients) at the Pobe CDTUB, Benin, to describe the clinical epidemiology of the disease and to explore the genetic architecture of human susceptibility to BU. Typically, patients with BU were children (median age at diagnosis 12 years) presenting with a unique (96%) large (≥15 cm, 36%) ulcerative (66%) lesion of the lower limb (60%). Atypical clinical presentation of BU included osteomyelitis with no identifiable present or past BU skin lesions. The sex ratio of BU widely varied with age, with male patients accounting for 57% of patients aged 15 years and younger, but only 33% of those older than 15 years. Clinical presentation of BU was significantly dependent on age and sex. 9% male patients had BU osteomyelitis, whereas only 4% of female patients did. 1 year after treatment, 22% of patients with follow-up information presented with permanent functional sequelae. Presentation with oedema, osteomyelitis, or large (≥15 cm in diameter), or multifocal lesions was significantly associated with occurrence of permanent functional sequelae (OR 7•64, 95% CI 5•29–11•31) and operationally defines severe BU. When coinfected with HIV, patients had a significantly higher risk to develop severe BU (OR 2.77, IC95% [1.32-6.33]). We explored the genetic architecture of susceptibility to BU in both mendelian and complex genetic frameworks. The most severe case of the disease to have been treated at the Pobe CDTUB belonged to a consanguineous family in which the segregation of the phenotype was indicative of a recessive mendelian genetic defect. Genetic linkage analysis by homozygosity mapping suggested the implication of the beta-defensin locus on chromosome 8 in BU pathogenesis and lead to the identification of a homozygous deletion, which co-segregated perfectly with the disease in the family. In a complex genetics approach, we undertook a genome-wide association study, which involved the genotyping of more than 2 million SNPs (Illumina Omni2.5) in a cohort of 400 cases and 400 exposed controls. We identified many signals of interest. The replication study is ongoing. Understanding BU physiopathology is crucial to the development of efficient vaccines and drugs. Dissection of the genetic control of the infection by M. ulcerans by its human host therefore constitutes an indispensable step

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Simmons, Michael. "Identifying Genetic Pleiotropy through a Literature-wide Association Study (LitWAS) and a Phenotype Association Study (PheWAS) in the Age-related Eye Disease Study 2 (AREDS2)." Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/623630.

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A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.
Genetic association studies simplify genotype‐phenotype relationship investigation by considering only the presence of a given polymorphism and the presence or absence of a given downstream phenotype. Although such associations do not indicate causation, collections of phenotypes sharing association with a single genetic polymorphism may provide valuable mechanistic insights. In this thesis we explore such genetic pleiotropy with Deep Phenotype Association Studies (DeePAS) using data from the Age‐Related Eye Study 2 (AREDS2). We also employ a novel text mining approach to extract pleiotropic associations from the published literature as a hypothesis generation mechanism. Is it possible to identify pleiotropic genetic associations across multiple published abstracts and validate these in data from AREDS2? Data from the AREDS2 trial includes 123 phenotypes including AMD features, other ocular conditions, cognitive function and cardiovascular, neurological, gastrointestinal and endocrine disease. A previously validated relationship extraction algorithm was used to isolate descriptions of genetic associations with these phenotypes in MEDLINE abstracts. Results were filtered to exclude negated findings and normalize variant mentions. Genotype data was available for 1826 AREDS2 participants. A DeePAS was performed by evaluating the association between selected SNPs and all available phenotypes. Associations that remained significant after Bonferroni‐correction were replicated in AREDS. LitWAS analysis identified 9372 SNPs with literature support for at least two distinct phenotypes, with an average of 3.1 phenotypes/SNP. PheWAS analyses revealed that two variants of the ARMS2‐HTRA1 locus at 10q26, rs10490924 and rs3750846, were significantly associated with sub‐retinal hemorrhage in AMD (rs3750846 OR 1.79 (1.41‐2.27), p=1.17*10‐7). This associated remained significant even in populations of participants with neovascular AMD. Furthermore, odds ratios for the development of sub‐retinal hemorrhage in the presence of the rs3750846 SNP were similar between incident and prevalent AREDS2 sub‐populations (OR: 1.94 vs 1.75). This association was also replicated in data from the AREDS trial. No literature‐defined pleiotropic associations tested remained significant after multiple‐testing correction. The rs3750846 variant of the ARMS2‐HTRA1 locus is associated with sub‐retinal hemorrhage. Automatic literature mining, when paired with clinical data, is a promising method for exploring genotype‐phenotype relationships.

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Zhao, Jiantao. "Combining Association and Haplotype Studies Towards the Improvement of Fruit Quality in Tomato Multiple haplotype-based analyses provide genetic and evolutionary insights into tomato fruit weight and composition Meta-analysis of genome-wide association studies provides insights into genetic control of tomato flavor Genomic designing for climate smart tomato." Thesis, Avignon, 2019. http://www.theses.fr/2019AVIG0712.

