L'évaluation du rôle des facteurs génétiques dans la genèse des terreurs nocturnes chez l'enfant : étude prospective chez les jumeaux.

Depuis plusieurs années, les études ont bien démontré que les troubles du sommeil tendent à être héréditaires. Il existe de plus en plus d’évidence scientifique démontrant l’implication des facteurs génétiques dans la manifestation des terreurs nocturnes. Les études de jumeaux sont essentielles pour évaluer l’influence des facteurs génétiques et environnementaux dans les affections complexes comme les terreurs nocturnes. Cependant, la plupart des études antérieures de jumeaux sur les terreurs nocturnes sont, soient des études rétrospectives ou encore des études avec un échantillon insuffisant de patients, ce qui résulte en des résultats peu concluants. L’objectif de ce mémoire était de déterminer la contribution des facteurs génétiques et des facteurs environnementaux dans la manifestation des terreurs nocturnes d’une large cohorte de jeunes jumeaux suivis d’une façon prospective. Ce mémoire a montré que la proportion de la variance phénotypique totale des terreurs nocturnes due aux influences génétiques est plus que 40% pour les jumeaux âgés de 18 et de 30 mois. La corrélation polychorique, à l’âge de 18 mois, est de 0,63 chez les jumeaux monozygotes et de 0,36 chez les jumeaux dizygotes du même âge. À l’âge de 30 mois, cette corrélation est de 0,68 chez les monozygotes et de 0,24 chez les dizygotes. Ceci démontre que les facteurs génétiques jouent un rôle important dans la manifestation des terreurs nocturnes chez les enfants de très jeune âge. Basée sur l’héritabilité, cette étude suggère que la prédisposition génétique soit associée avec la persistance des symptômes des terreurs nocturnes jusqu’à l’âge de 30 mois.

Quand la politique et la génétique se rencontrent : comment le public interprète-t-il la recherche?

L’objectif général de cette thèse de doctorat est de mieux comprendre comment le public interprète les nouvelles scientifiques portant sur la génétique humaine, plus précisément les nouvelles portant sur la génétique des comportements et celles portant sur la génétique des groupes raciaux. L’ouvrage prend la forme d’une thèse par article. Le Chapitre 1 introduit le lecteur aux buts et aux pratiques de la vulgarisation scientifique, présente un sommaire de la recherche sur les effets des médias, résume les principaux travaux produits par le champ de la génopolitique, et définit la structure des croyances du public à l’égard de l’influence de la génétique sur les traits humains. Le Chapitre 2 présente les fondements de la méthode expérimentale, il en explique les atouts et il offre des exemples de différents types de devis expérimentaux utilisés en science politique. Toutes les recherches produites dans cette thèse reposent au moins en partie sur cette méthode. Le Chapitre 3 présente les résultats d’une expérience de sondage qui vise à mesurer l’effet de la lecture d’une nouvelle à propos de la recherche en génétique des comportements sur des participants. L’étude démontre que le public interprète la nouvelle avec maladresse et tend à généraliser l’influence de la génétique à d’autres traits humains qui n’y sont pas mentionnés. J’avance l’hypothèse qu’un raccourci psychologique amplement documenté puisse expliquer cette réaction : l’heuristique de l’ancrage et de l’ajustement. Le Chapitre 4 présente lui aussi les résultats d’une expérience de sondage. L’étude consiste à manipuler certaines informations du contenu d’une nouvelle sur la génopolitique de manière à vérifier si certains éléments sont particulièrement susceptibles de mener à la généralisation hâtive mise en évidence dans le Chapitre 3. Les analyses suggèrent que cette généralisation est amplifiée lorsque la nouvelle présente de hauts niveaux d’héritabilité tirés d’études de jumeaux, ainsi que lorsqu’elle présente des travaux de génétique des populations visant à étudier l’origine des différences géographiques. Ce chapitre présente des recommandations à l’égard des journalistes scientifiques. Le Chapitre 5 s’intéresse à un aspect différent de la génétique humaine : celui de la génétique des races. L’objectif de cette recherche est de comprendre comment le public réagit aux travaux qui invalident l’idée selon laquelle les humains sont divisés en différentes races génétiquement distinctes. Les analyses de données transversales ainsi que les résultats d’une expérience de sondage convergent et indiquent que les conservateurs et les libéraux réagissent de manière diamétralement opposée à cette information. D’un côté, les libéraux acceptent le constat scientifique et réduisent leur impression que la génétique explique en partie les inégalités sociales; de l’autre, les conservateurs rejettent l’argument avec une intensité si forte que le rôle qu’ils attribuent aux différences génétiques s’en voit bonifié. Ces résultats sont interprétés à partir de la théorie du raisonnement motivé. Enfin, le Chapitre 6 résume les principaux constats, met en évidence les contributions que ma thèse apporte à la science politique et à la communication scientifique, et présente quelques pistes pour la recherche future.

