Thèses : « Gwashu »

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Tshaiviti, Thandeka Lovedalia. « Persuasion in the Xhosa drama text Isisila sehobe ». Thesis, Stellenbosch : Stellenbosch University, 2008. http://hdl.handle.net/10019.1/2275.

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Thesis (MA (African Languages))--Stellenbosch University, 20008.
The goal of this study is to investigate the speech act of persuasion in the Xhosa drama text Isisila sehobe by Satyo and Gwashu. The investigation into persuasive communication in Isisila sehobe takes as a starting point the persuasive strategies of Larson (1999). The study's main aim is to establish the linguistic realisation through which social aspects of isiXhosa persuasion are expressed in Isisila sehobe. The core persuasive message in this text is concerned with marriage. This study shows that some people take as their reasons for marriage materialistic things such as wealth and as a result such marriages seldom materialise or become stable, because people merely stay together for convenience and not love. In Isisila sehobe the results of such a marriage are disastrous, even leading to death. In addition, this study aims to present an account of how characters in Isisila sehobe realise premises and strategies of persuasion in authentic communication, using the framework of persuasion theory (O’Keefe, 1990).

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Magosi, Lerato Elaine. « Dissecting heterogeneity in GWAS meta-analysis ». Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:c853f7e7-93de-440c-b57c-fcfc03d3bb86.

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Statistical heterogeneity refers to differences among results of studies combined in a meta-analysis beyond that expected by chance. On the one hand, excessive heterogeneity can diminish power to discover genetic signals; on the other, moderate heterogeneity can reveal important biological differences among studies. Given its double-edged nature, this thesis dissects heterogeneity in genetic association meta-analyses from three vantage points. First, a novel multi-variant statistic, M is proposed to detect genome-wide (systematic) heterogeneity patterns in genetic association meta-analyses. This was motivated by the limited availability of appropriate methodology to measure the impact of heterogeneity across genetic signals, since traditional metrics (Q, I² and T²) measure heterogeneity at individual variants. Second, given that meta-analyses comprising small numbers of studies typically report imprecise summary effect estimates; GWAS-derived empirical heterogeneity priors are used to improve precision in estimation of average genetic effects and heterogeneity in smaller meta-analyses (e.g. ≤ 10 studies). Third, a critical evaluation of the Han-Eskin random-effects model shows how it can identify small effect heterogeneous loci overlooked by traditional fixed and random-effects methods. This work draws attention to the existence of genome-wide heterogeneity patterns, to reveal systematic differences among the ascertainment criteria of participating studies in a meta-analysis of coronary disease (CAD) risk. Furthermore, simulation studies with the Han-Eskin random-effects model revealed inflated genetic signals at small effect loci when heterogeneity levels were high. However, it did reveal an additional CAD risk variant overlooked by traditional meta-analysis methods. We therefore recommend a holistic approach to exploring heterogeneity in meta-analyses which assesses heterogeneity of genetic effects both at individual variants with traditional statistics and across multiple genetic signals with the M statistic. Furthermore, it is critically important to review forest plots for small effect loci identified using the Han-Eskin random-effects model amidst moderate-to-high heterogeneity (I² ≥ 40%).

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Ooi, Li Yin. « Post-GWAS functional characterisation of colorectal cancer risk loci ». Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/23514.

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Large bowel cancer, or colorectal cancer (CRC) is the third most common cause of cancer worldwide and the fourth biggest cause of cancer mortality. Twin studies have shown that the heritable contribution is ~35%, with ~5% of cases due to rare, high-penetrance mutations. In the last decade, the use of genome-wide association studies on large, well-characterised case-control cohorts of CRC has facilitated the identification of over 25 common genetic variants that carry with them an increased predisposition to colorectal cancer, invoking the common-disease common variant paradigm. As almost all of these variants lie within non-coding regions, the underlying causal mechanism is to-date poorly understood for the majority of these loci, and it is thought that they mediate risk by influencing gene expression levels. To test this hypothesis, an agnostic approach that utilises expression quantitative trait loci (eQTL) analysis was first carried on 115 normal colorectal mucosa samples and 59 peripheral blood mononuclear cells (PBMC). As these heritable variation on gene expression are likely to be subtle, there is a strong emphasis on the technical methodology to minimise experimentally-induced non-biological variations, including the extraction of high-quality RNA from primary tissue, the selection and validation of reference genes for normalisation of gene expression quantification, as well as internal validation of the samples and data processing. Thereafter, the association between the 25 CRC risk variants and the expression of their cis-genes were examined systematically, demonstrating that ten of these variants are also tissue-specific eQTLs. This intermediate phenotype strongly suggests that they confer risk, at least in part, by modifying regulatory mechanisms. One of the best eQTL associations (Xp22.2) is investigated in further detail to reveal a novel indel polymorphism (Indel24) at the distal promoter region of target gene SHROOM2 that influenced both transcript abundance and CRC risk more than the original tagging SNP. Functional verification with gene reporter assays indicated that Indel24 displays differential allelic control over transcriptional activity. Further in silico analysis and mutations to the reporter gene constructs provided evidence that Indel24 modulates transcription by modifying the spacing between CCAAT motifs and the consequent binding affinity of NF-Y transcription factor. siRNA depletion of NF-Y was associated with a reduction in transcriptional activity of the Indel24 gene construct as well as endogenous SHROOM2, which is strongly supportive of the interaction between Indel24 and NF-Y in the transcriptional activation of SHROOM2. Preliminary evidence is suggestive of SHROOM2 being expressed at the top of the intestinal epithelial crypt and playing a role in cell cycle regulation. Hypothesis-driven approaches can also be of utility in demonstrating functionality of CRC risk variants, complementing the hypothesis-free approach of eQTL analysis. Guided by a recently discovered gene-environment interaction between the 16q22.1 risk variant and circulating vitamin D levels, the influence of the rs9929218 SNP on CDH1 gene expression was examined, in relation to the expression of putative regulatory genes derived from in silico analysis and studies of other target genes. Although there was no direct association between rs9929218 and CDH1 expression, there were multiple two-way interactions that were together suggestive of rs9929218 influencing the VDR/FOXO4 regulation of CDH1. This provides functional support for the mechanism underlying the epidemiological observation of the gene-environment interaction between 16q22.1 and vitamin D, and demonstrates a candidate-based approach in deciphering the link between genetic locus and CRC susceptibility. In summary, the research presented in this thesis has validated the experimental rationale of utilising expression studies of normal colorectal mucosa to hone in on the molecular mechanisms and susceptibility genes underlying the association between common genetic variation and CRC risk.

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Hu, Xianghong. « Statistical methods for Mendelian randomization using GWAS summary data ». HKBU Institutional Repository, 2019. https://repository.hkbu.edu.hk/etd_oa/639.

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Mendelian Randomization (MR) is a powerful tool for accessing causality of exposure on an outcome using genetic variants as the instrumental variables. Much of the recent developments is propelled by the increasing availability of GWAS summary data. However, the accuracy of the MR causal effect estimates could be challenged in case of the MR assumptions are violated. The source of biases could attribute to the weak effects arising because of polygenicity, the presentence of horizontal pleiotropy and other biases, e.g., selection bias. In this thesis, we proposed two works, expecting to deal with these issues.In the first part, we proposed a method named 'Bayesian Weighted Mendelian Randomization (BMWR)' for causal inference using summary statistics from GWAS. In BWMR, we not only take into account the uncertainty of weak effects owning to polygenicity of human genomics but also models the weak horizontal pleiotropic effects. Moreover, BWMR adopts a Bayesian reweighting strategy for detection of large pleiotropic outliers. An efficient algorithm based on variational inference was developed to make BWMR computationally efficient and stable. Considering the underestimated variance provided by variational inference, we further derived a closed form variance estimator inspired by a linear response method. We conducted several simulations to evaluate the performance of BWMR, demonstrating the advantage of BWMR over other methods. Then, we applied BWMR to access causality between 126 metabolites and 90 complex traits, revealing novel causal relationships. In the second part, we further developed BWMR-C: Statistical correction of selection bias for Mendelian Randomization based on a Bayesian weighted method. Based on the framework of BWMR, the probability model in BWMR-C is built conditional on the IV selection criteria. In such way, BWMR-C delicated to reduce the influence of the selection process on the causal effect estimates and also preserve the good properties of BWMR. To make the causal inference computationally stable and efficient, we developed a variational EM algorithm. We conducted several comprehensive simulations to evaluate the performance of BWMR-C for correction of selection bias. Then, we applied BWMR-C on seven body fat distribution related traits and 140 UK Biobank traits. Our results show that BWMR-C achieves satisfactory performance for correcting selection bias. Keywords: Mendelian Randomization, polygenicity, horizontal pleiotropy, selection bias, variation inference.

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Martin, Paul. « Post-GWAS bioinformatics and functional analysis of disease susceptibility loci ». Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/postgwas-bioinformatics-and-functional-analysis-of-disease-susceptibility-loci(cc0e6cee-5c32-4b75-b3d3-f7c18b6f126d).html.

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Genome-wide association studies (GWAS) have been tremendously successful in identifying genetic variants associated with complex diseases, such as rheumatoid arthritis (RA). However, the majority of these associations lie outside traditional protein coding regions and do not necessarily represent the causal effect. Therefore, the challenges post-GWAS are to identify causal variants, link them to target genes and explore the functional mechanisms involved in disease. The aim of the work presented here is to use high level bioinformatics to help address these challenges. There is now an increasing amount of experimental data generated by several large consortia with the aim of characterising the non-coding regions of the human genome, which has the ability to refine and prioritise genetic associations. However, whilst being publicly available, manually mining and utilising it to full effect can be prohibitive. I developed an automated tool, ASSIMILATOR, which quickly and effectively facilitated the mining and rapid interpretation of this data, inferring the likely functional consequence of variants and informing further investigation. This was used in a large extended GWAS in RA which assessed the functional impact of associated variants at the 22q12 locus, showing evidence that they could affect gene regulation. Environmental factors, such as vitamin D, can also affect gene regulation, increasing the risk of disease but are generally not incorporated into most GWAS. Vitamin D deficiency is common in RA and can regulate genes through vitamin D response elements (VDREs). I interrogated a large, publicly available VDRE ChIP-Seq dataset using a permutation testing approach to test for VDRE enrichment in RA loci. This study was the first comprehensive analysis of VDREs and RA associated variants and showed that they are enriched for VDREs, suggesting an involvement of vitamin D in RA.Indeed, evidence suggests that disease associated variants effect gene regulation through enhancer elements. These can act over large distances through physical interactions. A newly developed technique, Capture Hi-C, was used to identify regions of the genome which physically interact with associated variants for four autoimmune diseases. This study showed the complex physical interactions between genetic elements, which could be mediated by regions associated with disease. This work is pivotal in fully characterising genetic associations and determining their effect on disease. Further work has re-defined the 6q23 locus, a region associated with multiple diseases, resulting in a major re-evaluation of the likely causal gene in RA from TNFAIP3 to IL20RA, a druggable target, illustrating the huge potential of this research. Furthermore, it has been used to study the genetic associations unique to multiple sclerosis in the same region, showing chromatin interactions which support previously implicated genes and identify novel candidates. This could help improve our understanding and treatment of the disease. Bioinformatics is fundamental to fully exploit new and existing datasets and has made many positive impacts on our understanding of complex disease. This empowers researchers to fully explore disease aetiology and to further the discovery of new therapies.

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Loken, Erik. « Identifying functional variation in schizophrenia GWAS loci by pooled sequencing ». VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3515.

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Schizophrenia demonstrates high heritability in part accounted for by common simple nucleotide variants (SNV), rare copy number variants (CNV) and, most recently, rare SNVs Although heritability explained by rare SNVs and CNVs is small compared to that explained by common SNVs, rare SNVs in functional sequences may identify specific disease mechanisms. However, current exome methods do not capture a large proportion of potentially functional bases where rare variation may impact disease risk: as much as two-thirds of conserved sequences lie outside the exome in non-coding regions of cross-species evolutionary constraint. We reasoned that the candidate loci from the Psychiatric Genomics Consortium Phase 1 (PGC-1) schizophrenia study represent good target loci to test for the impact of rare SNVs in non-coding constrained regions. We developed custom reagents to capture mammalian constrained non-coding regions, exons, and 5’- and 3’-untranslated regions (UTRs) in the 12 PGC-1 loci for pooled sequencing in 912 cases and 936 controls. Compared to our coding targets, our noncoding targets contain substantially more highly conserved bases (46,412 vs. 31,609) and variants (390 vs. 193). Using C-alpha to detect excess variance due to aggregate risk increasing or decreasing rare SNV effects, we identified signals attributable to alleles with MAF < 0.1% in both coding sequences and in functional non-coding sequences, including variants within ENCODE transcription factor binding sites, DNase hypersensitive regions, and histone modification sites in neuronal cell lines. We also observed significant excess risk-altering variation in the CUB domain of CSMD1, a gene expressed in the developing central nervous system. These results support the hypothesis that common and rare variants in the same loci contribute to schizophrenia risk, but highlight the need to expand capture strategies in order to detect trait-relevant sequence variation in a broader set of functional sequences.

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Evans-Jones, Gareth Hugh. « 'Mae'r Beibl o'n tu' : y dadleuon Beiblaidd ynghylch caethwasiaeth ar dudalennau gwasg gyfnodol Gymraeg America, 1838-1868 ». Thesis, Bangor University, 2017. https://research.bangor.ac.uk/portal/en/theses/maer-beibl-on-tu-y-dadleuon-beiblaidd-ynghylch-caethwasiaeth-ar-dudalennau-gwasg-gyfnodol-gymraeg-america-18381868(fc2aa9ed-df9c-44d0-9959-350aea287da9).html.

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Amcan yr astudiaeth hon yw archwilio rôl y Beibl ymysg Cymry America’r bedwaredd ganrif ar bymtheg wrth iddynt ymateb i gaethwasiaeth, un o brif heriau eu gwlad fabwysiedig. Ymdriniwyd â’r mater yn helaeth ar dudalennau gwasg gyfnodol Gymraeg America, a defnyddid testunau Beiblaidd a chysyniadau Cristnogol yn fynych er mwyn trafod yr hyn a ystyrid gan amryw yn un o ‘bechodau mwyaf ysgeler’ yr Unol Daleithiau. Gan fod y diwylliant print yn hynod ddylanwadol yn y bedwaredd ganrif ar bymtheg, canolbwyntia’r traethawd hwn ar yr ymateb llenyddol a gafwyd i gaethwasiaeth gan Gymry America yn eu cyfnodolion a gyhoeddid yn ystod y cyfnod 1838-1868: oes aur y wasg gyfnodol Gymraeg yn yr Unol Daleithiau. Er mwyn ystyried eu defnydd o’r Beibl yng nghyd-destun y broblem gyfoes, archwilir defnydd Cymry America o bedwar testun neu thema Feiblaidd unigol ym mhedair pennod gyntaf y thesis. Cynnwys y rhain: Cham a Gomer, deddfau’r Pumllyfr a’r Jiwbili, y Gaethglud ym Mabilon, ac Iesu a’r Testament Newydd. Wrth asesu’r modd y defnyddiwyd y testunau a’r themâu hyn, ystyrir pa mor debyg yr oedd ymdriniaeth gwahanol awduron ohonynt. Yn ogystal, ymholir i ba raddau yr oedd holl Gymry America’n gwrthwynebu caethwasiaeth, ac a oedd rhai, mewn gwirionedd, wedi parhau i gefnogi’r gyfundrefn ar bwys y Beibl. Mae’r bumed bennod o natur wahanol i’r rhelyw gan y cymerir cyfraith a basiwyd gan lywodraeth yr Unol Daleithiau, a oedd yn arwyddocaol i’r ymgyrch diddymol, Cyfraith Caeth Ffoëdig 1850 fel astudiaeth achos, ac ystyrir y modd yr ymatebwyd iddi ar seiliau Beiblaidd. Awgrymir yn y bennod hon i radicaliaeth y Cymry ei hamlygu ei hun ymhellach yn sgil pasio cyfraith ddadleuol 1850. Daw’r thesis i glo drwy bwyso a mesur arwyddocâd y dadleuon Beiblaidd mewn trafodaethau ynglŷn â chaethwasiaeth, a chasglu i’r Ysgrythur fod yn ddylanwadol yng ngweithgarwch llenyddol, gwleidyddol a chymdeithasol hil Gomer yr Unol Daleithiau.

