Genetic associations have been discovered for many human complex traits, and yet for most associated loci the causal variants and molecular mechanisms remain unknown. Studies mapping quantitative trait loci (QTLs) for molecular phenotypes, such as gene expression, RNA splicing, and chromatin accessibility, provide rich data that can link variant effects in specific cell types with complex traits. These genetic effects can also now be modeled in vitro by differentiating human induced pluripotent stem cells (iPSCs) into specific cell types, including inaccessible cell types such as those of the brain. In this thesis, I explore a range of approaches for using QTLs to identify causal variants and to link these with molecular functions and complex traits. In Chapter 2, I describe QTL mapping in 123 sensory neuronal cell lines differentiated from human iPSCs. I observed that gene expression was highly variable across iPSC-derived neuronal cultures in specific gene categories, and that a portion of this variability was explained by commonly used iPSC culture conditions, which influenced differentiation efficiency. A number of QTLs overlapped with common disease associations; however, using simulations I showed that identifying causal regulatory variants with a recall-by- genotype approach in iPSC-derived neurons is likely to require large sample sizes, even for variants with moderately large effect sizes. In Chapter 3, I developed a computational model that uses publicly available gene expression QTL data, along with molecular annotations, to generate cell type-specific probability of regulatory function (PRF) scores for each variant. I found that predictive power was improved when the model was modified to use the quantitative value of annotations. PRF scores outperformed other genome-wide scores, including CADD and GWAVA, in identifying likely causal eQTL variants. In Chapter 4, I used PRF scores to identify relevant cell types and to fine map potential causal variants using summary association statistics in six complex traits. By examining individual loci in detail, I showed how the enrichments contributing to a high PRF score are transparent, which can help to distinguish plausible causal variant predictions from model misspecification.

Les technologies actuelles permettent d'explorer le génome entier pour identifier des variants génétiques associés à des phénotypes particuliers, notamment de maladies. C’est le rôle de la bioinformatique de répondre à cette problématique. Dans le cadre de cette thèse, un nouvel outil logiciel a été développé qui permet de mesurer avec une bonne précision le nombre de marqueurs génétiques effectivement indépendants correspondant à un ensemble de marqueurs génotypés dans une population donnée. Cet algorithme repose sur la mesure de l’entropie de Shannon contenue au sein de ces marqueurs, ainsi que des niveaux d’information mutuelle calculés sur les paires de SNPs choisis au sein d’une fenêtre de SNPs consécutifs, dont la taille est un paramètre du programme. Il a été montré que ce nombre de marqueurs indépendants devient constant dès que la population est homogène avec une taille suffisante (N > 60 individus) et que l'on utilise une fenêtre assez grande (taille > 100 SNPs). Ce calcul peut avoir de nombreuses applications pour l'exploitation des données.Une analyse génome-entier a été réalisée sur le photo-vieillissement. Elle a porté sur 502 femmes caucasiennes pour lesquelles un grade de photo-vieillissement a été évalué selon une technologie bien établie. Les femmes ont été génotypées sur des puces Illumina OmniOne (1M SNPs), et deux gènes ont été identifiés (STXBP5L et FBX040) associés à un SNP passant le seuil de Bonferroni, dont l'implication dans le photo-vieillissement était jusqu'alors inconnue. De plus, cette association a aussi été retrouvé dans deux autres phénotypes suggérant un mécanisme moléculaire commun possible entre le relâchement cutané et les rides. On n'observe pas de réplication au niveau du critère lentigines, la troisième composante étudiée du photo-vieillissement.Ces travaux sont en cours de publication dans des revues scientifiques internationales à comité de lecture. / New technologies allow the exploration of the whole genome to identify genetic variants associated with various phenotypes, in particular diseases. Bioinformatics aims at helping to answer these questions. In the context of my PhD thesis, I have first developed a new software allowing to measure with a good precision the number of really independent genetic markers present in a set of markers genotyped in a given population. This algorithm relies on the Shannon's entropy contained within these markers and on the levels of mutual information computed from the pairs of SNPs chosen in a given window of consecutive SNPs, the window size is a parameter of the program. I have shown that the number of really independent markers become stable as soon as the population is homogeneous and large enough (N > 60) and as soon as the window size is large enough (size > 100 SNPs). This computation may have several applications, in particular the diminution of the Bonferroni threshold by a factor that may reach sometimes 4, the latter having little impact in practice.I have also completed a genome-wide association study on photo-ageing. This study was performed on 502 Caucasian women characterized by their grade of photo-ageing, as measured by a well-established technology. In this study, the women were genotyped with OmniOne Illumina chips (1M SNPs), and I have identified two genes (STXBP5L et FBX040) associated with a SNP that passes the Bonferroni threshold, whose implication in photo-ageing was not suspected until now. Interestingly, this association has been highlighted with two other phenotypes which suggest a possible common molecular mechanism between sagging and wrinkling. There was no replication for the lentigin criteria, the third component studied of photo ageing.These studies are on the process to be published in international peer-reviewed scientific journals.

