Des mutations germinales dans les gènes majeurs du cancer du sein BRCA1 et BRCA2 sont responsables de la maladie chez les patientes cumulant histoire familiale et apparition du cancer à un jeune âge. Environ 15% des femmes testées pour les mutations de BRCA1 et BRCA2 sont porteuses d’une mutation clairement pathogénique dans un des deux gènes. Cependant, des variants de signification clinique incertaine (VUS pour "variants of uncertain clinical significance") sont détectés dans 5% à 15% des cas testés. Pour évaluer la signification clinique des VUS, le Breast cancer Infomation Core (BIC) a développé un modèle Bayésien intégré, basé sur des données d'observations. Align-GVGD, un algorithme d'évaluation des substitutions faux-sens basé sur l'histoire évolutionnaire de la protéine fournit la probabilité a priori du modèle. Cependant, lorsqu'une substitution silencieuse est détectée, elle sera jugée comme neutre par l'évaluation in silico. Pourtant, une mutation au niveau de l'ARNm peut perturber la mécanique de l'épissage, par deux moyens principaux: endommagement des sites sauvages d'épissage, ou la création de sites exoniques d'épissage de novo. Notre premier objectif est de rassembler les variants déjà publiés, de les re-analyser avec le modèle d'évaluation intégrée. Nous voulons extraire le plus de variants publiés premièrement sous le statut de VUS vers un statut plus informatif, avec des recommandations cliniques associées. Par la suite, nous voulons étendre le modèle pour évaluer plus de variants, plus précisément, en intégrant l'évaluation des perturbations de l'épissage. Finalement, nous serons capable de présenter et de fournir ces informations librement sur Internet, via une interface web populaire, une Leiden Open Variation Database (LOVD) / Germline mutations in major breast cancer susceptibility genes BRCA1 and BRCA2 are responsible for the disease for high-risk patients (patients with early onset and familial history of breast cancer). Around 15% of screened women for BRCA1 and BRCA2 mutations carry one clearly pathogenic mutation in one of those two genes. However, variants of uncertain clinical significance (VUS) are detected in 5% to 15% of tested patients. To assess clinical significance of VUS, the Breast cancer Information Core (BIC) has developed a Bayesian integrated model, based on observational data. Align-GVGD, an algorithm evaluating damage of missense substitutions based on the evolutionary history of the protein, is providing the prior probability of the model. However, whenever a silent substitution arise, it is firstly treated as neutral by the in silico assessment. Indeed, a mutation at the mRNA level can disrupt the splicing machinery by two main means: damaging wild-type splice sites, or creating exonic de novo splice sites. Our first goal is to be a central repository of already published variants, to re-analyze them using the unified integrated evaluation model. We would like to extract the most variants from the original published status of VUS to a more informative status, with associated clinical recommendations. Then we would like to extend the model to be able to evaluate more variants more precisely by adding the splicing damages assessment in the integrated evaluation. In the end, we will be able to provide these informations freely on Internet, via a widely use web interface, a Leiden Open Variation Database (LOVD)

Les gliomes constituent les plus fréquentes des tumeurs malignes primaires du système nerveux central. Les liens qui existent entre ces tumeurs et un certain nombre de cancers rares héréditaires, comme les Neurofibromatoses I et II ou les syndromes de Turcot et de Li-Fraumeni, attestent d’une prédisposition génétique aux gliomes. L’observation d’un risque deux fois plus élevé de développer un gliome chez les parents de premier degré de patients atteints suggère aussi une possible prédisposition génétique dans les gliomes sporadiques. Par ailleurs, l’analyse à haut débit permet de préciser le profil somatique des gliomes et d’identifier des biomarqueurs pronostiques voire prédictifs et s’inscrire