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Mitropanopoulos, Sotiris. « GWAS for Bipolar Disorder in a European Cohort with CNV Discovery ». Thesis, The University of Arizona, 2012. http://hdl.handle.net/10150/221248.

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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.
Background: Bipolar disorder (BD) is a disabling disorder whereby individuals suffer from episodes of mania and depression. The mode of inheritance of BD is complex and likely multifactorial. The specific number of susceptibility loci, the recurrence risk ratio attributable to each locus, and the degree of interaction between loci are unknown. By determining whether single nucleotide polymorphisms (SNPs) or copy number variants (CNVs) predispose individuals to bipolar disorder, therapeutics and diagnostic tests may be developed. Method: A Genome Wide Association Study (GWAS) was performed using cases of bipolar disorder and normal controls hybridized on Affymetrix 6.0 Genome-Wide Human SNP Arrays. Data preprocessing removed 595 individuals from 2205 arrays. The probe intensities of the remaining 880 cases and 730 controls were normalized. A modified t-test algorithm was used to determine p-values for each SNP. A sliding window analysis was performed on SNPs ordered by chromosome and locus. The mean probe intensities of the cases and controls from regions of significance were then reanalyzed for differences. Results: Analysis yielded several SNPs and CNVs that may have involvement in the pathophysiology of bipolar disorder. One region was 15kbp within the Neuron Navigator 2 (NAV2) gene. A second region was found in the Down Syndrome Cell Adhesion Molecule Like 1 (DSCAML1) gene. A third region was within the Voltage-dependent Calcium Channel Alpha 1G (CACNA1G). Conclusion: Multiple SNPs and CNVs may play a role in the phenotype of Bipolar Disorder. A convergent functional genomics approach with a gene network analysis maybe warranted elucidating possible pathophysiologies involving the gene products found to be significant in this study.

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Aldasoro, Alex-Ander. « Post-GWAS Investigations for discovering pleiotropic gene effects in cardiovascular diseases ». Thesis, Université de Lorraine, 2017. http://www.theses.fr/2017LORR0247/document.

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Les maladies cardiovasculaires (MCV) sont d’une étiologie complexe et elles sont soumises à de nombreux facteurs environnementaux ainsi que génétiques. Malgré les succès obtenus, pendant la dernière décennie, et pour réduire la mortalité CV il est nécessaire l’identification de nouveaux biomarqueurs en utilisant des approches différentes. Cette thèse propose une approche intégrative pour découvrir de nouvelles associations génétiques associés avec les MCV. Nous avons d’abord réuni les résultats existants grâce à des GWAS précédents, puis nous avons recherché la pléiotropie de ces gènes et nous avons dirigé nos efforts vers une possible traduction des résultats obtenus dans l’application clinique. Nous avons détecté les effets pléiotropiques de différent gènes (IL-6R et ABO) avec différents phénotypes lipidiques et inflammatoires. Par ailleurs, nous avons trouvé quelques associations gène-genre intéressantes pour certains gènes étudiés (ABO et GNB3). Concernant l’implémentation clinique des connaissances obtenues par cette thèse, une SNP dans le gène TREM-1, pourrait être utilisé comme un marqueur de risque pour différentes maladies, et nous avons déposé un brevet Européen et nous envisageons de mener des essais cliniques de chez les patients. D’autre part, nous avons détecté une haplotype du gène IL6R qui pourrait être utilisés dans la médecine personnalisée. Nos résultats aident à mieux comprendre comment les gènes étudiés exercent leurs effets au niveau moléculaire, en influant finalement sur l’état des patients souffrant de MCV. Nous espérons que nos résultats vont être pris en compte pour faire progresser la médecine personnalisée
Cardiovascular diseases (CVD) are complex diseases where many environmental and genetic factors are involved. Although the genetic aetiology of the CVD has been extensively investigated the last two decades, alternative approaches are needed in order to keep advancing in the pathophysiology of CVD. In this thesis, we propose an integrative approach to discover new genetic associations potentially involved in CVD. We chose previous GWAS hits and we centred our efforts in studying the pleiotropic and gene-gender interaction effects. Finally, we focused on the implementation of personalized genome-based therapy of the results obtained. New pleiotropic effects were discovered in the IL-6R and ABO genes relating them with different inflammatory and lipid phenotypes. In addition, we studied the gene-gender interaction effects, finding some sex-specific associations in two of the genes studied (ABO and GNB3). Further, we centered our efforts in implementing the results obtained during the thesis at the clinical level. One SNP within the TREM-1 gene was associated with increased levels of its protein and could be used as a predictor or risk biomarker for different diseases. Due to the high potential of this SNP, we applied a European patent and we are planning to start clinical trials in patients. Also, one haplotype in the IL-6R gene could be used in the treatment of personalized medicine. During this thesis, we discovered new gene-phenotype associations involved in CVD and other diseases. Our results help to better understand how the studied genes are exerting their effects at the molecular level. Our results will hopefully be taken into account in future personalized treatments

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Resende, Rafael Tassinari. « Regional Heritability Mapping and GWAS for molecular breeding in eucalyptus hybrids ». Universidade Federal de Viçosa, 2017. http://www.locus.ufv.br/handle/123456789/11670.

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Conselho Nacional de Desenvolvimento Científico e Tecnológico
Embora os estudos de associação genômica (GWAS) forneçam informações valiosas na descodificação das relações entre a variação gênica e os fenótipos complexos, esta técnica explica uma pequena fração da herdabilidade. O mapeamento de herdabilidades regionais (RHM) fornece estimativas de herdabilidade para segmentos genômicos que contêm efeitos alélicos raros e que contribuem individualmente com baixa variação ao ponto de serem detectados pela GWAS. Neste estudo foi realizado a GWAS e o RHM para sete características de crescimento, madeira e resistência à doenças em uma população 768 árvores híbridas de Eucalyptus usando o moderno Chip Illumina EuCHIP60K. As herdabilidades genômicas totais representaram grandes proporções (64-89%) de herdabilidades baseadas em pedigree, fornecendo evidências adicionais de que características complexas em eucaliptos são controlados por muitas variantes ao longo do genoma, cada uma com pequenas contribuições para a variância fenotípica. O RHM detectou 26 QTLs (Quantitative Trait Loci) abrangendo 2.191 SNPs (Single Nucleotide Polymorphism), enquanto que a GWAS detectou 13 associações. Os QTLs detectados via RHM e GWAS explicaram individualmente 5 a 15% e 4 a 6% da herdabilidade genômica, respectivamente. O RHM foi superior à GWAS na captura de maiores proporções de herdabilidade genômica. Semelhantemente a QTLs previamente mapeados, os resultados destacaram as regiões genômicas que podem ser utilizadas em estudos mais aprofundados para descoberta de genes. Os RHM-QTLs contendo uma combinação de variantes comuns e raras representam um avanço para incorporar conhecimento prévio da arquitetura genética subjacente em modelos de predição genômica.
Although genome-wide association studies (GWAS) have provided valuable insights into the decoding of the relationships between sequence variation and complex phenotypes, they have explained little heritability. Regional heritability mapping (RHM) provides heritability estimates for genomic segments containing both common and rare allelic effects that individually contribute too little variance to be detected by GWAS. We carried out GWAS and RHM for seven growths, wood and disease resistance traits in a breeding population of 768 Eucalyptus hybrid trees using EuCHIP60K. Total genomic heritabilities accounted for large proportions (64 89%) of pedigree-based trait heritabilities, providing additional evidence that complex traits in eucalypts are controlled by many sequence variants across the frequency spectrum, each with small contributions to the phenotypic variance. RHM detected 26 quantitative trait loci (QTLs) encompassing 2,191 single nucleotide polymorphisms (SNPs), whereas GWAS detected 13 single SNP trait associations. RHM and GWAS QTLs individually explained 5 15% and 4 6% of the genomic heritability, respectively. RHM was superior to GWAS in capturing larger proportions of genomic heritability. Equated to previously mapped QTLs, our results highlighted genomic regions for further examination towards gene discovery. RHM-QTLs bearing a combination of common and rare variants could be useful enhancements to incorporate prior knowledge of the underlying genetic architecture in genomic prediction models.

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Eleftherochorinou, Charikleia. « Pathway and gene-based analysis of genome wide association studies (GWAS) ». Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/9175.

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My PhD thesis comprises the development and application of novel strategies to analyse genome-wide association studies (GWAS) in the context of functional pathways. I propose pathway and gene-centric methodologies as complementary tools to the conventional singlemarker analyses to mine further the GWAS hidden information. I developed the cumulative trend (CT) test statistic that assesses the cumulative genetic variation of single nucleotide polymorphisms (SNPs) of genes that interact in the same biological pathway and tests the association between a disease and the pathway as an entity. I applied this methodology to the genotypic data of the Wellcome Trust Case Control Consortium (WTCCC) study on Crohn’s disease (CD), type I diabetes (T1D), rheumatoid arthritis (RA), bipolar disorder, hypertension, type II diabetes, coronary artery disease; I identified highly significant associations between the autoimmune diseases (CD, T1D, RA) and inflammatory pathways; almost no association was identified between the same pathways and the non-inflammatory conditions. I extended my approach to a pathway-based gene stability selection methodology, which selects associated genes in the context of associated pathways. This methodology can be used to prioritise genes for follow up studies. I applied it on two GWAS of RA with different ethnic background and typed on different platforms and I demonstrated replication at the pathway, gene and in-silico functional levels. I finally extended my approach on family trios designed GWAS. I applied it on two casecontrol and family trio datasets of Kawasaki disease (KD). I explored the association between the TGF-β pathway and KD susceptibility. The involvement of this pathway in KD was further validated at the gene expression and protein levels. My proposed methodologies were tested on real datasets and provided reproducible results, which indicates rigor and robustness. I would therefore suggest their application to single or multiple GWAS as a complement to conventional single-SNP analysis.

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Swanson, David Michael. « Hypothesis Testing in GWAS and Statistical Issues with Compensation in Clinical Trials ». Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:10909.

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We first show theoretically and in simulation how power varies as a function of SNP correlation structure with currently-implemented gene-based testing methods. We propose alternative testing methods whose power does not vary with the correlation structure. We then propose hypothesis tests for detecting prevalence-incidence bias in case-control studies, a bias perhaps overrepresented in GWAS due to currently used study designs. Lastly, we hypothesize how different incentive structures used to keep clinical trial participants in studies may interact with a background of dependent censoring and result in variation in the bias of the Kaplan-Meier survival curve estimator.

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Förster, Julia. « Genomweite Untersuchung einer sorbischen Kohorte zur Identifikation neuer mit dem Lipidstoffwechsel assoziierter Polymorphismen ». Doctoral thesis, Universitätsbibliothek Leipzig, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-102123.

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Lipide erfüllen als Energiespeicher und Element verschiedener Verbindungen für den Organismus lebenswichtige Funktionen. Verändert sich ihre Konzentration im Blut spricht man von Dyslipidämien. Diese stellen, insbesondere als Risikofaktor für kardiovaskuläre Erkrankungen, vor allem in Industrienationen ein bedeutendes gesundheitsökonomisches Problem dar. Verschiedene Studien identifizierten in den letzten Jahren zahlreiche Genloci, die den Lipidstoffwechsel beeinflussen. Darunter befinden sich Gene wie APOC1, CETP oder LPL, die aufgrund ihrer Funktionalität eindeutig dem Fettstoffwechsel zuzuordnen sind. Zusätzlich gerieten bisher unbekannte Loci in den Gegenstand der Forschung. Zusammen erklären diese Loci derzeit lediglich 25 - 30 % der phänotypischen Ausprägung. In der vorliegenden Studie wurde mittels genomweiter Assoziationsstudien (GWAS) nach weiteren, potentiell im Zusammenhang mit den Merkmalen HDL-, LDL-Cholesterol und Triglyceriden stehenden Genloci gesucht. Dazu wurde in einer eigenständigen Population, den Sorben aus der Oberlausitz, eine genomweite Assoziationsstudie (N = 839) durchgeführt. Es zeigten sich 13 signifikant assoziierte Loci mit einem P-Wert < 10 5. Anschließend wurden SNPs mit einem P-Wert < 0,01 in der sorbischen Kohorte für eine Metaanalyse mit den Daten der Probanden der Diabetes Genetics Initiative (N ~ 2600) ausgewählt. So konnten 21 Genloci mit einem kombinierten P-Wert < 10 4 bestätigt werden. Von diesen wurden 5 neu identifizierte, bisher nicht publizierte Varianten in der unabhängigen Metabolisches Syndrom Berlin Potsdam Kohorte (N = 2000) repliziert. Mit einem P-Wert von 1,78x10 7 zeigte die Variante rs8135828 im THOC5 Gen für den Parameter HDL-Cholesterol die stärkste Assoziation in der kombinierten Metaanalyse aller 3 Kohorten. Weitere Analysen sind notwendig, um die Funktionen und den Regulationsmechanismus der identifizierten SNPs auf den Fettstoffwechsel genau zu verstehen.

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Anwer, Muhammad [Verfasser]. « Genome-wide-association studies (GWAS) on the interaction between the cyst nematode Heterodera schachtii and Arabidopsis thaliana : Genome-wide association mapping (GWAS), QTL, SNPs, Arabidopsis thaliana, Cyst nematode / Muhammad Anwer ». Bonn : Universitäts- und Landesbibliothek Bonn, 2018. http://d-nb.info/1170872336/34.

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Anwer, Muhammad Arslan [Verfasser]. « Genome-wide-association studies (GWAS) on the interaction between the cyst nematode Heterodera schachtii and Arabidopsis thaliana : Genome-wide association mapping (GWAS), QTL, SNPs, Arabidopsis thaliana, Cyst nematode / Muhammad Anwer ». Bonn : Universitäts- und Landesbibliothek Bonn, 2018. http://d-nb.info/1170872336/34.

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Juko-Pecirep, Ivana. « Analysis of genetic susceptibility to cervical cancer using candidate gene and GWAS approaches ». Doctoral thesis, Uppsala universitet, Institutionen för immunologi, genetik och patologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-248484.