Genome-wide associations studies (GWASs) have identified hundreds of loci that are strongly associated with coronary artery disease and its risk factors. However, the causal variants and genes remain unknown for the vast majority of the identified loci. Zebrafish model systems coupled with clustered regularly interspaced short palindromic repeats-C–associated 9 (CRISPR Cas-9) mutagenesis have enabled the possibility to systematically characterize candidate genes in GWAS-identified loci. In this thesis, canonical correlation analysis (CCA) was used to identify putative causal genes in multiplexed genetic screens for atherogenic traits in zebrafish larvae in an efficient manner. The two datasets used in this thesis contained genes and phenotypes obtained through sequencing and high-throughput imaging of fish larvae. Dataset 1 contained (7 genes, 11 phenotypes, n = 384) and dataset 2 (4 genes, 11 phenotypes, n = 384). CCA’s multiple genes vs. multiple phenotype analysis in dataset 1 identified the genes met, pepd, timd4 and vegfa to have an association with the total cholesterol, triglycerides, glucose, corrected lipid disposition, as well as co- localization of (macrophage and lipid deposition,) (neutrophils and lipid deposition) and (macrophage and neutrophils). In dataset 2, CCA found previously reported correlation of genes apobb1 and apoea with total cholesterol, low-density lipoprotein and triglycerides as well as co localization of neutrophils and lipids. In comparison with hierarchical linear model, CCA represents a powerful and promising tool to identify causal genes for cardiovascular diseases in data from zebrafish model systems.

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No. of bitstreams: 2 Tese - Gabriel Feresin Pantalião - 2016.pdf: 3525081 bytes, checksum: f216c5eaec8666868c34105435767ccd (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2016-04-06 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Cultivated rice (Oryza sativa L.) is one of the most important cereal for feeding. It is estimated that the demand for rice grains increases considerably in a reduction scenario of cultivable area and scarcity of water resources, which will require an increase in production compared to current levels. To solve this problem, a viable alternative would be the exploitation of genetic diversity available in rice germplasm banks. Rice breeding programs should prioritize the search for new strategies to increase yield in a variety of environmental conditions. The exploitation of genetic diversity allowed the identification of favorable alleles not present in the germplasm of rice varieties used in breeding programs, as well as obtaining new allelic combinations of genes related to important agronomic traits and that could significantly contribute to the achievement of more productive cultivars. In this context, genome-wide association studies (GWAS) are designed to analyze variations in the DNA sequence of the entire genome in an effort to identify associations with phenotypic traits of interest. It is expected, therefore, that the results of the GWAS analysis, together with the improvements obtained with the next generation sequencing technologies (NGS) in search of a large number of SNPs, such as genotyping by sequencing (GBS), be used to investigate the genetic control of traits related to yield. This study aimed to identify genomic regions of rice related to yield from the GWAS methodology using genotypes of Embrapa Rice Core Collection (ERiCC). The GWAS analysis was conducted from a panel of 550 accessions of the ERiCC, and after the imputation of raw data, were accounted 445,589 SNPs distributed along the 12 rice chromosomes. The molecular information was integrated with phenotypic data derived from yield evaluation experiments conducted in nine essays, divided into two cultivation systems (irrigated and rainfed) and three agricultural years (2004/2005, 2005/2006 and 2006/2007). From the joint analysis in all experiments, 31 SNPs were significantly associated with yield, but only three had the lowest frequency allele with positive effect. The joint analysis of irrigated experiments identified three SNPs associated with yield, of which one with lower frequency allele with a positive