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Les consommateurs se plaignent de la qualité gustative des tomates depuis des décennies. Celle-ci est influencée principalement par les sucres, les acides et un ensemble de divers composés volatils. L’amélioration de la saveur de la tomate reste l’un des principaux défis à relever pour améliorer la qualité de la tomate et l’acceptabilité des consommateurs pour l’amélioration moderne des tomates. Le but principal de cette thèse était de disséquer le contrôle génétique de la saveur de la tomate en utilisant des SNP à haute densité et un ensemble divers de traits liés à la saveur, notamment les sucres, les acides, les acides aminés et les composés volatils. Dans la première partie, j'ai effectué plusieurs analyses basées sur l’exploration des haplotypes dans une collection d’accessions. Plusieurs approches ont été utilisées et comparées pour identifier les régions génomiques en cours de sélection. Les modèles bayésiens de génétique d’association basés sur les haplotypes et une partie des SNP ont identifié 108 associations significatives pour 26 caractères. Parmi ces associations, certains gènes candidats prometteurs ont été identifiés. Certains avantages de l’utilisation des haplotypes ont également été présentés. Dans la deuxième partie, j'ai réalisé une méta-analyse d'études d'association pangénomique à l'aide de trois panels d'associations de tomates. J'ai démontré l'efficacité de l'imputation des génotypes pour augmenter la couverture de SNP à l'échelle du génome. Des méta-analyses de modèles à effets fixes et à effets aléatoires (pour les SNP présentant une hétérogénéité I2 > 25) ont été effectuées afin de contrôler l'hétérogénéité croisée des études. Au total, 305 locus significatifs ont été identifiés, dont 211 nouveaux. Parmi ceux-ci, 24 locus ont présenté des cis-eQTL lors d'une précédente étude d'association à l'échelle du transcriptome de fruits. L'analyse d'enrichissement pour toutes les associations a montré que jusqu'à 10 processus biologiques étaient enrichis de manière significative et que tous étaient étroitement impliqués dans les métabolites liés aux arômes. Une liste de gènes candidats prometteurs a été fournie, qui pourraient présenter un grand intérêt pour la validation fonctionnelle. J'ai également démontré la possibilité d'augmenter de manière significative le contenu en composés volatils qui contribuent de manière positive aux préférences des consommateurs tout en réduisant les volatils désagréables, en sélectionnant les combinaisons d'allèles pertinentes. Globalement, cette thèse augmente les connaissances du contrôle génétique du goût de la tomate, ce qui devrait contribuer à son amélioration
Consumers have been complaining about tomato flavor for decades. Tomato taste is mainly influenced by sugars, acids and a diverse set of volatiles. Improving tomato flavor remains one of the main challenges for improving tomato sensory quality and consumer acceptability in modern tomato breeding. The main purpose of this thesis was to decipher the genetic and evolutionary control of tomato flavor by using high density SNPs and a diverse set of flavor-related metabolites, including sugars, acids, amino acids and volatiles. In the first part, I performed multiple haplotype-based analyses on a tomato core collection. Several approaches were used and compared to identify the genomic regions under selection. Haplotype and SNP-based Bayesian models identified 108 significant associations for 26 traits. Among these associations, some promising candidate genes were identified. I also compared marker local haplotype sharing (mLHS) with LD in determining the candidate regions. In addition, some general benefits of using haplotypes were also provided as general discussions. In the second part, I pioneered in introducing meta-analysis of genome-wide association studies using three tomato association panels. I demonstrated the efficiency of genotype imputation in increasing the genome-wide SNP coverage. Both fixed-effect and random-effect models (for those SNPs with heterogeneity I2 > 25) of meta-analysis were performed in order to control cross-study heterogeneity. A total of 305 significant loci were identified and 211 of which were new. Among them, 24 loci exhibited cis-eQTLs in a previous transcriptome-wide association study in fruit tissue. Enrichment analysis for all associations showed that up to 10 biological processes were significantly enriched and all of which were closely involved in flavor-related metabolites. A list of promising candidate genes was provided, which could be of great interest for functional validation. I also demonstrated the possibility to significantly increase the content of volatiles that positively contribute to consumer preferences while reducing unpleasant volatiles, by selection of the relevant allele combinations. Taken together, this thesis provides a comprehensive knowledge of the genetic control of tomato flavor, which will promote its improvement

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Somavilla, Adriana Luiza [UNESP]. "Prediction of genomic-enabled breeding values and genome-wide association study for feedlot average daily weight gain in Nelore cattle." Universidade Estadual Paulista (UNESP), 2015. http://hdl.handle.net/11449/128158.