dans une démarche de traitement personnalisé du patient. Durant ma thèse, je me suis focalisé sur deux axes de recherches complémentaires; l’identification de gènes de susceptibilité et la découverte de nouveaux gènes fréquemment mutés dans les gliomes, afin de déterminer les voies de signalisation contribuant à la gliomagenèse. Dans leur ensemble, les résultats obtenus dans cette thèse apportent non seulement des informations importantes sur la nature de la prédisposition génétique aux gliomes mais également de son association spécifique pour les différents sous-types de tumeurs. La découverte d’un nouveau gène muté, offre la perspective à plus long terme d’un traitement personnalisé pour chaque patient sur la base du profil génétique de sa tumeur. / Gliomas are the most common adult malignant primary tumour of the central nervous system. Thus far, no environmental exposures has been linked to risk except for ionizing radiation, which only accounts for a very small number of cases. Direct evidence for inherited predisposition to glioma is provided by a number of rare inherited cancer syndromes, such as Turcot's and Li–Fraumeni syndromes, and neurofibromatosis. Even collectively, these diseases however account for little of the twofold increased risk of glioma seen in first-degree relatives of glioma patients. My research was centred on two complementary research activities: Identifying susceptibility genes for glioma to delineate key biological pathways contributing to disease pathogenesis and to identify new recurrent mutated genes for glioma to provide for further insights into glial oncogenesis and suggesting targets for novel therapeutic strategies. Collectively the findings in this thesis provide increased insight into the nature of genetic predisposition to glioma and substantiate the often distinct associations between susceptibility variants and glioma molecular groups. In addition the discovery of a new mutated gene in glioma offers the potential to support drug development and advance precision medicine for this tumours.

Introduction : L’hypertension est une condition complexe multifactorielle pouvant être influencée par des facteurs de risque génétiques et du mode de vie, tel le sommeil. En effet, une qualité et une durée du sommeil inadéquate sont liées à un risque accru d’hypertension. Peu d’études investiguent la modification du sommeil sur l’association entre la génétique et la pression artérielle. Objectif : Les objectifs de ce mémoire sont d’étudier, chez les jeunes adultes : i) la modification d’effet de la génétique sur la pression artérielle par la qualité du sommeil; et ii) la modification d’effet de la génétique sur la pression artérielle par la durée du sommeil. Méthodes : Ce mémoire est une étude transversale répétée utilisant les données de deux cycles de l’étude longitudinale Nicotine Dependence in Teens (NDIT), soit les cycles 22 (2011-2012 ; 24 ans, n = 529) et 23 (2017-2018 ; 30 ans, n = 395). Au sein de ces deux cycles, la pression artérielle a été mesuré et la qualité et la durée du sommeil ont été évaluées à l'aide de l'échelle validée Pittsburgh Sleep Quality Index. Le score de risque génétique pour la pression artérielle élevée a été basé sur 29 variants génétiques de risque. La modification d’effet du sommeil sur l’association entre la génétique et la pression artérielle a été estimée par des modèles de régression linéaire. De plus, une analyse combinant les données des cycles 22 et 23 a été effectuée à l'aide d'un modèle des moindres carrés généralisés. Résultats : Le score de risque génétique est significativement associé à la pression artérielle (Cycle combiné : β = 0.50; IC95% : 0.18, 0.81). Cependant, ni la qualité du sommeil (Cycle combiné : β = 0.02; IC95% : -0.19, 0.24) ni la durée du sommeil (Cycle combiné : β = -0.70; IC95% : -1.50, 0.10) ne sont associés significativement à la pression artérielle. De plus, aucune modification significative d’effet de la qualité et de la durée du sommeil sur l’association entre susceptibilité génétique à la haute pression et la pression artérielle n’a été observée. Conclusion : Chez les jeunes adultes, le sommeil n’atténue possiblement pas l’effet de la prédisposition génétique à la haute pression artérielle. / Introduction: Hypertension is a complex, multifactorial condition that can be influenced by genetic and lifestyle risk factors such as sleep. Inadequate quality and duration of sleep are linked to an increased risk of hypertension. However, few studies investigate the effect modification of sleep in the association between genetics and blood pressure. Objective: The objectives are to study in young adults i) the effect modification of genetics on blood pressure by sleep quality in young adults; and ii) the effect modification of genetics on blood pressure by sleep duration. Methods: This thesis examines the study objectives in a repeated cross-sectional study design using data from two cycles of the Nicotine Dependence in Teens (NDIT) longitudinal study separately - cycles 22 (2011-2012; age 24, n = 529), and 23 (2017-2018; age 30, n = 395). In both cycles, blood pressure was measured, and sleep quality and duration were assessed using the validated Pittsburgh Sleep Quality Index scale. The genetic risk score for high blood pressure is based on 29 risk variants. The effect modification of sleep on the association between genetics and blood pressure was assessed using linear regression models. Additionally, an analysis pooling data across cycles 22 and 23 was performed using a Generalized Least Square model. Results: Genetic risk score (GRS) is significantly associated with blood pressure (Pooled cycles: β = 0.50; 95% CI: 0.18, 0.81). However, neither sleep quality (Pooled cycles: β = 0.02; 95% CI: -0.19, 0.24) nor sleep duration (Pooled cycles: β = -0.70; 95% CI: -1.50, 0.10) are significantly associated with blood pressure. Furthermore, no effect modification of sleep quality and duration on the association between genetic susceptibility to high blood pressure and blood pressure were observed. Conclusion: In young adults, sleep may not attenuate the effect of genetic predisposition to high blood pressure.

No description available.

A exposição contínua ao ruído de alta intensidade é o fator ambiental mais importante como causa de problemas auditivos em adultos. Esses tipos de perdas crônicas e irreversíveis causadas pelo ruído são chamados de Perdas Auditivas Induzidas por Ruído (PAIR). O objetivo desse estudo foi estudar a influência de fatores genéticos na susceptibilidade à PAIR. Para atingir esse objetivo comparamos uma amostra de indivíduos com PAIR e de indivíduos sem PAIR que trabalharam expostos ao ruído em relação à etnia, à história familial de perda auditiva, idade, tempo de exposição ao ruído, tabagismo e alcoolismo social. Para verificar a possível contribuição de fatores genéticos, testamos a presença de mutações conhecidas como causas freqüentes de surdez. As mutações testadas foram 35delG e 167delT no gene GJB2, as deleções Δ(GJB6-D13S1830) e Δ(GJB6-D13S1854) no gene GJB6 e A1555G (RFLP) no gene MT-RNR1. Determinamos as freqüências alélicas e genotípicas de um polimorfismo no gene GJB2 (SNP RS877098) e dos polimorfismos do tipo presença/deleção dos genes GSTM1 e GSTT1. Também verificamos a ocorrência e a freqüência de variações nas seqüências dos genes mitocondriais MT-RNR1 e MT-TS1, dois genes mitocondriais importantes como causa de surdez de herança materna. Nossa amostra constituiu-se de 107 indivíduos que apresentavam audiometrias sugestivas de PAIR (grupo PAIR), 44 indivíduos afetados por perdas de audição com curvas audiométricas que não eram sugestivas de PAIR (grupo PANO) e 104 indivíduos com audição normal (grupo NORMAL). Nossos resultados apontaram aumento significativo no número de parentes afetados por problemas de audição no grupo PAIR. O tabagismo, a idade e o tempo de exposição ao ruído também influenciaram significativamente na manifestação da PAIR. Aparentemente, não houve contribuição das mutações associadas à manifestação de surdez, 35delG e 167delT no gene GJB2, Δ(GJB6-D13S1830) e Δ(GJB6-D13S1854) no gene GJB6 e A1555G no gene MT-RNR1. Não houve diferença significativa