Identification of Genomic Variants Associated with Adolescent Idiopathic Scoliosis (AIS) in French-Canadian Population

La scoliose idiopathique est une déformation tridimensionnelle de la colonne vertébrale dont la pathogenèse reste obscure. Cette maladie affecte 2-4% des adolescents de 10-18 ans parmi les garçons et les filles. Il est à noter que les filles sont plus sévèrement affectées et ce en plus grand nombre que les garçons. Les études de jumeaux ont montré que les facteurs génétiques jouent un rôle important dans la scoliose idiopathique de l'adolescent (SIA). Depuis 2010, les études d'association pan génomiques ont été multipliées dans les recherches, visant à trouver des gènes candidats impliqués dans la SIA à travers des examens des polymorphismes nucléotidiques (SNPs). Un test génétique nommé "ScoliScore" a été publié pour essayer de prédire la progression de courbure dans la population caucasienne. Cependant, l'association n'a pas été reproduite dans une grande étude japonaise, soulignant l'importance d'une étude de réplication dans une population caucasienne indépendante. Dans ce contexte, mon projet de maîtrise a permis de génotyper plus de 1,4 millions de SNPs dans une cohorte canadienne-française dans le but: 1) de valider l'association de ScoliScoreTM; et 2) d’identifier les variants génomiques associées à la SIA dans la population québécoise. Notre étude a montré qu’aucun des variants constituant le test ScoliScoreTM n’était associé à la SIA. Ceci suggère que l'absence d'association dans une cohorte japonaise n'est pas due à l'appartenance ethnique. Aussi, nous avons identifié des variants génomiques associés significativement à l’initiation et/ou la progression de SIA dans la population québécoise, suggérant des gènes candidats impliqués dans la pathogenèse de SIA.

El perfil criminal del asesino en serie colombiano desde la perspectiva psicodinámica. Una revisión de literatura

El objetivo de la presente investigación consiste en describir las características de un asesino en serie colombiano desde la perspectiva psicodinámica. En este sentido, el abordaje teórico realizado en este trabajo se compone inicialmente de una concepción de asesinos en serie, posteriormente se hace una revisión acerca de las bases biológicas y los factores sociales del homicida serial, igualmente, se explican tres teorías psicodinámicas a trabajar (Sigmund Freud y Erick Erickson). Finalmente, se hace mención dentro de la investigación a la comparación casuística de los asesinos en serie, teniendo en cuenta a cuatro asesinos en serie mediante el abordaje psicodinámico. Por otra parte, a nivel metodológico, el tipo de estudio realizado es descriptivo con un corte cualitativo y un diseño no experimental, basado en la revisión de fuentes bibliográficas. Como producto se pretende hacer una aproximación al perfil correspondiente de la personalidad de un asesino en serie colombiano mediante las teorías psicodinámicas.

Eficacia y seguridad de la melatonina para el manejo de los trastornos del sueño en el autismo: meta-análisis