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A seleção para taxa de crescimento utilizando o número de dias para atingir determinado peso ou ganho de peso médio resultaria em menores ciclos de produção. Manter o aumento da produtividade exige, entre outros fatores, a utilização de animais melhorados, tanto nos sistemas de pastagem quanto de confinamento. Além disso, as informações genômicas podem ser usadas para predizer os valores genéticos genômicos (GEBVs) mais cedo na vida dos animais, o que reduziria os intervalos de geração e aumentaria os ganhos de produtividade. Inúmeros trabalhos tem sido conduzidos para identificar metodologias apropriadas à determinadas raças e características, o que irá resultar em GEBVs mais acurados. Os objetivos deste estudo foram comparar a acurácia de predição dos GEBVs e a habilidade de identificar regiões genômicas e genes relacionados ao ganho de peso médio diário em bovinos da raça Nelore, pela aplicação de diferentes modelos de regressão e densidades genotípicas. Informações genômica e fenotípica de 804 novilhos nascidos em três safras, filhos de 34 touros, foram utilizadas para predizer GEBVs por meio de três modelos (Bayesian GBLUP, BayesA e BayesC ), quatro densidades genotípicas (Illumina BovineHD BeadChip, TagSNPs, GeneSeek indicus de alta (HDi) e baixa (LDi) densidades) e dois fenótipos ajustados. A estrutura de família foi considerada por meio da análise de componentes principais. Os animais foram distribuídos em subconjunto de treinamento (safras 1 e 2) ou validação (safra 3) para realização da análise de validação cruzada. Estimativas de correlação de Pearson, coeficientes de regressão e erro quadrado médio foram usados para avaliar acurácia, inflação e viés dos GEBVs estimados, respectivamente. O estudo de associação ampla do genoma (GWAS) também foi realizado nos mesmos conjuntos de dados, entretanto, os resultados foram comparados com...
Selection for fast growth rates using number of days to achieve specific weights or average weight gain would result in shorter production periods. Maintaining the rate of productivity increasing will demand, among other factors, genetically improved animals in both pasture and feedlot systems. Besides, genomic information could be used to predict genomic-enabled breeding values (GEBVs) earlier in animals' life, which would reduce generation intervals and increase productivity gains. Numerous studies have been conducted in order to identify appropriate methodologies to specific breeds and traits, which will result in more accurate GEBVs. The aim of this study was to compare the prediction accuracy of GEBVs and the ability to identify genomic regions and genes related to average weight daily gain in Nelore cattle, by applying different regression models and genotypes densities datasets. Genomic and phenotypic information of 804 steers born in three season, offspring of 34 bulls, were used to predict GEBVs through three models (Bayesian GBLUP, BayesA and BayesC ), four genotypic densities (Illumina BovineHD BeadChip, TagSNPs, GeneSeek Genomic Profiler High (HDi) and Low (LDi) density indicus) and two adjusted phenotypes. Family structure was accounted by using principal component analysis. Animals were assigned either to training (seasons 1 and 2) or testing (season 3) subsets to perform the cross-validation analysis. Estimates of Pearson correlation, regression coefficients and mean squared errors were used to access accuracy, inflation and bias of the estimated GEBVs, respectively. Genome-wide association study (GWAS) was also performed on above datasets, however, results were compared based on ...

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Rolling, William R. "A study of Phytophthora sojae Resistance in Soybean (Glycine max [L. Merr]) using Genome-Wide Association Analyses and Genomic Prediction." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1577706249228025.

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Somavilla, Adriana Luiza. "Prediction of genomic-enabled breeding values and genome-wide association study for feedlot average daily weight gain in Nelore cattle /." Jaboticabal, 2015. http://hdl.handle.net/11449/128158.