effect, whereas in the rainfed experiments was identified only one SNP with lower frequency allele associated to positive effect. Subsequently, a stepwise regression analysis was performed to keep in the model only SNPs without overlapping effects, so being selected 15 SNPs markers. After in silico analysis, it was found that the most productive accessions showed 80 to 100% of favorable alleles while the less productive showed 27 to 33% of favorable alleles. For this set of markers to be used in an assisted selection routine, they should also be validated in the laboratory. In the total joint analysis, from 44 genes identified, 14 had no particular function, while from the joint analysis of experiments irrigated and rainfed, from the six genes, only one had no particular function. The search for Arabidopsis homologues genes in the 15 unknown function rice genes resulted in four genes with known function. The expressed products of the set of genes were related to metabolic processes, response to biotic, abiotic, endogenous and external stimulus, post- embryonic multicellular development, growth and morphogenesis, which influence the number of grains, grains weight and photosynthetic capacity, all related to rice yield and be useful in indicating candidate genes to cloning and transformation, enabling the development of genetically superior rice cultivars. Among the genes identified as associated to productivity, nine were previously described in the literature, and of these, six were related proteins that influence the number and seed weight, and photosynthetic capacity: LOC_Os02g44290.1, LOC_Os04g35370.1, LOC_Os02g44260.1, LOC_Os02g44280 .1 LOC_Os09g36230.1 and LOC_Os01g66160.1. These genes are considered as candidates for cloning and transformation of rice, in order, through its overexpression, enable the development of higher yielding rice cultivars. / O arroz cultivado (Oryza sativa L.) é um dos cereais mais importantes para a alimentação humana. Estima-se que a demanda por grãos de arroz aumentará de forma considerável em um cenário de redução da área cultivável e escassez de recursos hídricos, o que demandará um aumento na produção em relação aos níveis atuais. Para solucionar esse problema, uma alternativa viável é a exploração da diversidade genética disponível em bancos de germoplasma de arroz. Os programas de melhoramento de arroz devem, portanto, priorizar a busca por novas estratégias que visem o aumento da produtividade em diversos tipos de condições ambientais. A exploração da diversidade genética permitiria a identificação de alelos favoráveis ainda não presentes no germoplasma das variedades de arroz utilizadas nos programas de melhoramento, assim como a obtenção de novas combinações alélicas de genes relacionados a caracteres de importância agronômica e que poderiam contribuir significativamente para a obtenção de cultivares mais produtivas. Nesse contexto, estudos de associação genômica ampla (GWAS) têm por finalidade analisar variações na sequência do DNA em todo o genoma, em um esforço para identificar associações a caracteres fenotípicos de interesse. Espera-se, assim, que os resultados das análises GWAS, juntamente com os aprimoramentos obtidos com as tecnologias de sequenciamento de nova geração (NGS) na busca por um grande número de SNPs, como é o caso da genotipagem por sequenciamento (GBS), sejam utilizados para investigar o controle genético dos caracteres relacionados à produtividade. Esse trabalho objetivou identificar regiões genômicas do arroz relacionadas à produtividade a partir da metodologia GWAS utilizando os genótipos da Coleção Nuclear de Arroz da Embrapa (CNAE). A análise GWAS foi conduzida a partir de um painel composto por 550 acessos da CNAE, sendo que após a imputação dos dados brutos, foram contabilizados 445.589 SNPs distribuídos ao longo dos 12 cromossomos do arroz. As informações moleculares foram integradas aos dados fenotípicos derivados dos experimentos de avaliação de produtividade conduzidos em nove ensaios, divididos em dois sistemas de cultivo (irrigado e sequeiro) e por três anos agrícolas (2004/2005, 2005/2006 e 2006/2007). A partir da análise conjunta em todos os experimentos, 31 SNPs foram associados de forma significativa à produtividade, com apenas