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Cervical cancer is the forth most commonly diagnosed cancer among women worldwide. It is caused by persistent infection with an oncogenic type of Human Papillomavirus (HPV). The HPV is a necessary but not sufficient cause of cervical cancer. Environmental factors such as smoking, high parity and long-term use of oral contraceptives increases the risk of cervical cancer. Genetic factors also affect the risk of developing the disease. The aim of this thesis is to search for and evaluate genetic risk factors for cervical cancer using both a candidate gene approach and a genome-wide association study (GWAS). Paper I examined the association of genetic variation in three Fanconi Anemia (FA) genes (FANCA, FANCC and FANCL), involved in DNA repair, with cervical cancer susceptibility in the Swedish population. No association was observed. Paper II evaluated the association of genetic variation in the TMC6 and TMC8 genes with susceptibility to cervical cancer in the Swedish population and an association of two SNPs (rs2290907 and rs16970849) with cervical cancer was observed. In paper III the first GWAS performed in cervical cancer was reported. Three independent loci in the major histocompatibility complex (MHC) region at 6p21.3 were found to affect the susceptibility to cervical cancer. Paper IV examined the sequence variation in the TMC6 and TMC8 region and its association with cervical cancer. A highly polymorphic 21 bp sequence was identified and found to be repeated 5 to 42 times in both cases and controls. Lack of this repeat was associated with increased risk of cervical cancer. An intronic SNP (rs2926778) located in between the TNRC6C and TMC6 genes was also found to be associated with cervical cancer. The thesis provides evidence for the importance of genes in the immune system for cervical cancer susceptibility. The genetic risk factors identified explain only a part of the genetic susceptibility, implying that other risk factors remains to be identified

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Júnior, Gerson Antônio de Oliveira. « Associação genômica ampla (GWAS) aplicada a características reprodutivas de novilhas da raça Nelore ». Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/74/74135/tde-17082017-111905/.

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Considerando a importância econômica da precocidade sexual no sistema de produção de bovinos de corte, o objetivo deste estudo foi identificar regiões genômicas associadas a características reprodutivas tais como a prenhez precoce e número de folículos antrais em novilhas da raça Nelore, identificando processos biológicos envolvidos para um melhor entendimento da variabilidade fenotípica destas características. O banco de dados foi composto por 2.283 novilhas, filhas de 78 touros, provenientes de três fazendas comerciais do Brasil. Destas, 1.267 foram genotipadas com aproximadamente 74 K SNPs. Após análises de controle de qualidade, permaneceram informações de 1.255 animais e 64.800 marcadores. A informação genotípica de 42 touros também estava disponível e touros não genotipados com mais de 5 progênies genotipadas foram imputados para a mesma densidade de marcador das novilhas. Análises de associação genômica ampla (GWAS) foram utilizadas considerando uma metodologia Bayesiana (BayesB) para identificar potenciais janelas genômicas (~ 1 Mb) responsáveis pela explicação de ≥ 1% da variância genética das características. Essas regiões foram utilizadas para a pesquisa de genes bem como nas análises de enriquecimento utilizando os termos MeSH. Ainda, blocos haplotípicos dessas regiões genômicas foram ajustados como efeitos classificatórios no modelo BayesB, com o objetivo de estimar a influência de cada alelo dos touros heterozigotos sobre os fenótipos. Os coeficientes de herdabilidade preditos foram 0,28 ± 0,07 e 0,49 ± 0,09 para PP e NF, respectivamente, com correlação genética de -0,21 ± 0,29. Os resultados do GWAS apontaram janelas genômicas significativas nos cromossomos 5, 14 e 18 para PP e 2, 8, 11, 14, 15, 16 e 22 para NF. As análises de enriquecimento revelaram termos significativos (p < 0,05) associados com PP: Munc-18 Proteins, Fucose e Hemoglobins, e com NF: Cathepsin B, Receptors-Neuropeptide e Palmitic Acid. Um total de 15 alelos haplotípicos tiveram efeitos diferentes (p < 0,10) de sua cópia alternativa para PP e 16 para NF. As análises genômicas contribuíram para uma melhor compreensão da estrutura genética das características reprodutivas PP e NF, podendo colaborar com estratégias de seleção para melhoria dos índices reprodutivos de bovinos da raça Nelore.
Considering the economic importance of sexual precocity in beef cattle production system, the objective of this study was to explore genomic regions associated with heifer pregnancy (HP) and total number of antral follicle (NF) in a population of Nellore (Bos indicus) heifers. The dataset was composed by 2,283 animals, which were daughters of 78 sires, coming from three different commercial farms in Brazil. From these, 1,267 were genotyped with around 74 K SNP markers. After quality control analyses, the remained dataset was formed by 1,255 animals and 64,800 markers. Genotypic information of 42 sires was also available, and non-genotyped sires with more than five genotyped progenies in the dataset were imputed for the same marker density of the heifers. A Genome-wide Association Study (GWAS) was performed under a BayesB method to identify potential genomic windows (~1 Mb) that explained at least 1% of the total additive genetic variance of the traits. The pointed genomic regions were used in MeSH enrichment analyses as well as for genes searching. Haplotype blocks that span these potential genomic regions were fitted as classificatory effects in the BayesB model, aiming to estimate the effect of each allele of the heterozygous sires for these regions. The estimated heritabilities coefficients were 0.28 ± 0.07 and 0.49 ± 0.09 for HP and NF, respectively, with genomic correlation of -0.21 ± 0.29. The GWAS results pointed to significant genomic windows on chromosomes 5, 14 and 18 for HP and 2, 8, 11, 14, 15, 16 and 22 for NF. The MeSH enrichment analyses revealed significant (p < 0.05) terms associated with HP: Munc-18 Proteins, Fucose and Hemoglobins, and with NF: Cathepsin B, Receptors-Neuropeptide and Palmitic Acid. The pointed regions by GWAS harbored important genes that can help explain the genetic basis of the considered traits. A total of 15 haplotype alleles obtained better results (p < 0,10) than their alternative copy for HP and 16 for NF. The genomic analyses contributed to a better understanding of the genetic control of the reproductive traits HP and NF and can be useful to selection strategies in improving reproductive indices in Nellore cattle.

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Yasmeen, Summaira [Verfasser]. « Association Analysis Using Set-Based Approaches in the Post-GWAS Era / Summaira Yasmeen ». Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2021. http://d-nb.info/1239061242/34.

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Crook, Sally Eleanor. « The dissonance between the rhetoric and reality of health policy and service delivery : a case study of gender and primary health care in Gwassi, Kenya ». Thesis, London School of Economics and Political Science (University of London), 2005. http://etheses.lse.ac.uk/1824/.

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This thesis exposes the gendered assumptions underlying primary health care policies and practices in developing countries and the power relations underpinning them. These are offered as reasons for the dissonance between the rhetoric of health policy and the reality of health service practice, drawing on a case study of primary health care in Gwassi in rural south-west Kenya, served by government, diocesan and international NGO health services. Theoretically the research is animated by organisational theory to develop an approach that goes beyond a traditional evaluative stance of the planning and delivery of health services, instead making visible and giving voice to the users. The thesis argues that gender frequently remains hidden, unexplored or untheorised, but is nevertheless embedded in the sociological, organisational, economic and medical models regularly used to both plan and research health care. The present globally prescribed model of primary health care rests on just such gendered premises, which have been incorporated and insinuated into national health policies and professions. Historical roots for today's rituals and practices in primary health care in Gwassi are examined using a gendered perspective. Due to the preponderance of maternal and child health activities in such rural locations, along with the use of community health workers in health care delivery, these aspects are focused upon in the literature review of primary health care that frames the research. The thesis concludes that the lack of attention paid to the gendered nature of primary health care by health policy analysts and planners has resulted in and perpetuated a health service, which is designed and delivered in response to a skewed view of the community and its health needs. This in turn limits effective and feasible solutions to health problems. Through a gendered analysis of the findings it is concluded that in practice, primary health care only recognises women's roles and consequently mandates health responsibilities and activities to women. Men's roles are ignored and their participation remains optional, with gendered consequences for all health care users as well as for the efficacy of the service.

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Coffee, Michelle. « Analysis of schizophrenia susceptibility variants identified by GWAS : a bioinformatics and molecular genetics approach ». Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/95790.

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Thesis (MSc)--Stellenbosch University, 2014.
ENGLISH ABSTRACT: Described as one of the costliest and most debilitating disorders, schizophrenia has proven to be among the greatest challenges for medical researchers. The disorder poses difficulties on all levels: from genotype to phenotype. Even though it is known that there is a substantial genetic contribution to schizophrenia susceptibility (~80%), it is unknown whether this is due to common variants, rare variants, epigenetic factors, polymorphisms in regulatory regions of the genome or a combination of all these factors. Over the past few decades, many approaches have been employed to elucidate the genetic architecture of schizophrenia, with the latest and most promising being genome wide association studies (GWAS). However, nearly a decade after the first GWAS, the limitations are increasingly being recognised and new avenues need to be explored. Studies have recently started to focus on the analysis of non-coding regions of the genome since these regions harbour the majority of variants identified in GWAS thus far. This study aimed to use recently developed programs that utilize data from large scale studies such as previous GWAS, the Encyclopaedia of DNA Elements (ENCODE), 1000 Genomes, HapMap and Functional Annotation of the Mammalian Genome (FANTOM) to establish a simple, yet effective bioinformatics pipeline for the identification and assessment of variants in regulatory regions. Using the established workflow, 149 single nucleotide polymorphisms (SNPs) in regulatory regions were implicated in schizophrenia susceptibility, with the most significant SNP being rs200981. Pathway and network analysis using the Database for Annotation, Visualization and Integrated Discovery (DAVID) and GeneMANIA respectively indicated that the most frequently affected genes were involved in immune responses or neurodevelopmental processes, which support previous findings. Yet, novel findings of this study implicated processes crucial for DNA packaging (from DNA level to chromatin level). The second part of the study used restriction fragment length polymorphism analysis of polymerase chain reaction-amplified fragments (PCR-RFLP) to genotype ten of the most significant SNPs (identified by bioinformatic analyses in the first part of the study) in a South African Xhosa cohort of 100 cases and 100 controls, while bi-directional Sanger sequencing was used to confirm the presence of these SNPs. Statistical analyses revealed two haplotypes of regulatory variants, rs200483-rs200485-rs2517611 (p = 0.0385; OR = 1.71; 95% CI = 1.01-2.91) and rs200981-rs2517611-rs3129701 (p = 0.041; OR = 0.51; 95% CI = 0.27-0.98) associated with schizophrenia susceptibility. Bioinformatic analysis indicated that these haplotypes affect DNA packaging, which supported the findings of the first part of the study and could implicate epigenetic processes. The findings of this study support the importance of regulatory variants in schizophrenia susceptibility. This study also showed the importance of combining GWAS data with additional analyses in order to better understand complex diseases. It is hoped that these findings could fuel future research, specifically in genetically unique populations.
AFRIKAANSE OPSOMMING: Skisofrenie kan beskryf word as een van die duurste en mees ernstige siektes en bly steeds een van die grootste uitdagings vir mediese navorsers. Hierdie versteuring behels probleme op alle vlakke: van genotipe tot fenotipe. Alhoewel dit bekend is dat daar 'n aansienlike genetiese bydrae tot skisofrenie vatbaarheid is (~ 80%), is dit onbekend of dit is as gevolg van algemene variasies, skaars variasies, epigenetiese faktore, variasies in regulerende gebiede van die genoom of 'n kombinasie van al hierdie faktore. Oor die afgelope paar dekades is verskeie benaderings gebruik om die genetiese samestelling van skisofrenie te bestudeer, met die nuutste en mees belowende synde genoom-wye assosiasie studies (GWAS). Byna 'n dekade na die eerste GWAS, word die beperkinge egter toenemend erken en nuwe navorsingstrategieë moet gebruik word. Studies het onlangs begin om meer te fokus op die analise van nie-koderende areas van die genoom aangesien hierdie areas die meerderheid van die variasies behels wat tot dusver in GWAS geïdentifiseer is. Hierdie studie het gepoog om onlangs ontwikkelde programme, wat gebruik maak van die data van grootskaalse studies soos vorige GWAS, die “Encyclopaedia of DNA Elements” (ENCODE), “1000 Genomes”, “HapMap” en “Functional Annotation of the Mammalian Genome” (FANTOM), te implementeer om sodoende 'n eenvoudige, maar doeltreffende bioinformatika pyplyn vir die identifisering en evaluering van variante in regulerende gebiede, te vestig. Deur die gebruik van die gevestigde bioinformatika pyplyn, is 149 enkel nukleotied polimorfismes (SNPs) in regulerende gebiede in skisofrenie vatbaarheid betrek, met rs200981 wat die mees betekenisvol was. Pad- en netwerk-analise met die onderskeidelike hulp van die “Database for Annotation, Visualization and Integrated Discovery” (DAVID) en “GeneMANIA”, het aangedui dat die gene wat die meeste geaffekteer was, betrokke is by immuunreaksies en neuro-ontwikkeling. Hierdie bevindinge ondersteun vorige studies. Tog het nuwe bevindinge van hierdie studie prosesse geïmpliseer wat uiters noodsaaklik is vir DNS verpakking (van DNS- tot chromatien-vlak). Die tweede deel van die studie het restriksie fragment lengte polimorfisme analise van polimerase ketting reaksie geamplifiseerde fragmente (PKR-RFLP) gebruik om tien van die belangrikste SNPs (wat geïdentifiseer is deur bioinformatiese ontledings in die eerste deel van die studie) in `n Suid-Afrikaanse Xhosa studiegroep van 100 skisofrenie gevalle en 100 kontroles te genotipeer, terwyl tweerigting Sanger volgordebepaling gebruik is om die teenwoordigheid van hierdie SNPs te bevestig. Statistiese analise het aangedui dat twee
National Research Foundation (DAAD-NRF)

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Adkins, Amy. « From Linkage to GWAS : A Multifaceted Exploration of the Genetic Risk for Alcohol Dependence ». VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/2920.

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Family, twin and adoption studies consistently suggest that genetic factors strongly influence the risk for alcohol dependence (AD). Although the literature supports the role of genetics in AD, identification of specific genes contributing to the etiology of AD has proven difficult. These difficulties are due in part to the complex set of risk factors contributing to the development of AD. These risk factors include comorbidities with other clinical diagnoses and behavioral phenotypes (e.g., major depression), physiological differences that contribute to the differences between people in their level of response to ethanol (e.g., initial sensitivity) and finally the large number of biological pathways targeted by and involved in the processing of ethanol. These complexities have probably contributed to the limited success of linkage and candidate gene association studies in finding genes underlying AD. The powerful and unbiased genome-wide association study (GWAS) offers promise in the study of complex diseases. However, due to the complexities of known risk factors, GWAS data has yet to provide consistent, replicable results. In light of these difficulties, this dissertation has five specific aims which attempt to investigate genetic risk loci for AD and related phenotypes through improved methods for candidate gene selection, analysis of a pooled genome-wide association study, genome-wide analyses of initial sensitivity and maximum alcohol consumption in a twenty-four hour period and finally, creation of a multivariate AD/internalizing phenotype.

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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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Baker, Emily Ann. « Investigation of new strategies for identifying causal mechanisms in Alzheimer's disease taking bioinformatics approaches beyond GWAS ». Thesis, Cardiff University, 2018. http://orca.cf.ac.uk/117724/.