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Orientador: Danísio Prado Munari
Coorientador: Luciana Correia de Almeida Regitano
Coorientador: Fabiana Barichello Mokry
Banca: Luiz Lehmann Coutinho
Banca: Rogério Abdallah Curi
Banca: Marcos Vinicius Gualberto Barbosa da Silva
Banca: Nedenia Bonvino Stafuzza
Resumo: A seleção para taxa de crescimento utilizando o número de dias para atingir determinado peso ou ganho de peso médio resultaria em menores ciclos de produção. Manter o aumento da produtividade exige, entre outros fatores, a utilização de animais melhorados, tanto nos sistemas de pastagem quanto de confinamento. Além disso, as informações genômicas podem ser usadas para predizer os valores genéticos genômicos (GEBVs) mais cedo na vida dos animais, o que reduziria os intervalos de geração e aumentaria os ganhos de produtividade. Inúmeros trabalhos tem sido conduzidos para identificar metodologias apropriadas à determinadas raças e características, o que irá resultar em GEBVs mais acurados. Os objetivos deste estudo foram comparar a acurácia de predição dos GEBVs e a habilidade de identificar regiões genômicas e genes relacionados ao ganho de peso médio diário em bovinos da raça Nelore, pela aplicação de diferentes modelos de regressão e densidades genotípicas. Informações genômica e fenotípica de 804 novilhos nascidos em três safras, filhos de 34 touros, foram utilizadas para predizer GEBVs por meio de três modelos (Bayesian GBLUP, BayesA e BayesC ), quatro densidades genotípicas (Illumina BovineHD BeadChip, TagSNPs, GeneSeek indicus de alta (HDi) e baixa (LDi) densidades) e dois fenótipos ajustados. A estrutura de família foi considerada por meio da análise de componentes principais. Os animais foram distribuídos em subconjunto de treinamento (safras 1 e 2) ou validação (safra 3) para realização da análise de validação cruzada. Estimativas de correlação de Pearson, coeficientes de regressão e erro quadrado médio foram usados para avaliar acurácia, inflação e viés dos GEBVs estimados, respectivamente. O estudo de associação ampla do genoma (GWAS) também foi realizado nos mesmos conjuntos de dados, entretanto, os resultados foram comparados com...
Abstract: Selection for fast growth rates using number of days to achieve specific weights or average weight gain would result in shorter production periods. Maintaining the rate of productivity increasing will demand, among other factors, genetically improved animals in both pasture and feedlot systems. Besides, genomic information could be used to predict genomic-enabled breeding values (GEBVs) earlier in animals' life, which would reduce generation intervals and increase productivity gains. Numerous studies have been conducted in order to identify appropriate methodologies to specific breeds and traits, which will result in more accurate GEBVs. The aim of this study was to compare the prediction accuracy of GEBVs and the ability to identify genomic regions and genes related to average weight daily gain in Nelore cattle, by applying different regression models and genotypes densities datasets. Genomic and phenotypic information of 804 steers born in three season, offspring of 34 bulls, were used to predict GEBVs through three models (Bayesian GBLUP, BayesA and BayesC ), four genotypic densities (Illumina BovineHD BeadChip, TagSNPs, GeneSeek Genomic Profiler High (HDi) and Low (LDi) density indicus) and two adjusted phenotypes. Family structure was accounted by using principal component analysis. Animals were assigned either to training (seasons 1 and 2) or testing (season 3) subsets to perform the cross-validation analysis. Estimates of Pearson correlation, regression coefficients and mean squared errors were used to access accuracy, inflation and bias of the estimated GEBVs, respectively. Genome-wide association study (GWAS) was also performed on above datasets, however, results were compared based on ...
Doutor

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Yu, Guoqiang. "Machine Learning to Interrogate High-throughput Genomic Data: Theory and Applications." Diss., Virginia Tech, 2011. http://hdl.handle.net/10919/28980.

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The missing heritability in genome-wide association studies (GWAS) is an intriguing open scientific problem which has attracted great recent interest. The interaction effects among risk factors, both genetic and environmental, are hypothesized to be one of the main missing heritability sources. Moreover, detection of multilocus interaction effect may also have great implications for revealing disease/biological mechanisms, for accurate risk prediction, personalized clinical management, and targeted drug design. However, current analysis of GWAS largely ignores interaction effects, partly due to the lack of tools that meet the statistical and computational challenges posed by taking into account interaction effects. Here, we propose a novel statistically-based framework (Significant Conditional Association) for systematically exploring, assessing significance, and detecting interaction effect. Further, our SCA work has also revealed new theoretical results and insights on interaction detection, as well as theoretical performance bounds. Using in silico data, we show that the new approach has detection power significantly better than that of peer methods, while controlling the running time within a permissible range. More importantly, we applied our methods on several real data sets, confirming well-validated interactions with more convincing evidence (generating smaller p-values and requiring fewer samples) than those obtained through conventional methods, eliminating inconsistent results in the original reports, and observing novel discoveries that are otherwise undetectable. The proposed methods provide a useful tool to mine new knowledge from existing GWAS and generate new hypotheses for further research. Microarray gene expression studies provide new opportunities for the molecular characterization of heterogeneous diseases. Multiclass gene selection is an imperative task for identifying phenotype-associated mechanistic genes and achieving accurate diagnostic classification. Most existing multiclass gene selection methods heavily rely on the direct extension of two-class gene selection methods. However, simple extensions of binary discriminant analysis to multiclass gene selection are suboptimal and not well-matched to the unique characteristics of the multi-category classification problem. We report a simpler and yet more accurate strategy than previous works for multicategory classification of heterogeneous diseases. Our method selects the union of one-versus-everyone phenotypic up-regulated genes (OVEPUGs) and matches this gene selection with a one-versus-rest support vector machine. Our approach provides even-handed gene resources for discriminating both neighboring and well-separated classes, and intends to assure the statistical reproducibility and biological plausibility of the selected genes. We evaluated the fold changes of OVEPUGs and found that only a small number of high-ranked genes were required to achieve superior accuracy for multicategory classification. We tested the proposed OVEPUG method on six real microarray gene expression data sets (five public benchmarks and one in-house data set) and two simulation data sets, observing significantly improved performance with lower error rates, fewer marker genes, and higher performance sustainability, as compared to several widely-adopted gene selection and classification methods.
Ph. D.