três apresentarando o alelo de menor frequência com efeito positivo. Nas análises conjuntas dos experimentos irrigados foram identificados três SNPs associados à produtividade, um dos quais com alelo de menor frequência com efeito positivo, enquanto que nos experimentos em sequeiro foi identificado apenas um SNP, com alelo de menor frequência associado ao efeito positivo. Posteriormente foi realizada uma análise de regressão stepwise para se manter no modelo apenas os SNPs sem efeitos de sobreposição, sendo então selecionados 15 marcadores SNP. Após uma análise in silico, constatou-se que os acessos mais produtivos apresentaram 80 a 100% dos alelos favoráveis, enquanto os menos produtivos apresentaram 27 a 33% dos alelos favoráveis. Para que esse conjunto de marcadores seja utilizado em uma rotina de seleção assistida, ainda deverão ser validados em laboratório. Na análise conjunta total, entre os 44 genes identificados, 14 não apresentavam função determinada, enquanto a partir da análise conjunta dos experimentos irrigados e em sequeiro, entre os seis genes, apenas um não apresentava função determinada. A busca por homólogos em Arabidopsis nos 15 genes de arroz de função desconhecida resultou em quatro genes com função conhecida. Os produtos expressos do conjunto de genes estavam relacionados a processos metabólicos, resposta a estímulos bióticos, abióticos, endógenos e externos, desenvolvimento multicelular pós-embrionário, crescimento e morfogênese, que influenciam no número, peso de grãos, e capacidade fotossintética, todos relacionados com a produtividade em arroz, sendo útil na indicação de genes candidatos à clonagem e transformação, possibilitando o desenvolvimento de cultivares de arroz geneticamente superiores. Dentre os genes identificados como associados a produtividade, nove foram descritos previamente na literatura, e destes, seis foram relacionados a proteínas que influenciam no número e peso de grãos, e capacidade fotossintética: LOC_Os02g44290.1, LOC_Os04g35370.1, LOC_Os02g44260.1, LOC_Os02g44280.1, LOC_Os09g36230.1 e LOC_Os01g66160.1. Esses são considerados genes candidatos à clonagem e transformação do arroz, a fim de, por meio de sua superexpressão, possibilitar o desenvolvimento de cultivares de arroz mais produtivas.

Les technologies actuelles permettent d’explorer le génome entier pour y découvrir des variants génétiques associés aux maladies. Cela implique des outils bioinformatiques adaptés à l’interface de l’informatique, des statistiques et de la biologie. Ma thèse a porté sur l’exploitation bioinformatique des données génomiques issues de la cohorte GRIV du SIDA et du projet international IHAC (International HIV Acquisition Consortium). Posant les prémices de l'imputation, j’ai d’abord développé le logiciel SUBHAP. Notre équipe a montré que la région HLA était essentielle dans la non progression et le contrôle de la charge virale et cela m’a conduit à étudier le phénotype non-progresseur non « elite ». J’ai ainsi révélé un variant du gène CXCR6 qui, en dehors du HLA, est le seul résultat identifié par approche génome-entier et répliqué. L’imputation des données du projet IHAC (10000 patients infectés et 15000 contrôles) a été réalisée et des premières associations sont en cours d’exploration. / Nowadays with the newest technologies, the entire genome can be explored to uncover genetic variants which may be linked to diseases. This requires bioinformatics tools which are adequate for studies which are at the border between computing, statistics and biology. My thesis work focused on the bioinformatical analysis of genomic data from the GRIV AIDS cohort and from the IHAC (International HIV Acquisition Consortium) project. I first laid the foundation for imputation work by developing the SUBHAP software. Our team showed that the HLA region was essential in non-progression and viral charge control. This led me to study the non progressor non elite phenotype. Thus, I uncovered a variant of the CXCR6 gene which is, apart from HLA, the only result identified with a GWAS approach so far and which has been reproduced. The imputation of data from the IHAC project (10000 infected patients and 15000 control subjects) was also performed and the first associations are now being studied.