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The ideal outcome for medical research is the ability to provide personalised treatment for the population. Genetics studies are necessary to achieve this, since a person's genetic code does not change over time. Alzheimer's disease (AD) is a neurodegenerative disorder with a significant genetic component. Clinical trials in AD are diffcult to design due to advanced neuropathological changes before development of symptoms, consequently, it would be beneficial to determine an individual's risk of AD. Genome-wide association studies (GWAS) have unearthed over 20 variants associated with AD. It is expected there are more variants associated with disease which may explain disease aetiology, however, GWAS is not able to detect additional variants without increasing sample size. Set-based analysis is an attractive alternative to determining the association of one single nucleotide polymorphism (SNP), since the combined effect of all SNPs in the set may be captured. A gene-based analysis using the MAGMA approach in the AD data shows this by finding additional independent gene associations using identical data. Polygenic Risk Scores (PRSs) are used for a variety of purposes in assessing the genetic liability to disorders. To further improve the power of set-based analyses, PRS as a setbased analysis is considered; this approach incorporates external data to improve power. This power increase is shown compared with other set-based methods using simulation studies and identifies two novel genes in imputed AD data; CSMD1 and MACROD2. The downside to the PRS approach is that it assumes independence between SNPs and thus data must be pruned for Linkage Disequilibrium (LD). Therefore, a novel approach which extends PRS and adjusts for LD is presented. This method is termed POLARIS and is shown to have better power compared to MAGMA in simulation studies and has determined three novel genes; PPARGC1A, RORA and ZNF423, in imputed AD data.

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Silva, Leonardo Corrêa da. « Linkage fine-mapping, GWAS and QTLs affecting morpho-agronomic traits of a common bean RIL population ». Universidade Federal de Viçosa, 2017. http://www.locus.ufv.br/handle/123456789/16357.

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Conselho Nacional de Desenvolvimento Científico e Tecnológico
O feijão comum (Phaseolus vulgaris L.) é uma das leguminosas mais cultivadas e consumidas em todo o mundo. É uma fonte relativamente barata de proteínas e nutrientes, firmando-se como um importante alimento na manutenção da segurança alimentar no planeta. Nesse sentido, o melhoramento genético é fundamental para a obtenção de cultivares mais produtivas, com arquitetura de plantas mais adequada aos sistemas de colheita, com ciclo compatível com às regiões de produção e de aspecto de grãos que atenda às exigências do mercado consumidor. Uma ferramenta auxiliar no melhoramento genético de plantas é a seleção assistida por marcadores moleculares do DNA. O mapeamento de ligação (Linkage Mapping, LM) é a abordagem mais comum no melhoramento para detectar marcadores moleculares associados a QTLs (Quantitative Trait Loci, ou locos controladores de características quantitativas). A abundância de marcadores no genoma das espécies fez do mapeamento de associação (Association Mapping, AM) uma nova estratégia pra detecção de QTLs. Uma importante metodologia do mapeamento de associação é o estudo de associação genômica ampla (Genome Wide Association Study, GWAS). Neste contexto, o Programa de Melhoramento do Feijoeiro da Universidade Federal de Viçosa (UFV) desenvolveu uma população formada por 376 RILs (Recombinant Inbred Lines, ou linhagens endogâmicas recombinantes) de feijão comum, obtidas do cruzamento entre Rudá e AND 277, para a obtenção de um mapa genético e detecção de QTLs relacionados a sete características morfo-agronômicas usando essas duas metodologias. Essa população foi denominada de RILs RA. Outro objetivo foi conhecer a função biológica destes QTLs pela sua localização em relação a genes candidatos com função biológicas que se relacionassem às características destes QTLs. A população foi genotipada com 3.098 marcadores do tipo SNP (Single Nucleotide Polymorphism, polimorfismo a partir de um único nucleotídeo) e fenotipada em campo para as características número de dias até o florescimento (DF) e até a maturação (DM), arquitetura de plantas (ARC), produtividade de grãos (YLD), grau de achatamento (SF) da semente, forma da semente (SS) e massa de cem grãos (SW). Pelo mapeamento de ligação (LM), foi obtido uma mapa genético com 1.962 SNPs e tamanho total de 1.065,48 cM. Também foram detectados 29 QTLs, para as sete características, distribuídos nos 11 cromossomos, que explicaram de 3,83 a 32,92% da variação fenotípica. Na anotação gênica, quatro sequências de SNPs identificados como ligados aos QTLs foram relacionados a 18 genes com função biológica conhecida. Pelo estudo de associação genômica ampla (GWAS), foram detectados 112 SNPs/QTLs em todos os cromossomos, com exceção dos cromossomos 06 e 07, relacionados a todas as características avaliadas. Alguns destes QTLs estavam posicionados próximos ou dentro de genes candidatos com função biológica que se relacionava com as características morfo-agronômicas avaliadas. Conclui-se que o tamanho da população de RILs RA (376 linhagens) permitiu a obtenção de um mapa genético com estimativas de frequência de recombinação acurada. O número de marcadores utilizados propiciou boa saturação em todos os cromossomos, o que permitiu a detecção de QTLs com mais eficiência e confiabilidade pelo mapeamento de ligação e pela GWAS. Os genes candidatos localizados nas regiões destes QTLs corroboram o potencial destes na seleção assistida por marcadores moleculares para as características morfo-agronômicas avaliadas.
Common bean (Phaseolus vulgaris L.) is one of the most cultivated and consumed legumes worldwide. It is a relatively inexpensive source of protein and nutrients, establishing itself as an important food in maintaining food security on the world. In this sense, genetic breeding is essential to obtain more productive cultivars, with plant architecture more adequate to the harvesting systems, with a cycle suitable to the regions of production, and grain type compatible with the requirements of the local market. An auxiliary tool in plant breeding is the DNA marker-assisted selection. Linkage mapping (LM) is the most common approach to detect molecular markers associated to quantitative trait loci (QTL). The abundance of molecular markers in the genome of the species made of association mapping (AM) a new methodology to QTLs detection. An important association mapping (AM) methodology is the genome wide association study (GWAS). In this context, the Common Bean Breeding Program of the Universidade Federal de Viçosa (UFV) developed a population consisting of 376 RILs, obtained from the crossing between Rudá and AND 277, to construct a genetic map and detect QTLs related to seven morpho-agronomic traits using these two methodologies. Another objective was to know the biological function of these QTLs by their location in relation to candidate genes with biological functions that related to the traits of these QTLs. The population was genotyped with 3,098 SNP (single nucleotide polymorphism) markers and phenotyped in the field conditions for the trais number of days to flowering (DF) and to maturity (DM), plant architecture (ARC), seed yield (YLD), degree of seed flatness (SF), seed shape (SS), and 100- seed weight (SW). A genetic map with 1,962 SNPs, spanning a total size of 1,065.48 cM, was obtained by linkage analysis. In addition, 29 QTLs were detected for the seven characteristics distributed on the 11 chromosomes, which explained from 3.83 to 32.92% of the phenotypic variation. In gene annotation, four sequences of SNPs identified as linked to QTLs were related to 18 genes with known biological function. 112 SNPs/QTLs related to the traits evaluated were detected in all chromosomes by genome wide association study (GWAS), except to chromosomes 06 and 07. Some of these QTLs were positioned near or within candidate genes with biological function that were related to the morpho-agronomic traits evaluated. It is concluded that the population size of RA RILs (376 lines) allowed to obtain a genetic map with accurate estimates of recombination frequency. The number of markers used in this study provided good saturation in all chromosomes, which allowed the efficiently and reliably QTL detection by linkage mapping and GWAS. The candidate genes located in the regions of these QTLs corroborate their potential in the marker-assisted selection for these seven morpho-agronomic traits.

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Shen, Hanyang, Bizu Gelaye, Hailiang Huang, Marta B. Rondon, Sixto Sanchez et 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
Revisión por pares

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Raghavan, Avanthi. « Leveraging CRISPR/Cas Genome Editing Technology to Identify and Characterize Causal GWAS Variants for Blood Lipids ». Thesis, Harvard University, 2017. http://nrs.harvard.edu/urn-3:HUL.InstRepos:32676132.

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Genome-wide association studies (GWAS) have identified a number of novel genetic loci linked to serum cholesterol and triglyceride levels. The causal DNA variants at these loci and the mechanism by which they influence phenotype and disease risk remain largely unexplored. Expression quantitative trait locus (eQTL) analyses of patient liver and adipose biopsies indicate that many lipid-associated variants influence gene expression in a cis-regulatory manner. However, linkage disequilibrium (LD) among neighboring single nucleotide polymorphisms (SNPs) at a GWAS-implicated locus makes it challenging to pinpoint the actual variant underlying an association signal. Here we performed high-throughput identification of putative disease-causal loci through a functional reporter-based screen, the massively parallel reporter assay (MPRA). We then validated prioritized variants using a combination of genome edited stem cells, clustered regularly interspaced short palindromic repeats (CRISPR) interference, and in vivo genome edited humanized mouse models to establish rs2277862-CPNE1, rs10889356-ANGPTL3, and rs12740374-SORT1 as causal SNP gene sets. These results highlight a novel experimental framework to discover causal genes and variants contributing to complex human traits.

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CARVALHO, Rebecca Cristina Linhares de. « Identificação de novos genes e SNPs relacionados ao mal de Parkinson e doenças relacionadas através de GWAS ». Universidade Federal de Pernambuco, 2015. https://repositorio.ufpe.br/handle/123456789/16318.

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FACEPE
Parkinsonismo é uma síndrome neurológica em que os neurônios que normalmente produzem o hormônio chamado dopamina se deterioram, causando a perda de controle progressivo do movimento (ex. bradicinesia, a rigidez muscular, o temor de repouso e os reflexos posturais prejudicados). Um mal com sintomas semelhantes ao parkinsonismo é a síndrome ScansWithout Evidence of Dopaminergic Deficits (SWEDDs), na qual os pacientes não apresentam evidências de déficit de dopamina. As causas de parkinsonismo primário como a doença de Parkinson (DP), bem como SWEDDs, não são completamente conhecidos. Os estudos de associações no genoma completo (Genome-wide association studies - GWAS) têm proporcionado ganhos tangíveis para a compreensão da arquitetura genética de doenças complexas, trazendo contribuições consistentes e importantes para DP. GWASs foram realizados no passado com os dados de DP com resultados que influenciaram fortemente desenvolvimentos posteriores. Nesse trabalho, nós desenvolvemos um estudo sobre fatores genéticos que possam contribuir para o entendimento da ocorrência da DP e SWEDDs. Para isso, nós usamos o conjunto de ferramentas de análise de associação envolvendo estudo de caso-controle do método PLINK para executar GWASs, a fim de identificar SNPs que estão associados à DP e SWEDDs. Para fixar o nível de significância dos nossos resultados, nós optamos por usar somente dados reais fornecidos por Parkinson’s Progression Markers Initiative (PPMI). O PPMI é um consórcio internacional projetado para identificar biomarcadores de progressão da DP, tanto para melhorar a compreensão da etiologia da doença, como para fornecer ferramentas cruciais para aumentar a probabilidade de sucesso na elaboração de novos ensaios terapêuticos para DP. Na análise de associação, feita com dados genótipos de três grupos de indivíduos (indivíduos saudáveis, indivíduos com DP e indivíduos com SWEDDs), recuperamos SNPs que mostram forte ligação com PD e SWEDDs, alguns deles já associados na literatura científica com a DP ou a outras doenças degenerativas. Mas, também encontramos cerca de 60 SNPs que não estão relatados na literatura, que mostram evidências de serem fortemente relacionadas com a propensão para DP ou SWEDDs. Estes resultados apresentam alvos promissores para futuros estudos genômicos e podem contribuir para o entendimento da ocorrência da DP e SWEDDs. Curiosamente, embora SWEDDs seja uma doença clinicamente ligada a DP por uma série de sintomas comuns, os SNPs recuperados com as melhores classificações a partir do conjunto de dados DP não faziam parte do conjunto de dados SWEDDs, e vice-versa, o que sugere que esses dois conjuntos de marcadores poderiam ser mais cuidadosamente explorados nos estudos genômicos como SNPs comuns de interesse para as duas doenças.
Parkinsonism is a neurological disorder neurons that normally produce the hormone called dopamine deteriorate, causing progressive loss of movement control (e.g. bradykinesia, muscle rigidity, tremor at rest, and impaired postural reflexes). A syndrome with similar symptoms is Scans Without Evidence of Dopaminergic Deficits (SWEDDs), in which the patients not present evidence of dopaminergic deficits. The causes of primary parkinsonism, or Parkinson’s disease (PD), as well as SWEDDs, are not completely known. Genome-wide association studies (GWASs) have provided substantial contribution to the understanding of the architecture of complex diseases, bringing consistent and important contributions to PD. GWASs have been performed in the past with PD data with results that strongly influenced later developments. In this work, a study of genetic factors that contributes to the set of tools of association analysis for a better understanding of occurency of PD and SWEDDs. To that end, the set of tools of association analysis is involved in a study case for the PLINK method to execute GWASs with the objective of identifying SNPs which are associated to DP and SweDDs. To determine the level of significance of our results, only real data provided by Parkinson’s Progression Markers Initiative (PPMI) was used. PPMI is an international consortium created to indetify biomarkers of DP progression, to better comprehend the etiology of this disease and to provide key tools to increase the probability of success in the development of new therapeutic trials for PD. The association analysis, done with genotype data from three groups of individuals (healthy, affected by PD and affected by SWEDDs), SNPS that have shown strong connection to PD and SWEDDs were recovered, some of them are already linked in the scientific literature to PD or other degenerative diseases. But, we also have found about 60 SNPs that are not reported in the literature, which show evidence to be strongly related to the propensity to PD or SWEDDs. These results are promising targets for future genomic studies and may contribute to the understanding of the occurrence of PD and SWEDDs. Interestingly, although SWEDDs is a disorder clinically linked to PD by a series of common symptoms, the top ranked SNPs recovered from the PD dataset were not part of the SWEDDs dataset and conversely, that suggests that those two sets of markers could be more carefully explored in the genomic studies as common SNPs of interest for the two diseases.

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Cesar, Aline Silva Mello. « Identification of genes associated with intramuscular fat deposition and composition in Nellore breed ». Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/11/11139/tde-12082014-103102/.