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Zhuang, Jiali. "Structural Variation Discovery and Genotyping from Whole Genome Sequencing: Methodology and Applications: A Dissertation." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/875.

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A comprehensive understanding about how genetic variants and mutations contribute to phenotypic variations and alterations entails experimental technologies and analytical methodologies that are able to detect genetic variants/mutations from various biological samples in a timely and accurate manner. High-throughput sequencing technology represents the latest achievement in a series of efforts to facilitate genetic variants discovery and genotyping and promises to transform the way we tackle healthcare and biomedical problems. The tremendous amount of data generated by this new technology, however, needs to be processed and analyzed in an accurate and efficient way in order to fully harness its potential. Structural variation (SV) encompasses a wide range of genetic variations with different sizes and generated by diverse mechanisms. Due to the technical difficulties of reliably detecting SVs, their characterization lags behind that of SNPs and indels. In this dissertation I presented two novel computational methods: one for detecting transposable element (TE) transpositions and the other for detecting SVs in general using a local assembly approach. Both methods are able to pinpoint breakpoint junctions at single-nucleotide resolution and estimate variant allele frequencies in the sample. I also applied those methods to study the impact of TE transpositions on the genomic stability, the inheritance patterns of TE insertions in the population and the molecular mechanisms and potential functional consequences of somatic SVs in cancer genomes.

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Zhuang, Jiali. "Structural Variation Discovery and Genotyping from Whole Genome Sequencing: Methodology and Applications: A Dissertation." eScholarship@UMMS, 2009. http://escholarship.umassmed.edu/gsbs_diss/875.

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A comprehensive understanding about how genetic variants and mutations contribute to phenotypic variations and alterations entails experimental technologies and analytical methodologies that are able to detect genetic variants/mutations from various biological samples in a timely and accurate manner. High-throughput sequencing technology represents the latest achievement in a series of efforts to facilitate genetic variants discovery and genotyping and promises to transform the way we tackle healthcare and biomedical problems. The tremendous amount of data generated by this new technology, however, needs to be processed and analyzed in an accurate and efficient way in order to fully harness its potential. Structural variation (SV) encompasses a wide range of genetic variations with different sizes and generated by diverse mechanisms. Due to the technical difficulties of reliably detecting SVs, their characterization lags behind that of SNPs and indels. In this dissertation I presented two novel computational methods: one for detecting transposable element (TE) transpositions and the other for detecting SVs in general using a local assembly approach. Both methods are able to pinpoint breakpoint junctions at single-nucleotide resolution and estimate variant allele frequencies in the sample. I also applied those methods to study the impact of TE transpositions on the genomic stability, the inheritance patterns of TE insertions in the population and the molecular mechanisms and potential functional consequences of somatic SVs in cancer genomes.

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Biasci, Daniele. "Predicting prognosis in Crohn's disease." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/270034.

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Ward, Brian Phillip. "Genomic Prediction and Genetic Dissection of Yield-Related Traits in Soft Red Winter Wheat." Diss., Virginia Tech, 2017. http://hdl.handle.net/10919/85503.

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In multiple species, genome-wide association (GWA) studies have become an increasingly prevalent method of identifying the quantitative trait loci (QTLs) that underlie complex traits. Despite this, relatively few GWA analyses using high-density genomic markers have been carried out on highly quantitative traits in wheat. We utilized single-nucleotide polymorphism (SNP) data generated via a genotyping-by-sequencing (GBS) protocol to perform GWA on multiple yield-related traits using a panel of 329 soft red winter wheat genotypes grown in four environments. In addition, the SNP data was used to examine linkage disequilibrium and population structure within the testing panel. The results indicated that an alien translocation from the species Triticum timopheevii was responsible for the majority of observed population structure. In addition, a total of 50 significant marker-trait associations were identified. However, a subsequent study cast some doubt upon the reproducibility and reliability of plant QTLs identified via GWA analyses. We used two highly-related panels of different genotypes grown in different sets of environments to attempt to identify highly stable QTLs. No QTLs were shared across panels for any trait, suggesting that QTL-by-environment and QTL-by-genetic background interaction effects are significant, even when testing across many environments. In light of the challenges involved in QTL mapping, prediction of phenotypes using whole-genome marker data is an attractive alternative. However, many evaluations of genomic prediction in crop species have utilized univariate models adapted from animal breeding. These models cannot directly account for genotype-by-environment interaction, and hence are often not suitable for use with lower-heritability traits assessed in multiple environments. We sought to test genomic prediction models capable of more ad-hoc analyses, utilizing highly unbalanced experimental designs consisting of individuals with varying degrees of relatedness. The results suggest that these designs can successfully be used to generate reasonably accurate phenotypic predictions. In addition, multivariate models can dramatically increase predictive accuracy for some traits, though this depends upon the quantity and characteristics of genotype-by-environment interaction.
Ph. D.