Chaque année en Europe, quelques 70.000 nouveaux patients requièrent un traitement permanent dans le cadre d'une insuffisance rénale terminale. Dans le même temps, on réalise environ 20.000 greffes, laissant quantité de patients en dialyse. Le taux de survie en dialyse est médiocre (2/3 à 3/4 moindre que chez les sujets non dialysés des mêmes âges) ce qui rend le problème de la disponibilité des greffons parfaitement criant. La pénurie de greffons est directement liée à leur survie limitée: 10 ans en valeur médiane et en l'absence de censure pour la mort des patients, ou bien 15 ans si l'on se limite à regarder les pertes de greffes liées à des causes intrinsèques. Plus de 60% des greffons sont perdus des suites de lésions de rejet chronique. Dans ce contexte, nous avons choisi de nous intéresser à de très rares patients, découverts fortuitement, qui en dépit de l'arrêt de leurs immunosuppresseurs pour diverses raisons, maintiennent pendant une durée prolongée d'au moins 1 an, une bonne fonction de leur greffon. Ces patients, tout en étant bien portants, semblent être devenus sélectivement incapables de monter une réaction inflammatoire, à tout le moins destructrice, à l'encontre de leur greffon. On dit qu'ils sont "opérationnellement tolérants". En pratique, ils disposent d'un rein allogénique qu'ils ne rejettent pas mais sans avoir à subir les conséquences néfastes et redoutables des immunosuppresseurs (infections, cancers, diabète, hypertension artérielle, ). Comprendre et maîtriser la tolérance opérationnelle ouvrirait la voie à des transplantations plus durables et plus sûres. Plusieurs études transcriptomiques, mécanistiques et épigénétiques laissent penser que la tolérance opérationnelle repose sur l'expansion de populations cellulaires régulatrices au sein des répertoires alloréactifs, aux dépends des cellules effectrices. Ces équilibresfins seraient maintenus grâce à une série de modifications épigénétiques (microARN, méthylations) assurant une stabilité relative au phénotype. Malgré notre meilleure compréhension des mécanismes responsables de l'homéostasie de la tolérance, ses mécanismes causaux restent à ce jour inconnus.Nous avons émis l'hypothèse que la tolérance requerrait une prédisposition génétique pour pouvoir s'installer, concrètement: que les patients tolérants se distinguent du reste de la population par un excès de variants à haute pénétrance localisés dans les exons de gènes jouant un rôle critique dans le développement de la dite tolérance.Pour valider cette thèse, nous avons, dans un premier temps:- contribué à montrer, au travers de la première étude pangénomique d'association ("GWAS") validée sur le rejet aigu d'allogreffe rénale que le génome des receveurs influençait les réponses alloimmunes, hors du système HLA.- réuni la plus grande cohorte de patients tolérants sur le territoire européen à ce jour composée de 22 patients de la biocollection l'université de Nantes et de 18 patients identifiés prospectivement dans le cadre d'une étude dédiée; TOMOGRAM,- montré que la tolérance était associée à une survie prolongée des greffons,- montré qu'il s'agissait d'une découverte rare, identifiée par les cliniciens chez seulement 0.03% de leurs patients greffés et sans condition prédisposante patente.Dans un second temps, nous avons- séquencé les exomes de 40 patients tolérants et les avons comparés à ceux de 209 contrôles in-house,- filtré nos données selon notre hypothèse de travail et circonscrit un ensemble de variants exoniques moyennement à hautement pathogènes (au total 84.643, répartis dans 16.343 gènes),- comparé les distributions de variants (par gène; par variant) chez les cas et chez les contrôles, à l'aide du test aSKAT-O; un test basé sur une analyse de la variance et ajusté pour les petits échantillons.Nos résultats immédiats ont été soumis à 3 contrôles: une correction pour les hypothèses multiples (FDR 0.05); des interventions pour repérer d'éventuelles stratifications (notamment d'après une analyse en composantes principales ou PCA) et enfin; l'examen soigneux des variants retenus dans les fichiers post-alignement (BAM).Au terme de ce processus, nous n'avons pas pu identifier de variant ou de gène ségréguant avec la tolérance. Nous concluons que la prédisposition à la tolérance repose peu vraisemblablement sur une hérédité monogénique simple et homogène ("mendélienne"). D'autres données, en ce compris nos propres travaux sur les déterminants génétiques du rejet aigu de greffe, nous encouragent à rechercher des causes génétiques plus complexes. De nouvelles études d'association tirant parti du séquençage génome-entier et exploitant des cohortes plus larges sont requises. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