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The amount and composition of intramuscular fat (IMF) influence the sensory characteristics, nutritional value of beef and human health. The amount of fatty acid and its composition in beef varies by breed, nutrition, sex, age or carcass finishing level. The fat deposition and composition are determined by many genes that participate directly or indirectly in adipogenesis and lipid metabolism. The selection of animals with fat amount and composition suitable for the consumer is complex due to high cost of measurement, the moderate heritability and polygenic traits (many genes are involved with these traits). In the last decade with a great advance in bovine genomics resulted in the complete genome sequencing and the development of high-density chips of SNPs. This scientific advance jointly with technological improvement allowed the identification of genes responsible for important quantitative traits in cattle. This study aimed to identify and characterize genes associated with the deposition and composition of intramuscular fat in Nellore. A genome-wide association study (genome- wide association studies, GWAS) was performed to identify genomic regions associated with traits of interest and positional candidate genes. A total RNA sequencing (RNA-Seq) analysis was applied to transcriptome study of Longissimus dorsi muscle. Three hundred and eighty six Nellore steers were used for the evaluation of lipid content and fatty acid profile of LD, and genotyping with high-density chip SNP (SNP800 Illumina BeadChip). A subset of 14 animals, seven animals for each extremes of genomic estimated values (GEBV) were used to RNA-Seq analysis. Twenty-five genomic regions (1 MB window) were associated with the deposition and composition of intramuscular fat, which explained >= 1 % of the genetic variance. These regions were identified on chromosomes 2, 3, 6, 7, 8, 9, 10, 11, 12, 17, 26 and 27, many of these have not previously been found in other breeds and in these regions important genes were identified. Genomic regions and genes identified and presented here should be contribute to a better understanding of the genetic control of deposition and fat composition in beef cattle, and can be applied in breeding programs for animals that produce a quality and healthy beef to human consumers.
A quantidade e composição da gordura intramuscular (GIM) pode influenciar as características sensoriais, o valor nutricional da carne bovina e na saúde humana. O perfil dos seus ácidos graxos pode se apresentar de maneira diversificada conforme a genética, o manejo e a nutrição dos animais de origem. A deposição e composição da gordura são determinadas por muitos genes que participam direta ou indiretamente da adipogênese e do metabolismo lipídico. A seleção de animais com teor e composição de gordura adequado para o consumidor é complexa pela difícil mensuração destas características, pela moderada herdabilidade e pelo desconhecimento dos genes envolvidos. Na última década, presenciamos um grande avanço na área da genômica bovina que resultou no sequenciamento completo do genoma e no desenvolvimento de chips de alta densidade de SNP. Este progresso científico, aliado aos avanços tecnológicos de equipamentos, resultou na identificação de genes responsáveis pela determinação de características quantitativas de interesse científico e comercial na bovinocultura. Este estudo teve como objetivo identificar e caracterizar genes associados à deposição e composição de gordura intramuscular em bovinos Nelore. Para este fim foi conduzido um estudo de associação genômica (Genome-wide association studies, GWAS) para identificar regiões genômicas associadas às características de interesse e identificar genes candidatos posicionais. Para o estudo de expressão diferencial foi conduzido um estudo do transcriptoma a partir do sequenciamento de RNA total (RNA-Seq) do músculo Longissimus dorsi. Foram utilizados 386 Nelores para a avaliação do teor de lipídeos total e perfil de ácidos graxos do músculo LD e, genotipagem com chip de alta densidade de SNP (Illumina SNP800 BeadChip). Um subconjunto de 14 animais, sendo sete animais de cada extremo para os valores genômicos estimados (GEBV) foi utilizado para o estudo de RNA-Seq. Foram encontradas 25 regiões genômicas (intervalos de 1 MB) associadas com deposição e composição de gordura intramuscular, as quais explicaram >= 1% da variância genética. Estas regiões foram identificadas nos cromossomos 2, 3, 6, 7, 8, 9, 10, 11, 12, 17, 26 e 27, muitas destas não foram previamente detectadas em outras raças. Nestas regiões foram identificados importantes genes e podem ajudar no entendimento da base genética envolvida na deposição e composição de gordura. As regiões genômicas e genes aqui identificados e apresentados contribuem para um melhor entendimento do controle genético da deposição e composição de gordura em gado de corte e ainda podem ser aplicados em programas de seleção genética de animais que produzam carne com qualidade e com perfil de gordura saudável ao homem.

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Rosier, Florian. « Au-delà des études d'association à l'échelle du génome : étude transcriptomique et identification des variants régulateurs impliqués dans le développement du sepsis ». Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0542.

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En 2017, l'Assemblée mondiale de la Santé et l'Organisation mondiale de la Santé ont fait du sepsis une priorité de santé mondiale en adoptant une résolution pour améliorer, prévenir, diagnostiquer et gérer le sepsis. Cette pathologie tue principalement des personnes déjà fragilisées. Il a été démontré que l'état du patient et la réponse immunitaire de l'hôte est primordiale dans le développement de la pathologie. Mon projet de thèse a tout d’abord consisté à caractériser la réponse transcriptionnelle de cellules du péritoine stimulées au LPS dans un modèle murin du sepsis. Par ailleurs, j’ai recherché les variants génétiques cis-régulateurs potentiellement impliqués dans la mortalité des patients en choc septique par une approche bioinformatique et une validation fonctionnelle expérimentale. Ces 2 projets mettent en évidence, chez l'homme, des mécanismes de la régulation de l’expression de gènes clés dans la survie des patients atteints de sepsis
In 2017, the World Health Assembly and the World Health Organization made sepsis a global health priority by adopting a resolution to improve, prevent, diagnose and manage sepsis. This pathology mainly kills people who are already vulnerable. It has been shown that the patient's condition and the host's immune response are essential in the development of the disease. My thesis project first consisted in characterizing the transcriptional response of peritoneal cells stimulated at the LPS in a mouse model of sepsis. In addition, I researched cis-regulatory genetic variants potentially involved in the mortality of patients in septic shock through a bioinformatics approach and experimental functional validation. These 2 projects highlight, in humans, mechanisms for regulating the expression of key genes in the survival of patients with sepsis

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Barros, Camila da Costa [UNESP]. « Estudo de seleção genômica para características de produção e qualidade do leite de búfalas ». Universidade Estadual Paulista (UNESP), 2017. http://hdl.handle.net/11449/151375.

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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Objetivou-se com o presente trabalho comparar diferentes métodos Bayesianos de predição genômica para as características de produção de leite (PL) e as porcentagens de gordura (%G) e proteína (%P) no leite de búfalas e, realizar um estudo de associação genômica ampla, a fim de identificar regiões cromossômicas e genes possivelmente relacionados às mesmas, utilizando informações de indivíduos genotipados e não genotipados. O número de animais com fenótipo foi 3.355, o arquivo de pedigree continha 15.495 animais, dos quais 322 foram genotipados com o 90 K Axiom® Buffalo Genotyping array. Os seguintes critérios de controle de qualidade dos SNPs foram utilizados: MAF < 0,05; Call Rate < 0,95 e Equilíbrio de Hardy-Weinberg p-value < 10-6. Em relação à amostra foi considerado call rate <0,90. Para as predições genômicas, os seguintes modelos Bayesianos foram utilizados: Bayes A (BA), Bayes B (BB), Bayes C (BC) e Bayes LASSO (BL). O fenótipo corrigido para os efeitos fixos (Y*) foi utilizado como variável resposta nas análises genômicas. A habilidade de predição dos diferentes modelos foi avaliada usando o método leave-one-out de validação cruzada. As acurácias de predição foram calculadas através da correlação de Pearson entre o valor genético genômico estimado (GEBV) e a variável resposta (Y*) para cada modelo e característica avaliados. Em relação ao estudo de associação genômica ampla, um processo iterativo foi realizado para calcular os pesos dos marcadores em função do quadrado dos efeitos dos SNPs e das frequências alélicas (ssGWAS). Em geral, todos os modelos Bayesianos demonstraram semelhantes acurácias de predição, variando de 0,41 a 0,42, 0,38 a 0,39 e 0,39 a 0,40 para a PL, %G e %P, respectivamente. Portanto, os métodos BA, BB, BC e BL podem ser utilizados nas predições dos efeitos dos SNPs, obtendo-se, praticamente, as mesmas acurácias de predição. Os dez SNPs de maiores efeitos para a PL, %G e %P explicaram 7,48, 9,94 e 6,56% da proporção da variância genética, respectivamente. Os resultados do ssGWAS revelaram regiões cromossômicas e genes que podem estar relacionados com as características analisadas. Tais regiões e genes identificados poderão contribuir para o melhor entendimento sobre a influência dos mesmos nas características produção de leite e as porcentagens de gordura e proteína no leite de búfalas.
The aim of this study was to compare different Bayesian methods of genomic prediction for milk yield (MY), fat (%F) and protein (%P) percentages in dairy buffaloes in Brazil, and to perform a genome-wide association study for the purpose of identify chromosomal regions and genes possibly related to the these traits, using information from genotyped and non-genotyped individuals. The number of animals with phenotype was 3,355, the pedigree file contained 15,495 animals, of which 322 were genotyped. The animals were genotyped using a 90K SNP panel (Axiom® Buffalo Genotyping Array). The following criteria for quality control of SNPs were used: MAF < 0.05, Call Rate < 0.95 and Hardy-Weinberg Equilibrium p-value < 10-6 . In relation to the sample, a Call Rate <0.90 was used. Four methods for genomic prediction were used: Bayes A (BA), Bayes B (BB), Bayes C (BC) and Bayes LASSO (BL). Phenotypes for the fixed effects (Y*) were used as response variables. The predictive ability of the different models was evaluated using a leave-one-out cross-validation approach. The prediction accuracy was calculated by Pearson's correlation between estimated genomic genetic value (GEBV) and response variable (Y*) for each model. In relation to genome-wide association studies, an iterative process was performed to derive SNP weights as function of squares of SNP effects and allele frequencies (ssGWAS). In general, all Bayesian models showed similar prediction accuracy, ranging from 0.41 to 0.42, 0.38 to 0.39 and 0,39 to 0,40 for MY, %F and %P, respectively. Therefore, the methods BA, BB, BC and BL can be used in the predictions of the effects of SNPs, obtaining, practically, the same prediction accuracy. The proportions of variance explained by the top 10 SNPs for MY, %F and %P were: 7.48, 9.94 and 6.56%, respectively. The results of ssGWAS revealed chromosomal regions and genes that may be related with the analyzed traits. These regions and genes may contribute to a better understanding of their influence on milk yield and fat and protein percentages in buffalo milk.
FAPESP: 2013/24427-3
FAPESP: 2015/18614-0

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Tomar, Sandeep Singh. « In vitro and field based evaluation for grain mold resistance and its impact on quality traits in sorghum [Sorghum bicolor (L.) Moench] ». Thesis, Kansas State University, 2016. http://hdl.handle.net/2097/32638.

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Master of Science
Department of Agronomy
Ramasamy Perumal
Tesfaye Tesso
Grain mold (GM) is an important biotic constraint limiting yield and market value of sorghum grains. It results in kernel discoloration and deterioration. Such kernels have reduced seed viability, low food and feed quality. Breeding for grain mold resistance is challenging because of the complex nature of host-pathogen-environment interactions. This complex task could be made simpler by utilizing molecular markers. Utilization of marker resources may help to find genomic regions associated with grain mold resistance. In this study, three sets of field and laboratory based experiments were performed which will help in finding potential grain mold pathogens responsible for kernel deterioration in the studied environment and search for genotypes with better kernel quality and grain mold resistance. In the first part of the study, in vitro screening of 44 grain mold resistant sorghum genotypes developed and released by Texas A & M AgriLife Research. This study was aimed at identifying sources resistance to grain mold infection through laboratory screening. The result revealed that genotypes Tx3371, Tx3373, Tx3374, Tx3376, Tx3407, Tx3400, and Tx3402 were have high level of resistance and were identified as potential sources of grain mold resistance as each showed minimal fungal infection and higher grain quality traits. The second experiment was performed to optimize surface sterilization protocol for the extraction of fungal pathogens from the kernel surface (pericarp) and to study the effect of bleach percentage and time period on pathogen extraction. Seven treatments using sterilized double distilled water (0 % bleach (v/v)) and different bleach (NaOCl) concentrations (2.5, 5, 7.5, 10, 12.5 and 15 %) were used with a time interval of 2.5, 5, 7.5 and 10 min. Optimized surface sterilization in the range of 7.5 to 15 % bleach (v/v) for 7.5 to 10 min resulted least contamination and fungal genera isolation from the surface of the kernel. The third study was aimed at characterizing genotypes (sorghum association panel) for grain mold pathogen F. thapsinum and by using genome wide association (GWA) tool in order to find genomic regions associated with grain mold resistance. We studied the effect of different agronomic and panicle architecture traits on grain mold incidence and severity. Effects of grain mold on kernel quality traits were also studied. We reported two loci associated with grain mold resistance. Based on first year field screening results, 46 genotypes having grain mold ratings 1-5 (1 = < 1% panicle kernel molded; 5 = > 50% panicle kernel molded) were selected for a detailed study aimed at understanding grain mold x fungal pathogen interactions to physical and chemical kernel traits. Seed germination test, vigor index, and tetrazolium viability test were performed to study effect of grain mold infection on kernel viability and vigor. Alternaria, Fusarium thapsinum, F. verticillioides and F. proliferatum were the main fungal genera isolated from bisected kernels. Based on two year screening, SC623, SC67, SC621, SC947 and SC1494 were most resistant based on both PGMR and TGMR rating while SC370, SC833, SC1484, and SC1077 showed the most susceptible reaction and this was consistent for individual location analysis. SC309, SC213, SC833, SC971 and SC1047 are genotypes having identified loci for grain mold resistance.

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Teumer, Alexander [Verfasser]. « Microarray-based Genome-Wide Association Studies (GWAS) using data generated by Allelotyping and by individual Genotyping / Alexander Teumer ». Greifswald : Universitätsbibliothek Greifswald, 2011. http://d-nb.info/1010242512/34.

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Nguyen, Le Khanh. « Caractérisation fonctionnelle d'un QTL de développement racinaire détecté par GWAS dans une collection de variétés vietnamiennes de riz ». Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTG044.

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Le riz est l'une des céréales les plus importantes au monde. Au Vietnam, le riz est également considéré comme un produit agronomique clé pour l'exportation. Cependant, le stress dû à la sécheresse menace la production de riz de plus en plus fréquemment et sur de plus longues périodes. Les racines coronaires constituent une partie importante du système racinaire du riz et jouent un rôle crucial dans le maintien du rendement en cas de sécheresse. Le nombre de racines coronaires affecte la biomasse de racines et détermine la capacité de la plante à extraire les ressources du sol. Un QTL de NRC, qNCR11, localisé sur le chromosome 11, avait été détecté dans une étude d’association précédente utilisant un panel de riz vietnamiens. Dans notre étude, son effet sur le NCR, léger, a été validé par cartographie de QTL en utilisant une population biparentale . Afin de déterminer les gènes sous-jacents à qNCR11 et régissant l'initiation et le développement des racines coronaires, une étude de séquençage du génome entier et une étude d'expression ont été réalisées. Deux gènes candidats, NCR2 (NBS-LRR) et NCR3 (OsbHLH014) ont été identifiés. NCR2 portait un SNP non synonyme dans son ORF, provoquant un codon stop prématuré corrélé avec un NCR élevé; NCR3 était moins exprimé dans les bases de la tige des plantes à haplotype NCR élevé que chez les plantes à haplotype NCR faible. Des mutations dans ces gènes ont été obtenues à l'aide du système CRISPR / Cas9 et le phénotypage des lignées obtenues est en cours. Le QTL qNCR11 à effet mineur pourrait être utile aux sélectionneurs pour produire des variétés de riz avec un NCR augmenté ou diminué pour les différents écosystèmes-cibles, afin de favoriser l'extraction de l'eau dans des conditions de sécheresse
Rice is one of the most important cereals worldwide. In Vietnam, rice is also known as a key agronomic product for exportation. However, drought stresses threaten rice production with an increasing frequency and for longer periods. Crown roots are a major component of rice root system and play a crucial role in maintaining yield under drought. The number of crown roots (NCR) impacts on root biomass and determines the ability of a plant to acquire soil resources. qNCR11, a QTL for NCR located on chromosome 11, was detected in a previous genome-wide association study using a Vietnamese rice panel. qNCR11 was validated to have a slight effect on NCR by QTL mapping using a biparental population in this study. To determine the genes underlying qNCR11 and governing crown root initiation and development, whole genome sequencing and expression study were performed. Two candidate genes, NCR2 (NBS-LRR) and NCR3 (OsbHLH014) were identified. NCR2 carried a non-synonymous SNP inside its ORF, causing a premature stop-codon that correlates with the high NCR trait; NCR3 was less expressed in stem bases of the high NCR haplotype plants relative to the low NCR haplotype plants. Mutations in these genes were obtained using the CRISPR/Cas9 system and the phenotyping of the obtained lines is on-going. The minor-effect qNCR11 could be useful for breeders to generate rice varieties with increased or decreased NCR for different target agro-systems, in order to enhance water extraction under drought stress

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Dantas, Stênio Andrey Guedes. « Estratégia de indução de déficit hídrico em soja e desenvolvimento de GWAS para germinação e vigor de sementes ». Universidade Federal de Viçosa, 2018. http://www.locus.ufv.br/handle/123456789/22007.