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Alvarenga, Amanda Botelho. "Feed efficiency traits in Santa Inês sheep under genomic approaches." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/11/11139/tde-20032018-160145/.

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The selection on genetic values predicted from markers could substantially increase the rate of genetic gain in animals by increasing accuracy of prediction and reducing generation interval, especially for difficult to measure traits, such as feed efficiency. Feed efficiency is the most important trait in animal production due to its impacts on cost of production and environmental factors. Many metrics measure the feed efficiency, such as ratio of gain to feed (FER), the ratio of feed to gain (FCR) and residual feed intake (RFI). Nevertheless, in ovine, no study with the aim of understand the genetic variants or the accuracy of genomic estimated breeding value (GEBV) for feed efficiency traits was published yet. Moreover, before to apply the genomic information, it is necessary to understand and characterized the population structure, for instance, by linkage disequilibrium (LD). Both genome-wide association studies (GWAS) and genomic selection (GS) leverage LD between marker and causal mutation. Based on the above considerations, the aim of this study was to map LD in ovine, characterized by Brazilian Santa Inês sheep; to search genetic variants for feed efficiency traits (FER, FCR and RFI) through GWAS; and to verify the accuracy of GEBV for RFI. In total, 396 samples (animals) of Longissimus dorsi muscle were collect. A high-density panel of SNP (Illumina High-Density Ovine SNP BeadChip®) comprising 54,241 SNPs was used to obtain the genotyping data. The phenotype data was comprised of 387 animals. The average LD between adjacent markers for two LD metrics, r² and |D\'|, were 0.166 and 0.617, respectively. The degree of LD estimated was lower than reported in other species and it was characterized by short haplotype blocks. Consequently, for genomic analyses, high-density panels of marker are recommended. Many markers were associated to feed efficiency traits in GWAS, mainly to RFI trait. Few candidate genes were reported in this study, highlighting NRF-1 (nuclear respiratory factor 1), which controls mitochondrial biosynthesis, the most important process responsible by a great fraction of the produced energy. Finally, we verified the accuracy of GEBV for RFI using few Bayesian regression models, and we found low accuracy, ranging from 0.033 (BayesB with π=0.9912) to 0.036 (BayesA), which might be explained by the low relationship among animals and small training population.
A seleção com base nos valores genéticos genômicos preditos pode aumentar substancialmente a taxa de ganho genético em animais por meio do aumento da acurácia de predição e redução do intervalo de gerações, especialmente para características de difícil e/ou onerosa mensuração, como eficiência alimentar. A eficiência alimentar é uma das características mais importantes na produção animal devido principalmente aos seus impactos econômicos e ambientais. Muitas métricas representam a eficiência alimentar, por exemplo: a relação do ganho de peso e consumo alimentar (EA), a proporção do consumo alimentar e ganho de peso (CA) e o consumo alimentar residual (CAR). Em ovinos, nenhum estudo com o objetivo de buscar variantes genéticas ou verificar a acurácia do valor genético genômico estimado para eficiência alimentar foi publicado. Adicionalmente, antes de aplicar a informação genômica, é necessário compreender e caracterizar a estrutura da população, como por meio do desequilíbrio de ligação (LD). O estudo de associação genômica (GWAS) e seleção genômica (GS) consideram o LD entre marcador e a mutação causal. Com base nas considerações acima, o objetivo deste estudo foi mapear o LD em ovinos, caracterizado pela raça ovina Santa Inês; localizar variantes genéticas para as características de eficiência alimentar (EA, CA e CAR) utilizando a abordagem GWAS; e verificar a acurácia da estimação dos valores genéticos genômico para o CAR. No total, foram coletadas 396 amostras (animais) do músculo Longissimus dorsi, para posterior genotipagem utilizando o painel de alta densidade (Illumina High-Density Ovine SNP BeadChip®), compreendendo 54.241 SNPs. O banco fenotípico é composto por 387 animais. O LD médio entre marcadores adjacentes para duas métricas de LD, r² e |D\'|, foram 0,166 e 0,617, respectivamente. O grau de LD estimado foi menor que o relatado em outras espécies e foi caracterizado por blocos de haplótipos curtos. Consequentemente, para as análises genômicas são recomendados painéis de marcadores de alta densidade. No GWAS, foram encontrados muitos marcadores associados aos fenótipos, em especial, à característica CAR. Alguns genes candidatos foram relatados neste estudo, destacando-se o NRF-1 (fator respiratório nuclear 1), que controla a biossíntese mitocondrial, o processo mais importante responsável por grande parte da produção de energia. Finalmente, verificamos a acurácia do valor genético genômico estimado para o CAR usando modelos de regressão Bayesiana, e encontramos baixos valores para acurácia (0,033 a 0,036) o que pode ser explicado pelo baixo grau de relacionamento entre os indivíduos e tamanho reduzido da população de treinamento.