nas freqüências dos alelos do SNP RS87098 (gene GJB2) entre os afetados e os não afetados. Observamos um aumento significativo do genótipo que corresponde a presença dos dois genes das enzimas GSTM1 e GSTT1 entre os indivíduos do grupo PAIR, sugerindo possível papel dessas enzimas relacionadas a proteção contra espécies reativas de oxigênio na etiologia da PAIR. Não observamos associação significativa entre nenhuma das 54 variantes de seqüências do DNA mitocondrial averiguadas nos genes MT-RNR1 e MT-TS1 (32 já previamente descritas e 22 detectadas nesse estudo) e a ocorrência de PAIR. Não observamos associação significativa da PAIR com o número total de variantes de seqüência do DNA mitocondrial observado em cada indivíduo. Não foi detectada associação significativa com os haplótipos constituídos por pares de variantes de seqüência do DNA mitocondrial. A comparação entre a concentração de peróxidos e de grupos sulfidril no soro de 15 indivíduos com PAIR com amostras de 15 indivíduos sem PAIR não revelou diferenças significativas. Em resumo, nosso estudo evidenciou a influência da história familial de perda auditiva na probabilidade de manifestação da PAIR e o possível papel das enzimas GSTT1 e GSTM1 na susceptibilidade a essa condição. Nossos achados reforçam a idéia de que a susceptibilidade à PAIR possa ser determinada por fatores genéticos. / Chronic exposure to loud noise is the most important environmental cause of hearing impairment among adults. Chronic and irreversible hearing loss due to exposure to noise is named Noise Induced Hearing Loss (NIHL). The aim of this study was to investigate the influence of genetic factors in the susceptibility to NIHL. We compared individuals with and without NIHL regarding ethnic origin, familial history of hearing loss, age, noise exposure time, alcohol consumption and smoking habits. In order to investigate genetic factors associated to NIHL we screened frequent deafness causative mutations. The investigated mutations were 35delG and 167delT in the GJB2 gene, Δ(GJB6- D13S1830) and Δ(GJB6- D13S1854) in the GJB6 gene and A1555G in the MT-RNR1 gene. Allelic and genotypic frequencies were determined for the SNP RS877098 in the GJB2 gene, and for the polymorphic deletions of GSTM1 and GSTT1 genes. We also investigated the frequency of variants in the mitochondrial genes MT-RNR1 and MT-TS1, which are known to harbor many hearing loss causative mutations. Our sample comprised 107 individuals with suggestive NIHL audiograms, 44 individuals with hearing impairment and non-suggestive NIHL audiograms, and 104 normal hearing individuals. A significant increase in the number of relatives affected by hearing impairment was detected in the NIHL group, when compared to the normal hearing group. Smoking habits, age and noise exposure time significantly affected the probability of NIHL. We did not detected any effect of the deafness-causing mutations 35delG and 167delT in the GJB2 gene, Δ (GJB6- D13S1830) and Δ (GJB6- D13S1854) in the GJB6 gene, and A1555G in the MT-RNR1 gene. There was no significant difference in allelic and genotypic frequencies of SNP RS87098 (gene GJB2), but the presence of the two genes encoding GSTM1 and GSTT1 enzymes was increased in the NIHL group. We did not detect any significant association of any of the 54 sequence variants in the mitochondrial genes MT-RNR1 and MT-TS1 (32 previously described and 22 novel) with the occurrence of NIHL. No significant associations were observed between NIHL and either the total number of sequence variants detected in each individual or haplotypes (combinations of two variants). The comparison of peroxides and sulfhydryl groups concentrations in serum from 15 individuals with NIHL and 15 individuals without NIHL did not show significant differences. In conclusion, our study demonstrated a significant effect of family history of hearing loss on the probability of presenting NIHL and pointed to a possible role of GSTT1 and GSTM1 enzymes on the susceptibility to this condition. These findings reinforce the idea that susceptibility to NIHL has a genetic basis.