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Conselho Nacional de Desenvolvimento Científico e Tecnológico
A soja é a leguminosa de maior importância econômica do mundo, ocupando 6% de todas as terras aráveis do planeta. No Brasil, a soja é plantada em 55% de toda a área de cultivo. Devido sua grande área plantada, rotineiramente a soja está exposta a estresses, principalmente por déficit hídrico, que têm se tornado cada vez mais comum nos últimos anos. O objetivo do presente trabalho foi estabelecer uma metodologia viável e de baixo custo para avaliação de plantas de soja tolerantes ao estresse hídrico durante a fase de germinação e em plantas adultas em casa de vegetação. Posteriormente, com o auxílio de GWAS, explorar a associação entre SNPs e características de interesse relacionadas à germinação e dinâmica de reservas de sementes em diferentes condições de estresse, para seu potencial uso no melhoramento genético. Para isso foi realizado uma revisão sobre metodologias de aplicação de estresse em plantas em casa de vegetação, respondendo as perguntas: como, quando e quanto estresse aplicar nas plantas de soja? O qual indicou diferentes estratégias conforme o objetivo do estudo e disponibilidade de recursos financeiros. Em seguida foi definido como realizar o estresse hídrico em sementes, testando quatro diferentes níveis de estresse (0,0 Mpa, - 0,2 Mpa, -0,4 Mpa e -0,6 Mpa), verificando que o potencial osmótico de -0,2 Mpa é o mais adequado para se selecionar genótipos tolerantes a seca durante a germinação, por expor a máxima variabilidade genética entre genótipos. Com essas informações foram realizadas análises de germinação e vigor de sementes em 97 genótipos de soja, genotipados com marcadores moleculares SNPs. A partir desses resultados se confirmou que as características relacionadas à germinação e vigor de sementes são governados vários por locus em diferentes regiões do genoma, independentemente do ambiente. Quanto à dinâmica de reservas de sementes para a germinação, foi verificado que somente a variável eficiência de conversão de reservas apresentou SNPs associados, e que essa característica também é de natureza quantitativa. Tanto para a germinação, como para o vigor e dinâmica de reservas, há variabilidade genética a ser explorada, e essas características podem ser melhoradas. Conclui-se que existem metodologias viáveis e de baixo custo para seleção de genótipos tolerantes a seca utilizando plantas adultas e sementes, e, que há associação genômica entre SNPs e características relacionadas à germinação, vigor e dinâmica de reservas, com possibilidade de uso no melhoramento genético, para se produzir genótipos superiores.
Soybeans are the most economically important legume in the world, accounting for 6% of all arable land on the planet. In Brazil, soybeans are planted in 55% of the total area under cultivation. Because of its large area planted, soybeans are routinely exposed to stresses, especially water stresses, which have become increasingly common in recent years. The objective of the present work was to establish a feasible and low-cost methodology for the evaluation of plants tolerant to water stress during the germination phase and in adult plants under greenhouse conditions. And later with GWAS, we explore the association between SNPs and characteristics related to control of germination and seed reserve dynamics under different stress conditions for their potential use in genetic breeding. For that, a review was carried out on methodologies of stress application in greenhouse plants, answering the questions: how, when and how much stress apply in soybean plants? which indicated different strategies according to the objective of the study and availability of financial resources. It was also defined how to perform water stress in seeds during germination. Four different stress levels (0.0 Mpa, -0.2 Mpa, -0.4 Mpa and -0.6 Mpa) were used. The osmotic potential of - 0.2 Mpa was the most adequate to select drought-tolerant genotypes during germination, because it exposes the maximum genetic variability among genotypes. With this information, seed germination and vigor analyzes were performed in 97 soybean genotypes, using SNPs markers. These results confirmed that characteristics related to germination and seed vigor are governed by several loci, being a quantitative trait that appear in different regions of the genome, according to the environment, with or without stress. Concerning the dynamics of seed reserves for germination, it was verified that only the reserve conversion efficiency variable had associated SNPs and that this characteristic has also quantitative nature. Germination, vigor and reserve dynamics presented genetic variability to be explored, and these characteristics can be improved in breeding programs. It was concluded that there are feasible and low-cost methodologies for selection of drought tolerant genotypes using adult plants and seeds. And that there are several loci associated with control of the germination, vigor and dynamics of reserves, but with the possibility of use in breeding, to produce better cultivars.

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Grussu, Dominic. « Influence of lignin in barley straw on agronomic traits and biofuel applications ». Thesis, University of Dundee, 2016. https://discovery.dundee.ac.uk/en/studentTheses/3054a490-e2a1-4d53-8ee9-2053032c085f.

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In the world today there is a massive dependency on fossil fuels as they are currently used to provide around 80% of the world’s energy. This is hugely detrimental to the environment and is a major contributory factor in climate change. Biofuel is a renewable energy source that is already being used to lessen some of the fossil fuel dependency. 2nd generation biofuels, by using non-food parts of plants, circumvent the food vs fuel argument, and by using farming waste or surplus can also avoid changing land use problems. Additionally liquid biofuels can use existing infrastructure for storage and delivery, and also fit into current lifestyles. Cost-effective 2nd generation biofuel production is directly affected by the presence of the polymer lignin in plant biomass, as it has been shown to impede enzymatic sugar release (saccharification) that is used for biofuel production. The work undertaken in this project developed a high-throughput methodology for the assessment of straw lignin content and composition across a large population of elite varieties in the economically important cereal crop, barley. Saccharification yield was also measured across the same population along with a number of other agronomically important traits, such as thousand-grain weight, biomass, mechanical stem properties and height. The data provided by these measurements allowed correlations between traits to be identified and their strength gauged. Genome wide association studies (GWAS) were also carried out and identified influential regions of the genome for each trait. The results revealed varying levels of association between measured traits and lignin content and monomeric constituents. Importantly a negative connection was shown between lignin content and saccharification yield, with lignin content being responsible for approximately 1/5th of the variation seen. Interestingly there was no correlation between lignin content and mechanical stem properties, an important factor in the agronomically important trait, lodging. GWAS results revealed a number of genomic regions that were influential across several traits indicating regions that would be difficult to separate through breeding due to their close proximities. However, unique QTL were identified for saccharification yield and lignin content providing candidates for breeding or genetic manipulation to improve the crop for biofuel production.

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Sun, Benjamin Boyang. « Genetic determinants of the human plasma proteome and their application in biology and disease ». Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/269287.

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Proteins are the primary functional units of biology and the direct targets of most drugs, yet there is limited knowledge of the genetic factors determining inter-individual variation in protein levels (protein quantitative trait loci (pQTLs)). Limitations in high-throughput proteomic measurement technology have meant well-powered genome-wide association studies for large number of proteins so far have lagged behind many of the other "omic" studies such as transcriptomics and metabolomics. This is made more challenging by the complexity of human plasma, characterised by high dynamic range spanning several magnitudes of concentrations and a large number of low abundance proteins. By using an expanded high-throughput multiplex aptamer-based proteomic assay with more than twice the proteome coverage of previous studies, I am able to greatly expand on existing knowledge on genetic determinants of human plasma proteins through testing 10.6 million DNA variants against levels of 2,994 proteins in 3,301 individuals. I identify 1,927 genetic associations with 1,478 proteins, replicating many previous associations as well as gaining novel insights into the genetic architecture of the human plasma proteome. I use several approaches to highlight the application of pQTLs to biology and disease. I show several examples linking distant pQTLs to biologically plausible genes and demonstrate the mediation of distant pQTL by local protein levels, highlighting the role of protein-protein interactions. In addition, I find epistatic effects of genetically determined phenotypes (blood group and secretor status) on protein levels. Through linking previous disease associations, I show that disease associated variants are enriched for pQTLs and I provide insights into possible mechanisms underpinning some of the disease loci. Finally, I identify causal roles for protein biomarkers in disease through multivariable Mendelian randomisation (MR) analysis, leveraging on the simultaneous measurement of multiple functionally related proteins in a locus to account for potential pleiotropic effects. Whereas MR studies of plasma proteins have been constrained by availability of few suitable genetic instruments, the data generated here remedy this bottleneck by furnishing an extensive toolkit. Overall, the work within this thesis foreshadows major advances in post-genomic science through increasing application of novel bioassay technologies to major population biobanks.

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Souza, Manuela Barbosa Rodrigues de. « Análise genética de novos potenciais polimorfismos de risco em Transtornos do Humor e utilização de abordagens computacionais em busca de genes candidatos a Doença de Alzheimer ». Universidade Federal de Pernambuco, 2013. https://repositorio.ufpe.br/handle/123456789/13412.

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FACEPE
Doenças neuropsiquiátricas afetam cerca de 450 milhões de pessoas em todo mundo e dentre estas patologias os Transtornos do Humor (TH) e Doença de Alzheimer (DA) são as mais comuns. Em relação à sua etiologia as doenças neuropsiquiátricas são resultados de variações em um grupo de genes e de fatores ambientais. Pesquisas recentes vêm mostrando associação positiva entre variações genéticas em genes envolvidos nos sistemas de neurotransmissores com o desenvolvimento de doenças neuropsiquiátricas. Por isso, os estudos sobre polimorfismos genéticos, nas doenças psiquiátricas são de grande importância para a compreensão dos mecanismos moleculares envolvidos e podem auxiliar no diagnóstico das mesmas. Neste cenário, mutações encontradas no DNA têm sido amplamente estudadas, a fim de elucidar aspectos genéticos relacionados às neuropatologias. Os polimorfismos do tipo SNPs (Polimorfismo de Base Única) e INDELs (inserções e deleções de fragmentos de DNA) têm se destacado devido as fortes associações com os TH e DA. Diversos métodos de biologia molecular têm sido utilizados para detectar estes tipos de polimorfismos, os experimentos moleculares geram grande quantidade de dados a serem analisados, fazendo-se necessário a utilização de ferramentas computacionais para se extrair informações a partir desses dados gerados. Assim, o objetivo desse estudo foi o uso de bioinformática e de genotipagem em larga escala na busca de novos polimorfismos genético em TH e aplicação de ferramentas computacionais em banco de dados de GWAS referente à DA. Para obter os resultados referentes à TH optamos por utilizar o software CLCbio Workbench®, sequenciamento automatizado mega Bace 1000 e experimentos preliminares da técnica de DNA pooling. Já para a DA, utilizamos o teste de associação e método de regressão linear do software PLINK e o pacote genetics da linguagem de programação R, para correlacionar os níveis da proteína βamiloide no plasma e líquido cefalorraquidiano e um total de 598.821 SNPs, ambos os dados oriundos do banco de dados ADNI (Alzheimer’s Disease Neuroimaging Initiative). Após uma sequência de passos in silico identificamos variações anteriormente descritas e novos polimorfismos candidatos à fisiopatologia dos TH, na fase de validação dessas variações, por meio de sequenciamento, falsos positivos foram frequentemente identificados, sendo descartados após a verificação na cadeia complementar. Apenas o SNP rs14068, localizado no exon 2 do gene GABRA5 foi validado em amostras de pacientes com TH. No estudo referente à DA, 5 SNPs nas regiões dos genes TOMM40, PAMR1, TRIM9 e CCDC112 e 3 SNPs em regiões de intron atingiram associação significativa, levantando a possibilidade de estejam relacionados a fisiopatologia da DA.

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Keller, Margaux Finn. « HERITABILITY AND SEX-EFFECT ANALYSES OF NEURODEGENERATIVE DISEASE ». Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/288134.

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Anthropology
Ph.D.
This work analyzes the genetic basis of three neurodegenerative diseases using several thousands of individuals of European descent to determine a range of phenotypic heritability outside of what has been identified by prior methods. By measuring additive genetic variance genome-wide, measures of its contribution to the phenotypic variance of these diseases were substantially increased, in some instances by a factor of 10 or more. Additionally, regional-mapping methods identified segments of the genome exhibiting significantly high heritability estimates associated with one of the neurodegenerative diseases, Amyotrophic lateral sclerosis. This resulted in the detection of novel candidate regions and provided conclusive evidence for the polygenic architecture of this disease. Lastly, novel risk variants associated with Parkinson's disease were identified on the X chromosome, a previously ignored genomic region. Overall, the employment of new analytic methods produced robust and novel results, adding substantial information to the neurodegenerative disease literature and connecting the anthropological perspective with growing informatics-based methods.
Temple University--Theses

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Akagi, Yumiko. « MMP20 and ARMS2/HTRA1 are Associated with Neovascular Lesion Size in Age-Related Macular Degeneration ». Kyoto University, 2016. http://hdl.handle.net/2433/204581.

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Redmond, Seth. « Population structure and genome-wide association in the malaria vectors Anopheles gambiae and Anopheles coluzzii ». Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066085/document.

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Malgré le succès des insecticides pour le contrôle du paludisme, la transmission continue dans la plupart des pays d’Afrique sub-saharienne. La recherche pour de nouveaux moyens de contrôle (plus spécialement la modification génétique des populations vecteurs), ou l'utilisation plus efficace des contrôles actuels, vont nécessiter une recherche sur les structures de populations de moustiques et les processus d’immunisation qui importent pour la transmission du Plasmodium chez les moustiques sauvages. Par ailleurs, l’utilisation des techniques d’association génomique ‘GWAS’ est basée sur un réelle compréhension des structures des populations.Ma thèse inclura une description detaillée du système immunitaire du moustique, basée sur la recherche actuelle et des comparaisons génomiques; ainsi que des descriptions des principales voies immunitaires, et des gênes potentiels mal-caracterisés qui peuvent être trouvés dans une étude GWAS. Ainsi qu’une description des connaissances actuelles des structures des populations, dont la speciation du gambiae / coluzzii, et les effets des grandes variations structurelles.Je présenterai le développement d’un nouveau moyen d'identification des variations structurelles ; utilisant les techniques d’ “apprentissage automatique” permettant d'identifier les karyotypes directement à partir des séquences haut-débit, menant à des résultats d’une précision sans précédent.Je présenterai également la première vraie cartographie génomique du ‘tout-génome’ du moustique. Les colonies sont fondées par des moustiques sauvages; les fondateurs sont controlées par strates, incluant également des sous-espèces et variations structurelles majeures. Avec ces colonies une méthode innovant de cartographie est utilisée: dans un premier temps, une identification des grandes régions au sein des groupes phenotypées par la perte de hétérogénéité; puis dans un second temps, le génotypage individuel ‘Sequenom’ sera utilisé pour une cartographie exacte. Cette méthode est utilisée pour l’identification d’une région avec un effet phenotypique sur la prévalence des infections dans la nature.Enfin, je suggèrerai comment ces techniques peuvent être importantes à l’avenir pour l’application du contrôle génomique dans la nature
Despite successes in the use of insecticides in the control of malaria, malaria transmission continues in much of sub-saharan Africa. The search for novel methods of control (in particular genetic modification of vector populations), or of superior implementation of the currently available methods will require both greater knowledge of the population structure of the mosquito, and of the immune processes that are important in the wild. It is important to note that the mapping of novel immune genes, via genome wide association studies (GWAS) is predicated on a firm understanding of the population structure.My thesis will include a detailed description of the mosquito innate immune system based on current research and comparative genomics; this will illustrate the major pathways that might be employed in the anti-malarial response, and some potential uncharacterised genes that might be implicated in any GWAS study. It will also include a summary of what is known about the mosquito’s population structure, in particular the gambiae / coluzzii speciation event and the implication of chromosomal inversions in the speciation process.I will present the development of a novel approach to the identification of chromosomal inversions; using machine-learning techniques in order to call inversion karyotypes directly from sequence, leading to calls of unprecedented accuracy.I will also present the first truly genome-wide association study to have been performed in the mosquito. Strata-controlled populations of mosquitoes were derived from the wild, including restriction on the basis of subspecies and chromosomal inversion. A two-stage mapping design was then devised in which loss-of-heterozygosity is used to identify broad regions in phenotype pools, before fine-resolution mapping by Sequenom genotyping in individuals. This was used to identify a novel locus with a phenotypic effect on infection prevalence.Finally I will describe how these techniques and findings could be important in the future application of genetic control in the wild

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Vila, Nova Meryl. « Détection et identification des mutations et des voies métaboliques associées à l'adaptation à l'hôte dans le pangénome de Salmonella ». Thesis, Paris Est, 2019. http://www.theses.fr/2019PESC0057.