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Ladejobi, Olufunmilayo Olubukola. "Testing new genetic and genomic approaches for trait mapping and prediction in wheat (Triticum aestivum) and rice (Oryza spp)." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/277449.

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Advances in molecular marker technologies have led to the development of high throughput genotyping techniques such as Genotyping by Sequencing (GBS), driving the application of genomics in crop research and breeding. They have also supported the use of novel mapping approaches, including Multi-parent Advanced Generation Inter-Cross (MAGIC) populations which have increased precision in identifying markers to inform plant breeding practices. In the first part of this thesis, a high density physical map derived from GBS was used to identify QTLs controlling key agronomic traits of wheat in a genome-wide association study (GWAS) and to demonstrate the practicability of genomic selection for predicting the trait values. The results from GBS were compared to a previous study conducted on the same association mapping panel using a less dense physical map derived from diversity arrays technology (DArT) markers. GBS detected more QTLs than DArT markers although some of the QTLs were detected by DArT markers alone. Prediction accuracies from the two marker platforms were mostly similar and largely dependent on trait genetic architecture. The second part of this thesis focused on MAGIC populations, which incorporate diversity and novel allelic combinations from several generations of recombination. Pedigrees representing a wild rice MAGIC population were used to model MAGIC populations by simulation to assess the level of recombination and creation of novel haplotypes. The wild rice species are an important reservoir of beneficial genes that have been variously introgressed into rice varieties using bi-parental population approaches. The level of recombination was found to be highly dependent on the number of crosses made and on the resulting population size. Creation of MAGIC populations require adequate planning in order to make sufficient number of crosses that capture optimal haplotype diversity. The third part of the thesis considers models that have been proposed for genomic prediction. The ridge regression best linear unbiased prediction (RR-BLUP) is based on the assumption that all genotyped molecular markers make equal contributions to the variations of a phenotype. Information from underlying candidate molecular markers are however of greater significance and can be used to improve the accuracy of prediction. Here, an existing Differentially Penalized Regression (DiPR) model which uses modifications to a standard RR-BLUP package and allows two or more marker sets from different platforms to be independently weighted was used. The DiPR model performed better than single or combined marker sets for predicting most of the traits both in a MAGIC population and an association mapping panel. Overall the work presented in this thesis shows that while these techniques have great promise, they should be carefully evaluated before introduction into breeding programmes.

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Shen, Xia. "Novel Statistical Methods in Quantitative Genetics : Modeling Genetic Variance for Quantitative Trait Loci Mapping and Genomic Evaluation." Doctoral thesis, Uppsala universitet, Beräknings- och systembiologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-170091.

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This thesis develops and evaluates statistical methods for different types of genetic analyses, including quantitative trait loci (QTL) analysis, genome-wide association study (GWAS), and genomic evaluation. The main contribution of the thesis is to provide novel insights in modeling genetic variance, especially via random effects models. In variance component QTL analysis, a full likelihood model accounting for uncertainty in the identity-by-descent (IBD) matrix was developed. It was found to be able to correctly adjust the bias in genetic variance component estimation and gain power in QTL mapping in terms of precision. Double hierarchical generalized linear models, and a non-iterative simplified version, were implemented and applied to fit data of an entire genome. These whole genome models were shown to have good performance in both QTL mapping and genomic prediction. A re-analysis of a publicly available GWAS data set identified significant loci in Arabidopsis that control phenotypic variance instead of mean, which validated the idea of variance-controlling genes. The works in the thesis are accompanied by R packages available online, including a general statistical tool for fitting random effects models (hglm), an efficient generalized ridge regression for high-dimensional data (bigRR), a double-layer mixed model for genomic data analysis (iQTL), a stochastic IBD matrix calculator (MCIBD), a computational interface for QTL mapping (qtl.outbred), and a GWAS analysis tool for mapping variance-controlling loci (vGWAS).

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Schneider, Rhiannon N. "Genome-Wide Analyses for Partial Resistance to Phytophthora sojae Kaufmann and Gerdemann in Soybean (Glycine max L. Merr.) Populations from North America and the Republic of Korea." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429741967.

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Żyła, Joanna. "Zastosowanie modelowania matematycznego oddziaływań genetycznych oraz metod integratywnej analizy danych w badaniach typu GWAS o mało licznych próbach." Rozprawa doktorska, 2018. https://repolis.bg.polsl.pl/dlibra/docmetadata?showContent=true&id=51950.

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Żyła, Joanna. "Zastosowanie modelowania matematycznego oddziaływań genetycznych oraz metod integratywnej analizy danych w badaniach typu GWAS o mało licznych próbach." Rozprawa doktorska, 2018. https://delibra.bg.polsl.pl/dlibra/docmetadata?showContent=true&id=51950.

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Barrero, Farfan Ivan D. "Exploiting Historical Data and Diverse Germplasm to Increase Maize Grain Yield in Texas." Thesis, 2013. http://hdl.handle.net/1969.1/151101.