In this thesis we have studied genetic elements potentially contributing to the pathophysiology of psychiatric disorders, focusing on different sources of human genome variability, including SNPs and CNVs, which can affect not only coding genes but also RNA regulatory elements, such as miRNAs. First, we have interrogated different candidate genes for psychiatric disorders overlapping with known CNVs, finding 14 different genes variable in copy number in psychiatric disorders but not in control individuals. Then, narrowing the analysis on mood disorders, we explored GSK3β gene considering both SNPs and a partially overlapping CNV. The GSK3β promoter and intron 1 region was found significantly associated with an earlier onset of the major depressive disorder. Finally, we have found evidence possibly pointing to a precise post-transcriptional regulation of circadian rhythms by miRNAs in mood disorder patients. Concretely, a variant in the precursor form of miR-182 could play an important role in fine-tuning its target sites involved in the control of sleep/wake cycles. Overall, we have provided evidence of different types of genome variation on neuronal genes or miRNA regulatory regions that can potentially contribute to the development of psychiatric disorders. / En aquesta tesi hem estudiat elements genètics que podrien contribuir potencialment en la fisiopatologia dels trastorns psiquiàtrics, centrant-nos en diferents fonts de variabilitat genòmica humana, incloent els SNPs i els CNVs, els quals poden afectar no només a gens codificants sinó també a elements reguladors, com els miRNAs. Primer, vam interrogar diferents gens candidats per trastorns psiquiàtrics solapats amb CNVs coneguts, trobant que 14 gens eren variables en el número de còpia en pacients però no en individus controls. Després, restringint l'anàlisi a trastorns afectius, vam explorar el gen GSK3β considerant SNPs així com també un CNV que se solapa parcialment amb el gen. Vam trobar la regió del promotor i de l'intró 1 del gen GSK3β associada de manera significativa amb una inferior edat d'inici del trastorn de depressió major. Finalment, hem trobat evidències que possiblement indiquen una precisa regulació post-transcriptional dels ritmes circadians per miRNAs en pacients amb trastorns afectius. Concretament, una variant en la forma precursora del miR-182 podria jugar un paper important en la fina regulació dels seus gens diana implicats en el control dels cicles de son i vigília. En general, hem aportat evidències de què diferents tipus de variació genòmica en gens neuronals o regions reguladores com els miRNAs podrien contribuir potencialment en el desenvolupament de trastorns psiquiàtrics.

No description available.

Made available in DSpace on 2014-12-17T14:16:34Z (GMT). No. of bitstreams: 1 HeglaynePVS_DISSERT.pdf: 2645894 bytes, checksum: da2c7ec39b2e87b75a199511857a4e83 (MD5) Previous issue date: 2013-03-27 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Of all of the genes associated with the development of Diabetes mellitus type 1 (T1D), the largest contribution comes from the genes in the Human Leukocyte Antigen (HLA) region, mostly the class II DR e DQ genes. Specific combinations of alleles DRB1, DQA1 and DQB1 constituting haplotypes, and further, a combination of more than one haplotype, providing multilocus genotypes are associated with susceptibility, protection and neutrality to DM1. Thus, the aim of present study was to verified the association of polymorphisms of HLA genes class II with susceptibility to type 1 diabetes mellitus (T1D). Ninety-two patients with T1D and 100 individuals normoglycemics (NG) aged between 6 and 20 years were studied. Genomic DNA was obtained from peripheral whole blood, collected in EDTA tube, using the extraction kit Illustra Triple Prep?, GE Healthcare. For HLA