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L’évolution du genre Salmonella a conduit à l’apparition d’espèces et de sous-lignées adaptées à différents hôtes jouant un rôle majeur dans la compréhension des mécanismes biologiques de l’adaptation bactérienne. En raison du lourd fardeau sanitaire et socio-économique que représente les salmonelloses, le genre Salmonella est donc contrôlé par des laboratoires hospitaliers et de sécurité alimentaire. Nous avons donc développé deux approches analytiques permettant de détecter et identifier les mutations associées à l’adaptation aux hôtes de Salmonella sans a priori sur les éléments génomiques explicatifs, en identifiant les variants du coregénome fixés aux nœuds de reconstruction phylogénomique ou en identifiant les mutations pangénomiques associées à ces hôtes indépendamment des sous-lignées bactériennes considérées (c.à.d. GWAS). Ces deux approches ont été couplées à des études d’enrichissement des voies métaboliques correspondantes (c.à.d. GOAE). En raison de pressions de sélection de l’environnement naturel des animaux, de leurs régimes alimentaires, ou des supplémentations administrées par l’Homme, nos résultats montrent que l’adaptation aux hôtes de Salmonella a pu avoir lieu au sein ou entre les sous-lignées. Ces résultats renforcent la nécessité d’intégrer des sous-lignées clonales et panmictiques afin d’identifier les mutations causales associées à l’adaptation aux hôtes. Dans un contexte de contrôle des TIAC tout au long de la chaîne alimentaire, l’identification de ces mutations récentes permettrait d’améliorer les modèles d’attribution des sources animales de Salmonella et de confirmer des résultats d’investigations de TIAC à l’échelle génomique
The evolution of the genus Salmonella has led to the appearance of species and sub-lineages adapted to different hosts that have a major role in understanding the biological mechanisms of bacterial adaptation. Due to the heavy health and socio-economic burden of salmonellosis, the genus Salmonella is therefore controlled by hospital and food safety laboratories. We have therefore developed two analytical approaches to detect and identify mutations associated with Salmonella host adaptation without a priori on the explanatory genomic elements, identifying the fixed coregenome variants at each node of the phylogenomic inference or identifying pangenomic mutations associated with host adaptation independently of considered bacterial sublineages (GWAS). These two approaches have been linked to the enrichment of corresponding metabolic pathways (GOEA). Because of selection pressures from natural environment of animals, their feeding diets or supplements administered by humans, our results show that the host adaptation of Salmonella may have occurred inside sublineages or between them. These results reinforce the necessity to integrate clonal and panmictic sublineages in order to identify causal mutations associated with host adaptation. In a context of FBO control throughout the food chain, the identification of its recent mutations would improve the attribution models of Salmonella animals’sources and confirm the results of FBO investigations at genomic scale

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Bussiman, Fernando de Oliveira. « Estudo de associação genômica ampla para as diferenças genéticas entre as marchas batida e picada em equinos Mangalarga Marchador ». Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/74/74131/tde-14032019-110207/.

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O gene DMRT3 tem sido descrito como o principal gene a atuar na determinação da marcha em diversas raças equinas. O alelo A do SNP 23:g.22999655C>A do DMRT3 foi apontado como responsável por essa característica. Na raça brasileira Mangalarga Marchador, a qual apresenta dois padrões de marcha com características bem definidas, os genótipos AA e CA vem sendo associados à marcha picada e o genótipo CC à marcha batida. O objetivo geral do presente prospectar regiões genômicas associadas às marchas batida e picada em equinos Mangalarga Marchador. Foram utilizados 1.230 dados fenotípicos sobre o tipo de andamento (marcha batida N = 1.006; marcha picada N = 227) e, considerando a totalidade da genealogia conhecida para cada animal, 3172 animais no pedigree. Primeiramente foram testadas estratégias de modelagem para esta característica a fim de determinar os efeitos a serem considerados no modelo, bem como a melhor forma de inclusão (efeito fixo ou aleatório). Posteriormente, foi estudada a relação entre as frequências alélicas e genotípicas do gene DMRT3 com os padrões de parentesco e endogamia de acordo com cada tipo de marcha. Um estudo de associação genômica ampla em passo único (considerando informações de animais genotipados e não-genotipados simultaneamente) foi conduzido para verificar regiões genômicas, polimorfismos de nucleotídeo único e genes relacionados com a determinação do tipo de marcha em cavalos Mangalarga Marchador. Vinte e dois polimorfismos de nucleotídeo único localizados nos cromossomos 4(N = 5), 6 (2), 16 (1), 23 (11), 26 (1) e 29 (2), foram responsáveis por 42,43% da variância genética aditiva. Foram associados ao tipo de marcha 69 genes, mas cerca de 39 não estavam anotados em equinos. Foi conduzido um blast a fim de recuperar a função mais provável destes genes. Foram encontradas oito vias metabólicas associadas ao tipo de marcha. Os principais genes envolvidos estavam relacionados à percepção de estímulos externos, metabolismo energético-oxidativo, sistema imune e aprendizado e ritmo da locomoção. Não foi possível identificar a(s) variante(s) causal(ais) do tipo de marcha, contudo este estudo foi o primeiro e verificar que a possível determinação genética do tipo de marcha em cavalos Mangalarga Marchador passa por diferenças em níveis metabólicos que garantem a adaptação dos animais ao tipo de andamento.
The DMRT3 gene has been described as the main gene to act in gait determination in several equine breeds. The allele A of the SNP 23:g.22999655C>A of DMRT3 gene was identified as responsible for this trait. In the Brazilian Mangalarga Marchador breed, which presents two gait patterns with characteristics well defined, the AA and CA genotypes have been associated with marcha picada gait and CC genotype with marcha batida gait. The general aim of this study was to prospect genomic regions associated with marcha batida and marcha picada gaits in Mangalarga Marchador equines. 1,230 phenotypic data were used on the type of gait (marcha batida N = 1.006; marcha picada N = 227) and, considering the totality of known genealogy for each animal, 3,172 animals in the pedigree. Firstly, modelling strategies were tested for this trait in order to determine the effects to be considered in the model, as well as the best form of inclusion (fixed or random effect). Based on the best modelling strategy to be used, the relationship between the allelic and genotypic frequencies of the DMRT3 gene with kinship and inbreeding patterns was studied according to each type of gait. A single-step wide genomic association study (considering information from both genotyped and non-genotyped animals simultaneously) was conducted to verify genomic regions, single nucleotide polymorphisms and genes related to determination of gait type in Mangalarga Marchador horses. Twenty two single nucleotide polymorphisms located on chromosomes 4 (N = 5), 6 (2), 16 (1), 23 (11), 26 (1) and 29 (2) were responsible for 42.43% of the additive genetic variance. 69 genes were associated with gait type, but about 39 were not annotated in horses. A blast was conducted in order to recover the most likely function of these genes. Eight metabolic pathways were found associated with gait type and the main genes involved were related to the perception of external stimuli, energy-oxidative metabolism, immune system and learning and rhythm of locomotion. It was not possible to identify the causal variant(s) of the type of gait; however, this study was the first and to verify that the possible genetic determination of gait type in Mangalarga Marchador horses goes through differences in the metabolic levels that guarantee the adaptation of the animals to the type of gait.

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Santana, Miguel Henrique de Almeida. « Estudo genético e genômico da ingestão e eficiência alimentar em bovinos da raça Nelore (Bos indicus) ». Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/74/74131/tde-11022014-104223/.

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O objetivo dessa pesquisa foi avaliar os parâmetros genéticos e correlações das medidas de ingestão e eficiência alimentar com desempenho e características de carcaça, além de realizar o estudo de associação de amplo genoma (GWAS) para ingestão de matéria seca (IMS), consumo alimentar residual (CAR) e ganho de peso (GMD) em bovinos da raça Nelore (Bos indicus). Foram utilizados dados de 1.058 animais com fenótipo para IMS, taxa de conversão alimentar (CA), CAR, ganho de peso residual (GPR), consumo e ganho residuais (CGR), ganho de peso diário (GMD) e características de carcaça. Os parâmetros genéticos da IMS, CA, CAR, GPR e CGR e suas as correlações com GMD e características de carcaça foram estimados utilizando abordagem bayesiana. Quatro marcadores do tipo SNP (Single Nucleotide Polymorphism), localizados em genes relacionados ao controle de apetite (NPY e PDE3B) e transporte iônico (TRPM3 e ITPR1), foram associados com o desempenho, ingestão e medidas de eficiência alimentar. Adicionalmente, os animais foram genotipados em dois chips distintos (Illumina Bovine HD e Illumina BovineSNP50) e as informações genotípicas foram combinadas por meio de estudo de imputação. As centenas de milhares de SNPs foram utilizadas para o GWAS da IMS, CAR e GMD pelo teste de associação GRAMMAR-Gamma. A herdabilidade da IMS, CAR e CGR foi de 0,40, 0,38 e 0,54, respectivamente. Não foram encontradas associações nos SNPs localizados nos genes TRPM3, NPY e ITPR1, no entanto, o SNP no gene PDE3B foi associados significativamente (P≤0,05) com IMS, CAR e CGR. Os SNPs mais associados com a IMS e CAR, no GWAS, estão localizados nos cromossomos 4, 8, 14 e 21 em regiões genômicas relacionadas com transporte iônico e regulação da ingestão. O GWAS para o GMD apontou os cromossomos 3, 6 e 10 como os que continham os marcadores com maior associação. A ingestão e eficiência alimentar são passíveis de seleção genética, principalmente o CGR. O gene PDE3B deve ser melhor estudado pois, aparenta ter relação com esses fenótipos. Por fim, esse trabalho apontou regiões genômicas, por meio de associação de amplo genoma, relacionadas com a IMS, CAR e GMD, acredita-se ser o primeiro estudo desse tipo para esses fenótipos em animais da raça Nelore.
The aim of this study was to evaluate the genetic parameters and correlations of intake and feed efficiency with performance and carcass traits, and perform the genome-wide association study (GWAS) for dry matter intake (DMI), residual feed intake (RFI) and average daily gain (ADG) in Nelore cattle (Bos indicus). Data from 1,058 animals phenotyped for DMI, feed conversion ratio (FCR), RFI, residual body weight gain (RG), residual intake and body weight gain (RIG), average daily gain (ADG) and carcass traits were used. Genetic parameters of DMI, FCR, RFI, RG and RIG and their correlations with ADG and carcass traits were estimated using Bayesian approach. Four SNPs (Single Nucleotide Polymorphism), located in genes related to appetite control (NPY and PDE3B) and ion transport (TRPM3 and ITPR1), were associated with performance, intake and feed efficiency traits. Additionally, the animals were genotyped in two different chips (Illumina Bovine HD and Illumina BovineSNP50) and genotypic information were combined by imputation. The hundreds of thousands of SNPs were used for GWAS of DMI, RFI and ADG by GRAMMAR-Gamma association test. The heritability of DMI, RFI and RIG was 0.40, 0.38 and 0.54, respectively. No associations were found in SNPs in genes TRPM3, NPY and ITPR1, however, the SNP in PDE3B gene was significantly associated (P≤0.05) with DMI, RFI and RIG. The SNPs most associated with DMI and RFI, in GWAS, are located on chromosomes 4, 8, 14 and 21 in genomic regions associated with ion transport and appetite regulation. The GWAS pointed chromosomes 3, 6 and 10 as those containing more associated markers for ADG. Feed intake and feed efficiency are amenable to genetic selection, especially the RIG. The PDE3B gene should be further studied thus appears to be related to these phenotypes. Finally, this work shows genomic regions by genome-wide association, related to DMI, RFI and ADG, believed to be the first study of its kind for these phenotypes in Nellore cattle.

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ARAÚJO, Gilderlanio Santana de. « Uso de random forests e redes biológicas na associação de poliformismos à doença de Alzheimer ». Universidade Federal de Pernambuco, 2013. https://repositorio.ufpe.br/handle/123456789/18012.

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FACEPE
O desenvolvimento de técnicas de genotipagem de baixo custo (SNP arrays) e as anotações de milhares de polimorfismos de nucleotídeo único (SNPs) em bancos de dados públicos têm originado um crescente número de estudos de associação em escala genômica (do inglês, Genome-Wide Associations Studies - GWAS). Nesses estudos, um enorme número de SNPs (centenas de milhares) são avaliados com métodos estatísticos univariados de forma a encontrar SNPs associados a um determinado fenótipo. Testes univariados são incapazes de capturar relações de alta ordem entre os SNPs, algo comum em doenças genéticas complexas e são afetados pela alta correlação entre SNPs na mesma região genômica. Métodos de aprendizado de máquina, como o Random Forest (RF), têm sido aplicados em dados de GWAS para realizar a previsão de riscos de doenças e capturar os SNPs associados às mesmas. Apesar de RF ser um método com reconhecido desempenho em dados de alta dimensionalidade e na captura de relações não-lineares, o uso de todos os SNPs presentes em um estudo GWAS é computacionalmente inviável. Neste estudo propomos o uso de redes biológicas para a seleção inicial de SNPs candidatos a serem usados pela RF. A partir de um conjunto inicial de genes já relacionados à doença na literatura, usamos ferramentas de redes de interação gene-gene, para encontrar novos genes que possam estar associados a doença. Logo, é possível extrair um número reduzido de SNPs tornando a aplicação do método RF viável. Os experimentos realizados nesse estudo concentram-se em investigar quais polimorfismos podem influenciar na suscetibilidade à doença de Alzheimer (DA) e ao comprometimento cognitivo leve (MCI). O resultado final das análises é a delineação de uma metodologia para o uso de RF, para a análise de dados de GWAS, assim como a caracterização de potenciais fatores de riscos da DA.
The development of low cost genotyping techniques (SNP arrays) and annotations of thousands of single nucleotide polymorphisms (SNPs) in public databases has led to an increasing number of Genome-Wide Associations Studies (GWAS). In these studies, a large number of SNPs (hundreds of thousands) are evaluated with univariate statistical methods in order to find SNPs associated with a particular phenotype. Univariate tests are unable to capture high-order relationships among SNPs, which are common in complex genetic diseases, and are affected by the high correlation between SNPs at the same genomic region. Machine learning methods, such as the Random Forest (RF), have been applied to GWAS data to perform the prediction of the risk of diseases and capture a set of SNPs associated with them. Although, RF is a method with recognized performance in high dimensional data and capacity to capture non-linear relationships, the use of all SNPs present in GWAS data is computationally intractable. In this study we propose the use of biological networks for the initial selection of candidate SNPs to be used by RF. From an initial set of genes already related to a disease based on the literature, we use tools for construct gene-gene interaction networks, to find novel genes that might be associated with disease. Therefore, it is possible to extract a small number of SNPs making the method RF feasible. The experiments conducted in this study focus on investigating which polymorphisms may influence the susceptibility of Alzheimer’s disease (AD) and mild cognitive impairment (MCI). This work presents a delineation of a methodology on using RF for analysis of GWAS data, and characterization of potential risk factors for AD.

