La famille est une notion paradoxale. Bien qu’universellement connue, elle n’est pas l’objet d’une acception consensuelle. Les différentes sciences sociales, ainsi que les différentes branches du droit ne parviennent pas à s’accorder pour en donner une définition unanime. La famille présente également le paradoxe de relever de l’intime tout en dépendant de la sphère publique en ce qui a trait à sa reconnaissance et à l’exercice des droits qui en découlent. Ces dernières années, la notion de famille a subi l’influence grandissante des droits fondamentaux et de l’internationalisation des relations personnelles. Le droit, norme rigide et générale, semble éprouver des difficultés à appréhender la complexité et la variabilité d’hypothèses familiales. Dès lors, l’utilisation de notions floues par le législateur offre au juge un pouvoir important d’appréciation de ce qui constitue une famille. Dans ce contexte, l’étude comparée de la jurisprudence de la Cour européenne des droits de l’homme et de la Cour suprême du Canada permet de mettre en exergue les éléments pris en compte par les juges au moment de se positionner dans un contentieux familial. Si l’élaboration d’une définition ne semble pas permettre de déterminer efficacement les contours de la notion de famille, l’utilisation d’un mécanisme semble, à l’inverse, offrir une approche plus souple du phénomène familial. Les variables au cœur du mécanisme utilisé dans cette étude sont au nombre de deux et correspondent aux multiples versants que peut regrouper une famille : un versant structurel, qui sera lui-même divisé en deux composantes, une juridique et une biologique, et un versant fonctionnel. Cette dichotomie permet de prendre en compte le réel et le complexe dans un domaine très évolutif. De plus, elle propose des clés de réflexion en invitant les juristes à penser la famille sans créer de liens de causalité entre les différents versants de la famille qui s’articulent constamment, se rencontrant souvent, s’opposant parfois. / Although universally known, there is no consensual agreement of the concept of family. The different social sciences, as well as the various branches of law, can’t agree on an unanimous definition. The family presents the paradox of being intimate while depending on the public sphere with regard to its recognition and exercising of the rights related to it. In recent years, the notion of family has been increasingly influenced by fundamental rights and the internationalization of personal relationships. The law, which is normally rigid, seems to have difficulty apprehending the complexity and variability of family situations. Therefore, the use of vague opinions by the legislator offers the judge more latitude of what constitutes a family. In this context, the comparative study of the jurisprudence of the European Court of Human Rights and the Supreme Court of Canada highlights the elements taken into account by judges when they take up family litigation. While the elaboration of a definition does not seem to be able to effectively determine the frame of the notion of family, the use of a mechanism seems, on the contrary, to offer a more flexible approach to the family phenomenon. There are two variables at the heart of the mechanism used in this study that correspond to the two sides a family can fall into: a structural side, which itself will be divided into two components, a legal and a biological one, and a functional side. This dichotomy makes it possible to take into account the real and the complex in a very evolutionary area. In addition, it offers the keys to reasoning by inviting jurists to think about the family without creating causal links between the different sides of the family that are constantly articulated, often agreeing, sometimes conflicting.

The integration of biological and genetic data has established that diverse biological processes, involving multiple effectors, influence circulating levels of triglyceride and cholesterol. This diversity may underlie the genetic complexity of human dyslipidemias, including the common and highly atherogenic condition, Familial Combined Hyperlipidemia (FCHL). The aetiologies of FCHL are currently undetermined. In this thesis, a multi-pronged approach was employed to identify genes/variants contributing to the linkage observed between the chromosome 21q22.2-22.3 interval and lipid traits, in white-British FCHL families. Additionally GPIHBP1, which encodes glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1, was studied. GPIHBP1 represents a strong FCHL candidate gene due to its role in the lipolytic processing of triglyceride-rich lipoproteins. Combined genetic and gene expression analyses, focussed upon a refined 3.8Mb interval on chromosome 21q22.3 that was linked to lipid abnormalities in subsets of FCHL families, identified two genes (COL18A1 and PKNOX1 ) that warrant further investigation with regard to their contribution to FCHL. Promising results were also obtained for C21orf57, which resides just outside the 3.8Mb interval. Genetic association analyses in 1725 members of 239 FCHL families identified nominal association (P=0.0009) between a TSPEAR variant, rs34163868, and plasma triglyceride levels. Furthermore, transcript levels of CBS and TRPM2 were significantly altered by treatment with the PPAR-agonist bezafibrate in a rat hepatoma cell line, thus implicating these genes in triglyceride/fatty acid metabolism. In combined analysis of five independent cohorts, the minor allele of the GPIHBP1 variant, rs11538388 was protective against hypertriglyceridemia (P=2.98x10-4). The same allele was associated with decreased risk of coronary heart disease in the prospective Northwick Park Heart Study II (hazard ratio for carriers=0.76, P=0.0480) and delayed age of onset in the Southampton Atherosclerosis Study (odds ratio=0.76, P=0.0146). Collectively, these data demonstrate that the rs11538388 minor allele, or variant in linkage disequilibrium, is associated with more favourable processing of atherogenic lipoproteins.