typing was used DNA LABType system by One Lambda kit applying Luminex? technology to the method of PCRSSO typing reverse. The alleles DRB1*03:01, *04:05, *04:01, *04:02, DQA1*03:01g, *05:01g, DQB1*02:01g, *03:02, the haplotypes DRB1*03:01-DQA1*05:01-DQB1*02:01, DRB1*04:05-DQA1*03:01g-DQB1*03:02, DRB1*04:02-DQA1*03:01g-DQB1*03:02, DRB1*04:01-DQA1*03:01g-DQB1*03:02 and DR3-DQ2/DR4-DQ8 genotype were significantly associated with the chance of developing T1D. The alleles DRB1*11:01, *15:03, *15:01, *13:01, DQA1*01:02, *04:01g, *01:03, DQB1*06:02, *03:01g, *06:03, *04:02, the haplotypes DRB1*11:01-DQA1*05:01-DQB1*03:01, DRB1*13:01-DQA1*01:03-DQB1*06:03 and DRX-DQX/DRX-DQX genotype, formed by other than the DR3-DQ2 or DR4-DQ8 haplotypes, were significantly associated with T1D protection Despite the major racial Brazilian, even at the regional level, these results are similar to the majority of alleles, genotypes and haplotypes of HLA class II-related susceptibility or resistance to T1D, extensively described in the literature for Caucasian population. Children with age at diagnosis less than 5 years of age had significantly higher frequency of the heterozygous genotype DR3-DQ2/DR4-DQ8 compared to children with age at diagnosis than 5 years old. These results also demonstrate strong association of the genetic profile of the class II HLA for this age group, possibly associated with the severity and rapid progression to the onset of T1D. The knowledge of HLA class II genes may be useful in genetic screens that allow the prediction of T1D / De todos os genes j? relacionados com o desenvolvimento do Diabetes mellitus tipo 1 (DM1), a maior contribui??o vem da regi?o do genoma onde est?o localizados os genes do Ant?geno Leucocit?rio Humano (HLA), sobretudo os genes da classe II do HLA: DR e DQ. Espec?ficas combina??es de alelos DRB1, DQA1 e DQB1 formando hapl?tipos, e ainda, a combina??o de mais de um hapl?tipo, formando gen?tipos multilocus s?o associados com a susceptibilidade, neutralidade e prote??o ao DM1. Dessa forma, o objetivo do estudo foi verificar a associa??o dos polimorfismos dos genes do complexo HLA classe II com a susceptibilidade ao DM1, em pacientes do Rio Grande do Norte. Foram estudados 92 indiv?duos com DM1 e 100 indiv?duos normoglic?micos (NG), com idade entre 6 e 20 anos. O DNA gen?mico foi obtido a partir do sangue total perif?rico, coletado em tubo com EDTA, utilizando o kit de extra??o Illustra Triple Prep?, GE Healthcare. Para a tipagem do HLA foi utilizado o sistema DNA LABType atrav?s de kits One Lambda, que aplica a tecnologia Luminex? ao m?todo de tipagem por PCR-SSO reverso. Os alelos DRB1*03:01, *04:05, *04:01, *04:02; DQA1*03:01g, 05:01g; DQB1*02:01g, *03:02; os hapl?tipos DRB1*03:01-DQA1*05:01-DQB1*02:01, DRB1*04:05-DQA1*03:01g- DQB1*03:02, DRB1*04:02-DQA1*03:01g-DQB1*03:02, DRB1*04:01-DQA1*03:01g- DQB1*03:02 e o gen?tipo heterozigoto, DR3-DQ2/DR4-DQ8 foram significativamente associados com a chance de desenvolvimento do DM1. J? os alelos DRB1*11:01, *15:03, *15:01, *13:01; DQA1*01:02, *04:01g, *01:03; DQB1*06:02, *03:01g, *06:03, *04:02; os hapl?tipos DRB1*11:01-DQA1*05:01-DQB1*03:01, DRB1*13:01-DQA1*01:03-DQB1*06:03 e o gen?tipo DRX-DQX/DRX-DQX, formado por outros hapl?tipos que n?o DR3-DQ2 ou DR4-DQ8, foram significativamente associados a prote??o ao DM1. Apesar da grande miscigena??o racial brasileira, at? em n?vel regional, estes resultados s?o semelhantes a maioria dos alelos, hapl?tipos e gen?tipos de HLA classe II relacionados ? susceptibilidade ou prote??o ao DM1, extensivamente descritos na literatura para a popula??o caucasiana. Crian?as com idade ao diagn?stico inferior a 5 anos de idade apresentaram significativamente maior frequ?ncia do gen?tipo heterozigoto DR3-DQ2/DR4-DQ8, quando comparada ?s crian?as com idade ao diagn?stico superior a 5 anos de idade. Esses resultados demonstram tamb?m forte envolvimento do perfil gen?tico da classe II do HLA para esta faixa et?ria, que estaria relacionada possivelmente com a gravidade e a r?pida progress?o para o in?cio do DM1. O conhecimento dos genes HLA de classe II pode ser ?til em triagens gen?ticas que possibilitem a predi??o do DM1