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The U.S. is the largest maize producer in the world with a production of 300 million tons in 2012. Approximately 86% of the maize production is focused on the Midwestern states. The rest of the production is focused in the Southern states, where Texas is the largest maize producer. Grain yield in Texas ranges from 18 tons/ha in the irrigated production zones to 3 tons/ha in the dryland production zones. As a result, grain yield has increased slowly because of the poor production in the non-irrigated acres. Methods to improve the grain yield in Texas is to breed for maize varieties adapted to Texas growing conditions, including mapping genes that can be incorporated into germplasm through marker assisted selection. This dissertation includes two separate projects that exploit historical data and maize diversity to increase grain yield in Texas. For the first project, a large dataset collected by Texas AgriLife program was analyzed to elucidate past trends and future hints on how to improve maize yield within Texas. This study confirmed previous reports that the rate of increase for grain yield in Texas is less than the rate observed in the Midwestern US. For the second project, a candidate gene and whole genome association mapping analysis was performed for drought and aflatoxin resistance in maize. In order to do so, maize inbred lines from a diversity panel were testcrossed to isogenic versions of Tx714. The hybrids were evaluated under irrigated and non-irrigated conditions. The irrigated trials were inoculated with Aspergillus flavus and the aflatoxin level was quantified. This study found that the gene ZmLOX4 was associated with days to silk, and the gene ZmLOX5 gene was associated with plant and ear height. In addition, this study identified 13 QTL variants for grain yield, plant height, days to anthesis and days to silk. Furthermore, this study shows that diverse maize inbred lines can make hybrids that out yield commercial hybrids under heat and drought stress. Therefore, there are useful genes present in these diverse lines that can be exploited in maize breeding programs

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(9187739), Hannah E. Willson. "Genetic and biological architecture of pork quality, carcass, primal-cut and growth traits in Duroc pigs." Thesis, 2020.

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Within the last few decades, swine breeding programs have been refined to include pork quality and novel carcass traits alongside growth, feed efficiency, and carcass leanness in the selection programs for terminal sire lines with a goal to produce high quality and efficient pork product for consumers. In order to accurately select for multiple traits at once, it becomes imperative to explore their genetic and biological architecture. The genetic architecture of traits can be explored through the estimation of genetic parameters, genome-wide association studies (GWAS), gene networks and metabolic pathways. An alternative approach to explore the genetic and biological connection between traits is based on principal component analysis (PCA), which generates novel “pseudo-phenotypes” and biological types (biotypes). In this context, the main objective of this thesis was to understand the genetic and biological relationship between three growth, eight conventional carcass, 10 pork quality, and 18 novel carcass traits included in two studies. The phenotypic data set included 2,583 records from female Duroc pigs from a terminal sire line. The pedigree file contained 193,764 animals and the genotype file included 21,344 animals with 35,651 single nucleotide polymorphisms (SNPs). The results of the first study indicate that genetic progress can be achieved for all 39 traits. In general, the heritability estimates were moderate, while most genetic correlations were generally moderate to high and favorable. Some antagonisms were observed but those genetic correlations were low to moderate in nature. Thus, these relationships can be considered when developing selection indexes. The second study showed that there are strong links between traits through their principal components (PCs). The main PCs identified are linked to biotypes related to growth, muscle and fat deposition, pork color, and body composition. The PCs were also used as pseudo-phenotypes in the GWAS analysis, which identified important candidate genes and metabolic pathways linked to each biotype. All of this evidence links valuable variables such as belly, color, marbling, and leanness traits. Our findings greatly contribute to the optimization of genetic and genomic selection for the inclusion of valuable and novel traits to improve productive efficiency, novel carcass, and meat quality traits in terminal sire lines.

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Chen, Yan-Ming, and 陳彥銘. "A standard Flow Path of Making a Genome-wide Association (GWA) Study Analysis." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/68569387908119886054.

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碩士
國立交通大學
統計學研究所
96
There are increasing evidences that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases [1]. Many studies had successfully performed the GWA study to identify novel susceptible loci. However, there is a lack of agreement about what constitutes an adequate analytic procedure. In this study, we review existing genome-wide association studies to identify such a procedure and implement the built procedure to real datasets from the Wellcome Trust case-control Consortium. Our procedure includes four steps: data management, preliminary analysis, association testing and result visualization. In order to get the true association between disease and SNP, we execute 2 preliminary processes, the quality control (QC) and population stratification. Furthermore, we can plot the quantile-quantile (Q-Q) plot and Manhattan plot to visualize association analysis results. At the end of the study, we have successfully (1) identified the necessary and important analyses for GWA, (2) identified currently available software for these analyses, (3) performed the analysis on the Wellcome Trust case-control Consortium data, and (4) provided general guidelines for performing GWA.

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Dissertations / Theses on the topic 'Genomic Wide Association Study (GWAS)'

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