Indiana University-Purdue University Indianapolis (IUPUI) / New neurons are generated throughout adulthood in two regions of the brain, the dentate gyrus of the hippocampus, which is important for memory formation and cognitive functions, and the sub-ventricular zone of the olfactory bulb, which is important for the sense of smell, and are incorporated into hippocampal network circuitry. Disruption of this process has been postulated to contribute to neurodegenerative disorders including Alzheimer’s disease [1]. AD is the most common form of adult-onset dementia and the number of patients with AD escalates dramatically each year. The generation of new neurons in the dentate gyrus declines with age and in AD. Many of the molecular players in AD are also modulators of adult neurogenesis, but the genetic mechanisms influencing adult neurogenesis in AD are unclear. The overall goal of this project is to identify candidate genes and pathways that play a role in neurogenesis in the adult brain and to test the hypotheses that 1) hippocampal neurogenesis-related genes and pathways are significantly perturbed in AD and 2) neurogenesis-related pathways are significantly associated with hippocampal volume and other AD-related biomarker endophenotypes including brain deposition of amyloid-β and tau pathology. First, potential modulators of adult neurogenesis and their roles in neurodegenerative diseases were evaluated. Candidate genes that control the turnover process of neural stem cells/precursors to new functional neurons during adult neurogenesis were manually curated using a pathway-based systems biology approach. Second, a targeted neurogenesis pathway-based gene analysis was performed resulting in the identification of ADORA2A as associated with hippocampal volume and memory performance in mild cognitive impairment and AD. Third, a genome-wide gene-set enrichment analysis was conducted to discover associations between hippocampal volume and AD related endophenotypes and neurogenesis-related pathways. Within the discovered neurogenesis enriched pathways, a gene-based association analysis identified TESC and ACVR1 as significantly associated with hippocampal volume and APOE and PVLR2 as significantly associated with tau and amyloid beta levels in cerebrospinal fluid. This project identifies new genetic contributions to hippocampal neurogenesis with translational implications for novel therapeutic targets related to learning and memory and neuroprotection in AD.

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<p>Complex traits are influenced by genetic and environmental factors and their interactions. Most common human disorders such as cardiovascular, metabolic, autoimmune, and neurological diseases are complex. Understanding their genetic architecture and etiology is an important step to prevent, diagnose and treat these conditions. Genome Wide Association Studies (GWAS) have emerged as a powerful and widely used tool that can be used to explore and identify the genetic variants associated with complex traits. In this dissertation, we present some of the downstream applications of GWAS studies to analyze and understand the genetic risk and etiology of complex traits and provide important insights into the genetic architecture and background of several complex phenotypes. First, we examined whether prevalence of complex disorders around the world correlates to Polygenic Risk Scores (PRS). To do so, we determined the average PRS of 14 such complex disorders across 24 world populations using results of GWAS studies. We found variation in risk across populations and significant correlation was obtained between average disease risk and prevalence for seven of the studied disorders. Further exploring the power of PRS- based calculations, we performed a PRS - based phenome wide association study (PheWAS) for Tourette Syndrome (TS) and identified 57 phenotypic outcomes significantly associated with TS PRS. The strongest associations were found between TS PRS and mental health factors. Cross- disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. Furthermore, we performed a sex specific PheWAS that highlighted differences in associations of complex disorders with TS PRS in males and females. Finally, we used large- scale GWAS results to identify causal associations between different biological markers (proteins, metabolites, and microbes) and subcortical brain structure volumes using Mendelian Randomization (MR) analysis. We identified eleven proteins and six metabolites to be significantly associated with subcortical brain volume structures. Enrichment analysis indicated that the associated proteins were enriched for proteolytic functions and regulation of apoptotic pathways. Overall, our work demonstrates the power of GWAS studies to help disentangle the genetic basis of complex diseases and also provides important insights into the etiology of the studied complex traits. </p>