Abstract Bronchiolitis is an infection of the small airways of the lung and is a common reason for infant hospitalizations. The most common causative pathogen is the respiratory syncytial virus (RSV). Genetic factors are thought to influence the risk of bronchiolitis, and better knowledge of bronchiolitis genetics will likely help to elucidate the disease process. Severe bronchiolitis in childhood may predispose to asthma. Therefore, an effective treatment of bronchiolitis may affect the present-day as well as lifelong respiratory health. In this project, we aimed to identify genetic loci of bronchiolitis susceptibility by a genome-wide association study (GWAS) and suitable follow-up studies, and to study a previously asthma-associated CDHR3 variant for association across five bronchiolitis populations by meta-analysis. We performed the GWAS on a Finnish-Swedish case-control population and identified several loci below the suggestive genome-wide significance level. Of these, three variants showed nominal associations in a replication population from the Netherlands. One of the loci affected KCND3 expression, and two others were intergenic variants with putative regulatory potential. In a follow-up study conducted on a GWAS sub population, we identified the NKG2D locus as a candidate of susceptibility to bronchiolitis. The genomic region encompassing NKG2D variants was reportedly associated with NKG2D mRNA and protein abundance. We validated the association between NKG2D genotypes and protein expression with flow cytometry. The association between NKG2D and bronchiolitis was supported by a Finnish replication study. The meta-analysis was performed on populations from Denmark, Finland, Sweden, Germany, and the Netherlands. A potential virus-specific role for the CDHR3 variant was detected in a population that comprised mostly RSV-negative cases. In conclusion, we identified new candidates of bronchiolitis susceptibility in GWAS and subsequent studies. We found the CDHR3 variant was a potential susceptibility factor in severe non-RSV bronchiolitis and asthma. Our preliminary results provide interesting starting points for further studies. In the future, better understanding of the disease mechanisms and the relationship of bronchiolitis and asthma could provide means to design new therapeutic options. / Tiivistelmä Bronkioliitti on viruksen aiheuttama alahengitystieinfektio, joka usein johtaa pienten lasten sairaalahoitoon. Yleisin bronkioliitin aiheuttaja lapsilla on respiratory syncytial -virus (RSV). Perintötekijöiden arvellaan altistavan bronkioliitille, joten uusi tieto altistavista geeneistä voi auttaa ymmärtämään taudin taustalla olevia biologisia mekanismeja. Lapsuusiän bronkioliitin ajatellaan voivan altistaa astmalle, joten bronkioliitin tehokas hoito voi vaikuttaa merkittävästi hengitysterveyteen myös pitkällä aikavälillä. Työssä pyrittiin selvittämään lapsuusajan bronkioliitille altistavia geneettisiä tekijöitä genominlaajuisella assosiaatiokartoituksella, joka toteutettiin suomalais-ruotsalaisessa tapaus-verrokkiväestössä. Löydökset pyrittiin varmentamaan soveltuvilla jatkotutkimuksilla. Lisäksi tarkastelimme astmalle altistavaa CDHR3-geenin polymorfismia viidessä eurooppalaisessa bronkioliittikohortissa käyttäen meta-analyysia. Assosiaatiokartoituksessa havaittiin useita mahdollisia bronkioliittialttiuteen vaikuttavia geenikohtia. Näistä kolme sai tukea hollantilaisessa väestössä tehdyssä assosiaatioanalyysissä, jossa testattiin