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Oda, Letícia Tiemi Egami. « Análises da competência vetorial e associação global do genoma em mosquitos Aedes aegypti da cidade de Botucatu infectados com Dengue vírus ». Botucatu, 2018. http://hdl.handle.net/11449/158306.

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Orientador: Jayme Augusto de Souza Neto
Resumo: Dengue é a arbovirose de maior crescimento nos últimos anos, repercutindo em impactos sociais e econômicos devido às altas taxas de morbidade e mortalidade desencadeadas pela infecção. O vírus dengue tem como principal vetor o mosquito Aedes aegypti. Por apresentar hábito hematofágico, antropofílico, de rápido desenvolvimento, é um excelente transmissor do vírus. Medidas de controle estão restritas à eliminação do mosquito vetor, uma vez que um tratamento específico ou uma vacina não estão disponíveis à população. E uma característica que determina a disseminação de doenças é a alta competência vetorial de seus mosquitos vetores, a qual tem sido associada à fatores genéticos do mosquito e ambientais. Sabe-se que a variabilidade genética dos mosquitos é um dos fatores que pode determinar o sucesso da relação mosquito-patógeno específico. Com isso, no presente trabalho foram estudadas as competências vetoriais de mosquitos Aedes aegypti da cidade de Botucatu infectados com DENV-2 e DENV-4 a fim de entender melhor a competência vetorial desses mosquitos. Além disso, foram feitas tentativas para selecionar linhagens resistentes e susceptíveis desses mosquitos infectados com ambos os sorotipos. Os mosquitos infectados com DENV-2 foram genotipados pela metodologia de SNP chip e posteriormente foram realizadas análises de estudo global do genoma (GWAS) afim de encontrar fatores genéticos relacionados com os diferentes fenótipos susceptív... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Dengue is the arboviruses with the greatest growth in recent years, with social and economic impacts due to the high morbidity and mortality rates triggered by the infection. Dengue has as main vector the mosquito Aedes aegypti. Because of the haematophagic habit, been antropophilic, fast development, Aedes aegypti mosquitoes are excellent transmitter of the dengue virus. Control measures are restricted to vector mosquito elimination since a specific treatment or vaccine is not available to the population. The characteristic that determinates the diseases dissemination is the high vector competence of the mosquitoes, which has been associated with mosquito genetic and environmental factors. It is known that the genetic variability of mosquitoes is one of the factors that can determine the success of the specific mosquito-pathogen relationship. In the present study, the vector competence of Aedes aegypti mosquitoes from Botucatu city infected with DENV-2 and DENV-4 were compared in order to understand the vector competence of these specific mosquitoes. In addition, we tried to do resistant and susceptible strains selections of these mosquitoes infected with both serotypes. And mosquitoes infected with DENV-2 were genotyped by the SNP chip methodology and later analyzes were carried out to study the genome (GWAS) in order to find genetic factors related to the different susceptible and resistant phenotypes of them. As results we observed different vector competence of the same ... (Complete abstract click electronic access below)
Doutor

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Oda, Leticia Tiemi Egami. « Análises da competência vetorial e associação global do genoma em mosquitos Aedes aegypti da cidade de Botucatu infectados com Dengue vírus ». Universidade Estadual Paulista (UNESP), 2018. http://hdl.handle.net/11449/158306.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Dengue é a arbovirose de maior crescimento nos últimos anos, repercutindo em impactos sociais e econômicos devido às altas taxas de morbidade e mortalidade desencadeadas pela infecção. O vírus dengue tem como principal vetor o mosquito Aedes aegypti. Por apresentar hábito hematofágico, antropofílico, de rápido desenvolvimento, é um excelente transmissor do vírus. Medidas de controle estão restritas à eliminação do mosquito vetor, uma vez que um tratamento específico ou uma vacina não estão disponíveis à população. E uma característica que determina a disseminação de doenças é a alta competência vetorial de seus mosquitos vetores, a qual tem sido associada à fatores genéticos do mosquito e ambientais. Sabe-se que a variabilidade genética dos mosquitos é um dos fatores que pode determinar o sucesso da relação mosquito-patógeno específico. Com isso, no presente trabalho foram estudadas as competências vetoriais de mosquitos Aedes aegypti da cidade de Botucatu infectados com DENV-2 e DENV-4 a fim de entender melhor a competência vetorial desses mosquitos. Além disso, foram feitas tentativas para selecionar linhagens resistentes e susceptíveis desses mosquitos infectados com ambos os sorotipos. Os mosquitos infectados com DENV-2 foram genotipados pela metodologia de SNP chip e posteriormente foram realizadas análises de estudo global do genoma (GWAS) afim de encontrar fatores genéticos relacionados com os diferentes fenótipos susceptível e resistente dos mosquitos. Como resultados observou-se diferentes competências vetoriais dos mesmos mosquitos infectados com diferentes sorotipos. Os mosquitos infectados com DENV-2 foram aproximadamente 70% susceptíveis, e mosquitos infectados com DENV-4 aproximadamente 70% foram resistentes, possuindo assim competências vetoriais opostas. Já no estudo da seleção dos fenótipos foi possível uma seleção de 80% até a geração F3 de mosquitos infectados com DENV-2, apesar do número baixo de indivíduos nas seleções. Os mosquitos infectados com DENV-4 não obtiveram uma taxa de seleção muito elevada, visto que as seleções foram feitas só até a geração F-2. Os resultados das análises de GWAS mostraram possíveis associações dos SNPs com os fenótipos estudados, apesar de não serem estatisticamente significantes para a correção de Bonferroni. Com isso, concluímos que a diferença vetorial é bastante dependente do sorotipo viral; para as análises de seleção e formação de linhagem é necessário um maior número de indivíduos nas primeiras infecções; e no estudo GWAS apesar da associação não ter sido significativa, devido ao baixo número de indivíduos, e dos parâmetros de correção estatística não serem ideais para indivíduos de uma única população, acredita-se que as associação encontradas de alguns SNPs com os fenótipos estudados sejam verdadeiras.
Dengue is the arboviruses with the greatest growth in recent years, with social and economic impacts due to the high morbidity and mortality rates triggered by the infection. Dengue has as main vector the mosquito Aedes aegypti. Because of the haematophagic habit, been antropophilic, fast development, Aedes aegypti mosquitoes are excellent transmitter of the dengue virus. Control measures are restricted to vector mosquito elimination since a specific treatment or vaccine is not available to the population. The characteristic that determinates the diseases dissemination is the high vector competence of the mosquitoes, which has been associated with mosquito genetic and environmental factors. It is known that the genetic variability of mosquitoes is one of the factors that can determine the success of the specific mosquito-pathogen relationship. In the present study, the vector competence of Aedes aegypti mosquitoes from Botucatu city infected with DENV-2 and DENV-4 were compared in order to understand the vector competence of these specific mosquitoes. In addition, we tried to do resistant and susceptible strains selections of these mosquitoes infected with both serotypes. And mosquitoes infected with DENV-2 were genotyped by the SNP chip methodology and later analyzes were carried out to study the genome (GWAS) in order to find genetic factors related to the different susceptible and resistant phenotypes of them. As results we observed different vector competence of the same mosquitoes infected with different serotypes. Mosquitoes infected with DENV-2 were approximately 70% susceptible, and mosquitoes infected with DENV-4 were approximately 70% resistant, thus the opposing vector competence. In the selection study it was possible to select 80% up to the F3 generation of mosquitoes infected with DENV-2, despite the low number of individuals in the selections. Mosquitoes infected with DENV-4 did not obtain a very high selection rate, since the selections were made only up to the F-2 generation. The results of the GWAS analysis showed possible associations of the SNPs with the studied phenotypes, although they were not statistically significant for the Bonferroni correction. With this, we conclude that the vector competence difference is quite dependent on the viral serotype; for the analysis of selection and formation of lineage is necessary a greater number of individuals in the first infections; and in the GWAS study, although the association was not significant because of the low number of individuals, and the statistical correction parameters are not ideal for individuals from the same population, it is believed that the association of some SNPs with the studied phenotypes is true.

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Huang, Wenhui. « Towards constructing disease relationship networks using genome-wide association studies ». Thesis, Virginia Tech, 2009. http://hdl.handle.net/10919/46326.

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Background: Genome-wide association studies (GWAS) prove to be a powerful approach to identify the genetic basis of various human[1] diseases. Here we take advantage of existing GWAS data and attempt to build a framework to understand the complex relationships among diseases. Specifically, we examined 49 diseases from all available GWAS with a cascade approach by exploiting network analysis to study the single nucleotide polymorphisms (SNP) effect on the similarity between different diseases. Proteins within perturbation subnetwork are considered to be connection points between the disease similarity networks. Results: shared disease subnetwork proteins are consistent, accurate and sensitive to measure genetic similarity between diseases. Clustering result shows the evidence of phenome similarity. Conclusion: our results prove the usefulness of genetic profiles for evaluating disease similarity and constructing disease relationship networks.
Master of Science

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Timmer, Sander Willem. « Understanding the epigenome using system genetics ». Thesis, University of Cambridge, 2015. https://www.repository.cam.ac.uk/handle/1810/246693.

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Genetics has been successful in associating DNA sequence variants to both dichotomous and continuous traits in a variety of organisms, from plant and farm animal studies to human disease. With the advent of high-throughput genotyping, there has been an almost routine gen- eration of genome-wide association studies (GWAS) between human disease traits and genomic regions. Despite this success, a particular frustration is that the majority of associated loci are in non-coding regions of the genome and thus interpretation is hard. To improve characterisation of non-coding regions, molecular as- says can be used as a phenotype, and subsequently be used to explain how genetics alter molecular mechanisms. In this thesis, the inter- play of three molecular assays that are involved in regulating gene expression is studied. On 60 individuals, several assays are performed: FAIRE-chip, CTCF- seq, RNA-seq and DNA-seq. In the first part, the discovery and characteristics of FAIRE-QTLs is presented. The identified FAIRE-QTLs show strong overlap with other molecular QTLs, histone modifications, and transcription factors. The second part consists of the integration of genome-wide molecu- lar assays in a human population to reconstruct the human epigenome. Each of the molecular assays is associated with each of the other assays to discover phenotype-to-phenotype correlations. Furthermore, QTL data are used to dissect the causality for these phenotype-to-phenotype correlations in a system genetic manner. The third part presents a comprehensive view of CTCF binding on the X chromosome, and its implications for X-chromosome inactivation. A novel X chromosome-wide CTCF effect is observed. Using the gender of each of the cell lines, observations are made about which CTCF sites are dosage-compensated, active on both chromosomes, or are only bound in females.

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Antoine, Darlène. « Functional Regulation at the 9p21.3 Genetic Risk Locus in Coronary Artery Disease (CAD) ». Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/33148.

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The first genetic CAD risk locus to be identified by genome-wide association studies, single nucleotide polymorphisms (SNPs) at 9p21.3 predispose to increased risk of CAD. By bioinformatics scan analysis of the 9p21.3 locus; we interrogated the 59 linked SNPs over the 53,202bp to identify putative transcription factor-binding consensus sequences. We hypothesize that some genetic polymorphisms at the 9p21.3 locus are functional and will disrupt specific regulatory sequences within enhancers. Here, I investigated how polymorphisms affect TEAD-dependent regulation at the 9p21.3 locus, and also how polymorphisms affect GATA factor-dependent regulation at the 9p21.3 locus, using cultured HEK293 and primary human aortic smooth muscle cells (HAoSMCs) to transfect the pGL3-promoter plasmid constructs containing the reference or risk variant sequences (rs10611656, rs4977757, rs10757269, rs9632885). We showed by luciferase reporter assay that the risk allele of the SNPs disrupt activation by various TEAD transcription factors. We also performed electrophoretic mobility shift assay (EMSA) to test for allele-specific transcription factor binding that affect the family of TEAD transcription factors and the GATA factors. EMSA showed binding of TEAD3 and TEAD4, and differential binding for both GATA genotypes, and luciferase reporter assay confirmed that TEAD3 and TEAD4 activate the non-risk but not the risk allele, and for GATA factors no significant activation was shown. Our investigations lead us to conclude that rs10811656 and rs4977757 are functional and disrupt specific TEAD regulatory sequences within enhancers

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Rocanin-Arjo, Maria-Ares. « Genetic and Epigenetic Determinants of Thrombin Generation Potential : an epidemiological approach ». Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T067/document.

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Le potentiel de génération thrombine (TGP en anglais) est une nouvelle mesure qui permet de quantifier in vitro l'activité globale de la thrombine reflétant bien les mécanismes in vivo de la coagulation. Ce méthode de dosage est sensible aux déficits de facteurs de coagulation, à la prise d'anti-coagulants et à de nombreux troubles de la coagulation. Au moment où j'ai débuté ma thèse, seuls deux polymorphismes génétiques, tous les deux situés dans le gène F2 codant pour la prothrombine, étaient connus pour influencer la variabilité plasmatique du TGP. Mon projet de thèse avait pour objectifs d'identifier de nouveaux facteurs génétiques, mais également épigénétiques, pouvant influencer les taux plasmatiques de TGP. Dans une première partie, j'ai mené la toute première étude d'association génome-entier (GWAS pour Genome Wide Association Study en anglais) sur 3 biomarqueurs (temps de latence, quantité totale de thrombine produite et niveau maximal de thrombine produite) du TGP dans deux études françaises rassemblant 1267 sujets et j'ai répliqué les résultats les plus significatifs dans deux autres études françaises indépendantes de 1344 sujets. Cette stratégie a permis de mettre en évidence qu'un polymorphisme génétique du gène ORM1 était associé de manière robuste au temps de latence, biomarqueur caractérisant le temps nécessaire pour initier la coagulation après induction. Dans la seconde partie de ma thèse, en suivant une stratégie similaire mais cette fois-ci en étudiant non plus des polymorphismes génétiques mais des marques de méthylation d'ADN, j'ai recherché si des niveaux de méthylation de site CpG, mesurés à partir d'ADN sanguin et couvrant l'ensemble du génome, pouvaient être associés à la variabilité des 3 mêmes biomarqueurs de TGP. Malheureusement, à partir de deux échantillons mis à ma disposition et rassemblant 425 sujets, je n'ai pas pu mettre en évidence d'association robuste entre des marques de méthylation sanguine et la génération trombine
Thrombin Generation Potential (TGP) is a promising in vitro measurement that allows quantifying thrombin activity, in a close way to what happens in vivo. It is sensitive to coagulation factors deficiencies, anticoagulant proteins and is associated to thrombotic disorders. There exists two polymorphisms located in the F2 (prothrombin) gene known to influence TGP levels, and altogether they explain 11.3% of the TGP inter-individual variability. With the aims of identifying novel genetic and epigenetic factors that influence TGP variability, I have performed two different studies in the present work. First, I conducted the first genome-wide association study for the three TGP biomarkers (ETP, Peak and Lagtime) using imputation data from two French studies. The most significant single nucleotide polymorphisms (SNPs) were then replicated in two independent French studies. This analysis lead to the discovery of ORM1 as a new gene participating to the control of TGP. Second, I followed a similar strategy using this time whole blood DNA methylation levels at CpG sites to identify DNA methylation marks involved in TGP variability. I analyzed the association between methylation-wide patterns from a French study and a French-Canadian families measured for TGP. Unfortunately, I did not identify robust associations between whole DNA methylation levels and thrombin generation

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