Cette recherche a pour objectif d’analyser l’influence de la prise de participation familiale en matière de propriété, de gestion et de conseil d’administration sur la performance des entreprises familiales. Les nombreux travaux de recherche précédents ont mis à jour des résultats divers et hétérogènes, notamment en ce qui concerne la diversité des genres siégeant au conseil d’administration. Les femmes au conseil sont souvent liées à une gestion efficace, améliorant en conséquence la performance financière. Les avantages et les inconvénients de la participation de la famille au capital et à la gestion de l’entreprise ont révélé l’existence d’effets non-linéaires, créés par ces deux variables, sur la performance. Une analyse de régression sur un échantillon de 97 entreprises a permis de révéler une corrélation quadratique négative entre la prise de participation de la famille dans la gestion et la performance, et aucune relation liant la prise de participation de la famille dans le capital et la performance. La littérature associe souvent la présence de membres de la famille dans la gestion de l’entreprise à des relations positives. Les conclusions obtenues dans cette recherche ont montré que cette corrélation n’était pas suffisamment significative pour compenser les inconvénients créés par une orientation des objectifs non monétaires. Il en est de même pour les couts générés par l’urgence de résoudre les conflits entre les gestionnaires de la famille ainsi que l’impossibilité d’envisager un élargissement du capital de l’entreprise, tant intellectuel que social. / This study aims to research the impact of family involvement in ownership, management and board of directors, on financial performance in family owned firms. The numerous previous studies have shown diverse and heterogeneous results, in the case of non-listed firms, particularly when gender diversity is observed in the board of directors. Women in boards are usually linked to effective management techniques, thus increasing financial performance. The existence of advantages and inconvenience of family participation in ownership and management have raised non-linear effects of these two variables on performance. With a sample of 97 private family firms in Lebanon, we performed a regression analysis. The findings showed a negative quadratic correlation between the involvement of the family in the management and performance whereas no relation linked family involvement in ownership to performance. According to the former literature on family firms, there is a positive relationship associated with the presence of family managers. The findings of this study showed that this correlation was not significantly sufficient to compensate for the drawbacks created from a goal orientation not related to money. The same goes for the cost generated by the urge to resolve differences between family managers and the impossibility of enlarging the organization’s social and intellectual capital by hiring non family managers.

The theme of this dissertation is to develop statistical methods for genetic studies with family history of diseases. Family history of disease is a major risk factor for many health outcomes. To study diseases that aggregate in the families of patients, genetic epidemiological studies recruit independent study participants, often referred to as probands. Probands also provide information on their relatives through a family health history interview. However, due to the high cost of in-person collection of blood samples or death of a relative, dense genotypes are often collected only in probands but not in their family members. In these designs, estimating genetic risk of a disease or identifying genetic risk factors for a complex disease is challenging due to unavailable genotypes in relatives as well as correlation presented among family members' phenotypes. This dissertation contains three parts to tackle these barriers in family studies: (1) develop methods to estimate the genetic risk of a disease more precisely; (2) develop methods to test for association between genetic markers and correlated phenotypes; and (3) develop methods to control population substructure and familial relatedness in genome-wide association studies (GWAS). In the first part of the dissertation, we propose a method to estimate the age-specific disease risk of genetic mutation in family studies that permits the adjustment for multiple covariates and interaction effects in the presence of unobserved genotypes in relatives. Compared to our previous nonparametric approaches that do not control covariates, our semiparametric estimation method allows controlling for individual characteristics such as sex, ethnicity, environmental risk factors, and genotypes at other loci. Moreover, gene-gene interactions and gene-environment interactions can also be handled within the framework of a semiparametric model. The analyses may provide insights on whether demographics or environmental variables play a role in modifying the genetic risk of a disease. We examine the performance of the proposed methods by simulations and apply them to estimate the age-specific cumulative risk of Parkinson's disease (PD) in relatives predicted to carry the LRRK2 G2019S mutation. The utility of the estimated carrier risk is demonstrated through designing a future clinical trial under various assumptions. The second part of the dissertation is motivated by extending the single genetic variant set up in the first part to genome-wide genotype data, but focuses on the genetic association tests. Here, we propose a computationally efficient multilevel model to analyze the association of a genetic marker with correlated binary phenotypes in family studies. Our method accounts for both random polygenic effects as well as shared non-genetic familial effects while handling unavailable genotypes in relatives. To discover genetic variants of a complex disorder that aggregates in the families of patients, we consider the combined data of probands with genome-wide genotypes and family history of diseases in relatives (GWAS+FH). To allow for large-scale genetic testing in GWAS+FH, we handle the unobserved genotypes as well as estimate the random effects with reduced computational cost through fast and stable EM-type algorithm as well as score test. Through simulations, we demonstrate that our method of incorporating family history of disease improves efficiency as well as power of detecting disease-associated genetic variants over the methods of using probands data alone, which emphasizes the importance of family studies. Lastly, we apply these methods to discover genetic variants associated with the risk of Alzheimer's disease (AD) for GWAS+FH collected in Washington Heights-Inwood Columbia Aging Project (WHICAP) Caribbean Hispanics. We identified several genetic variants which would not have been discovered by GWAS using proband data alone. In the third part of the dissertation, we build on the previously introduced random effects to propose a method for genetic association tests in order to control confounding due to familial relatedness in GWAS. It is critical to correct for confounding due to familial relatedness in GWAS in order to minimize spurious associations as well as maximize power to detect true association signals. With available pedigree data, our method uses the polygenic effects as well as the shared non-genetic familial effects in order to control confounding due to familial relatedness in GWAS. Through application to the WHICAP Caribbean Hispanic probands, we show that our method of using the polygenic effects as well as the shared familial effects achieves similar or better performance of controlling the familial relatedness compared to using principal components in GWAS. Notably, our method allows for controlling the confounding due to using family history data, but without requiring dense genotypes in the relatives. We conclude this dissertation by discussing future extensions of this work.