assosiaatiokartoituksen lupaavimmat löydökset. Yksi altistavista polymorfismeista vaikutti KCND3-geenin ilmentymiseen, ja kaksi muuta olivat geenien välisiä, mahdollisesti geeninsäätelyyn osallistuvia variantteja. Assosiaatiokartoituksen osa-analyysissä NKG2D tunnistettiin mahdolliseksi bronkioliitille altistavaksi geeniksi. NKG2D-immuunireseptorin alentunut ilmentyminen voi tulostemme perusteella altistaa vakavalle bronkioliitille. Meta-analyysissä, jonka tutkimuskohortit olivat peräisin Tanskasta, Suomesta, Ruotsista, Saksasta ja Hollannista, todettiin mahdollinen yhteys CDHR3-geenin polymorfismin ja muun viruksen kuin RSV:n aiheuttaman bronkioliitin välillä. Toteutimme tässä työssä ensimmäisen genominlaajuisen bronkioliittialttiutta koskevan assosiaatiokartoituksen. Assosiaatiokartoituksessa, sitä seuranneissa jatkotutkimuksissa ja meta-analyysissä tunnistimme useita lupaavia alttiusgeenejä, mutta tuloksemme vaativat varmentamista suuremmissa tutkimusväestöissä.

Les études d'association à grande échelle consistent à étudier la corrélation de plusieurs millions de polymorphismes nucléotidiques avec un risque de cancer chez des milliers d'individus, sans avoir besoin de connaissances préalables sur la fonction biologique de ces variants. Ces études ont été utiles pour établir des hypothèses étiologiques et comprendre l'architecture génétique sous-jacente de plusieurs maladies humaines. Cependant, la plupart des facteurs héréditaires de ces maladies restent inexpliqués. Une partie de cette variation pourrait venir de variants rares qui ne sont pas ciblés par les puces de génotypage actuelles ou encore de variants avec un effet plus modéré voire faible pour lesquels une détection par les études d'association actuelles n'est pas envisageable. Dans ce contexte et comme illustré dans cette thèse, les récentes études d'association peuvent maintenant servir de point de départ pour de nouvelles découvertes, en mettant en place des stratégies innovantes pour étudier à la fois les variants rares et les maladies rares. Nous avons plus particulièrement exploré ces techniques dans le cadre du cancer du poumon, des voies aérodigestives et du lymphome de Hodgkins. L'utilisation de la bioinformatique pour combiner les résultats des études avec d'autres sources d'information, l'intégration de différents types de données génomiques ainsi que l'investigation de la relation entre altérations germinales et somatiques représentent les principales opportunités poursuivies dans ce travail de thèse / Genome-wide association (GWA) studies consist in testing up to one million (or more) single nucleotide polymorphisms (SNPs) for their association with cancer risk in thousands of individuals, without requiring any prior knowledge on the functional significance of these variants. These studies have been valuable for establishing etiological hypotheses and understanding the underlying genetic architecture of human diseases. However, most of the heritable factors of these traits remain unexplained. Part of this variation may come from rarer variants that are not targeted by current genotyping arrays or variants with moderate to low effects for which detection by current GWA studies is impractical. In this context and as illustrated in this thesis, GWA studies can now serve as starting points towards further discoveries, looking for new strategies to study both rarer variants and rarer diseases. We have specifically explored these approaches in the context of lung cancer, head and neck cancer and Hodgkin's lymphoma. The use of bioinformatics to combine recent GWA study results with other sources of information, the integration of different types of genomic data as well as the investigation of the interrelationship between germline and somatic alterations represent the main opportunities pursued in this thesis work