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The purpose of this study was to examine attitudes about gay marriage. The main research question was: Do traditional attitudes toward familial gender roles and conservative, moderate, and liberal views about religiosity impact attitudes about gay marriage? I used data from the 2006 General Social Survey (GSS) of 1,977 adults living in the United States. Results of this study found people with traditional attitudes toward familial gender roles have more negative attitudes about gay marriage. Also, people with strong religious affiliation and more frequent attendance at religious services have more negative attitudes about gay marriage. Furthermore, people who were very religious and belonged to specific religious affiliations have more negative attitudes about gay marriage. Conversely, this study found people who were slightly religious, not religious, and very spiritual have more positive attitudes about gay marriage and people who belonged to specific religious affiliations have more positive attitudes about gay marriage. / Dr. Melissa Swauger Dr. Diane Shinberg Dr. Kay Snyder

Texte remanié de: Thèse de doctorat--Sciences de l'éducation--Paris 10, 2006. / Bibliogr. p. 151-170.

The expectation for a gene dose effect in an X-linked phenotype is that the corresponding metrical trait in heterozygous females will lie between values for affected hemizygous males and unaffected males and females. I made sequential measurements (at 30, 60, 90, 120 and 150 days) of serum phosphate concentration and tail length in mice with X-linked hypophosphatemia (mutant genotypes: Hyp/+, Hyp/Y and Hyp/Hyp) and in their normal littermates (genotypes: +/+ +/Y). I also measured renal mitochondrial 24-OHase activity in mice fed control and low phosphate diets and representing all five genotypes. I further studied serum AP activity and vertebral bone histomorphometry in the five genotypes. The mutant animals all had uniformly and significantly different values than unaffected littermates. There was no evidence of a gene dose effect because values were not significantly different among the three mutant genotypes. / I also studied the influence of gamete of origin on serum phosphate, tail length, renal mitochondrial 24-OHase activity, serum AP activity and vertebral bone histomorphometry in the Hyp/+ offspring of affected males (Hyp/Y) or affected females (Hyp/+ or Hyp/Hyp). I found no effect on the distribution of trait values. / I conclude that parental origin of the mutant allele does not explain the absence of a gene dose effect in Hyp mice.

The X-linked Hyp mutation is characterized by a specific defect in phosphate (Pi) transport at the renal brush-border membrane (BBM). To understand the mechanism for the 50% decrease in Vmax of the high affinity Pi transport system in BBM of Hyp mice, we compared the effects of external Na$ sp+$ concentration, membrane potential, external pH, and Pi transport inhibitors on Pi uptake in BBM vesicles (BBMV) prepared from normal mice and Hyp littermates. / The apparent affinity for Na$ sp+$, the Na$ sp+{:}$Pi stoichiometry, the response to membrane potential and the response to external pH are similar in BBMV from both normals and mutants. / The Ki for phosphonoformic acid (PFA) inhibition of Na$ sp+$-Pi cotransport is lower in BBMV prepared from Hyp mice when compared to normal mice but not different in BBMV from Pi-deprived mice which are characterized by an increase in Vmax of the high affinity Na$ sp+$-Pi cotransport system. / We conclude that the decrease in Vmax of the high affinity Na$ sp+$-Pi cotransport system in the Hyp mouse is not the result of an inappropriate response of the transport system to Na$ sp+$, membrane potential or pH.

Na$ sp+$-Pi cotransport across the brush border membrane is the rate limiting step in renal Pi reabsorption. To determine its precise role in the maintenance of Pi homeostasis, we cloned and characterized the renal-specific Na$ sp+$-Pi cotransporter/Npt2 gene and generated a gene targeting vector for the creation of a knockout mouse. The gene was cloned by screening a genomic DNA library with a rat Npt2 cDNA probe. The Npt2 gene is approximately 17kb and contains 13 exons and 12 introns. A targeting construct was generated by inserting 5$ sp prime$ and 3$ sp prime$ homologous arms of 2.1 and 2kb, respectively, into the pPNT vector and replacing 7.7kb of Npt2 with a neomycin resistance gene. The vector also contained the herpes simplex virus thymidine kinase gene for negative selection. After electroporation into embryonic stem cells, clones were picked following selection in G418 and FIAU. Of 100 doubly-resistant clones that were screened by Southern analysis, 6 positive clones were detected giving a targeting frequency of 6%.