INTRODUCCIÓN: El 80% de los niños y adolescentes con trastornos del espectro autista (TEA) presenta algún trastorno del sueño, en cuya génesis al parecer intervienen alteraciones en la regulación de la melatonina. El objetivo de este metaanálisis fue determinar la eficacia y seguridad de la melatonina para el manejo de ciertos trastornos del sueño en niños con TEA. MÉTODOS: Tres revisores extrajeron los datos relevantes de los ensayos clínicos aleatorizados doble ciego de alta calidad publicados en bases de datos primarias, de ensayos clínicos, de revisiones sistemáticas y de literatura gris; además se realizó búsqueda en bola de nieve. Se analizaron los datos con RevMan 5.3. Se realizó un análisis del inverso de la varianza por un modelo de efectos aleatorios para las diferencias de medias de los desenlaces propuestos: duración del tiempo total, latencia de sueño y número de despertares nocturnos. Se evaluó la heterogeneidad interestudios con el parámetro I2 RESULTADOS: La búsqueda inicial arrojó 355 resultados, de los cuales tres cumplieron los criterios de selección. La melatonina resultó ser un medicamento seguro y eficaz para aumentar la duración total del sueño y disminuir la latencia de sueño en niños y adolescentes con TEA; hasta el momento la evidencia sobre el número de despertares nocturnos no es estadísticamente significativa. DISCUSIÓN: A la luz de la evidencia disponible, la melatonina es una elección segura y eficaz para el manejo de ciertos problemas del sueño en niños y adolescentes con TEA. Es necesario realizar estudios con mayores tamaños muestrales y comparados con otros medicamentos disponibles en el mercado.

Análise de ligação e associação no genoma com gagueira desenvolvimental persistente em famílias do Estado de São Paulo-Brasil

Pós-graduação em Ciências Biológicas (Genética) - IBB

Genetic determinants of alcoholic liver disease

Alcoholic liver disease (ALD) accounts for the majority of chronic liver disease in Western countries. The spectrum of ALD includes steatosis with or without fibrosis in virtually all individuals with an alcohol consumption of >80 g/day, alcoholic steatohepatitis of variable severity in 10-35% and liver cirrhosis in approximately 15% of patients. Once cirrhosis is established, there is an annual risk for hepatocellular carcinoma of 1-2%. Environmental factors such as drinking patterns, coexisting liver disease, obesity, diet composition and comedication may modify the natural course of ALD. Twin studies have revealed a substantial contribution of genetic factors to the evolution of ALD, as demonstrated by a threefold higher disease concordance between monozygotic twins and dizygotic twins. With genotyping becoming widely available, a large number of genetic case-control studies evaluating candidate gene variants coding for proteins involved in the degradation of alcohol, mediating antioxidant defence, the evolution and counteraction of necroinflammation and formation and degradation of extracellular matrix have been published with largely unconfirmed, impeached or even disproved associations. Recently, whole genome analyses of large numbers of genetic variants in several chronic liver diseases including gallstone disease, primary sclerosing cholangitis and non-alcoholic fatty liver disease (NAFLD) have identified novel yet unconsidered candidate genes. Regarding the latter, a sequence variation within the gene coding for patatin-like phospholipase encoding 3 (PNPLA3, rs738409) was found to modulate steatosis, necroinflammation and fibrosis in NAFLD. Subsequently, the same variant was repeatedly confirmed as the first robust genetic risk factor for progressive ALD.

The role of genetic polymorphisms in alcoholic liver disease

Chronic alcohol consumption is a major cause of liver cirrhosis which, however, develops in only a minority of heavy drinkers. Evidence from twin studies indicates that genetic factors account for at least 50% of individual susceptibility. The contribution of genetic factors to the development of diseases may be investigated either by means of animal experiments, through linkage studies in families of affected patients, or population based case-control studies. With regard to the latter, single nucleotide polymorphisms of genes involved in the degradation of alcohol, antioxidant defense, necroinflammation, and formation and degradation of extracellular matrix are attractive candidates for studying genotype-phenotype associations. However, many associations in early studies were found to be spurious and could not be confirmed in stringently designed investigations. Therefore, future genotype-phenotype studies in alcoholic liver disease should meet certain requirements in order to avoid pure chance observations due to a lack of power, false functional interpretation, and insufficient statistical evaluation.

Knockdown of Kiaa0319 Reduces Dendritic Spine Density

Developmental Dyslexia is a reading disorder that affects individuals that possess otherwise normal intelligence. Until the four candidate dyslexia susceptibility genes were discovered, the cause of cortical malformations found in post mortem dyslexic brains was unclear. Normal brain development is crucial for the proper wiring of the neural circuitry that allow an individual to perform cognitive tasks like reading. For years, familial and twin studies have suggested that there was a genetic basis to the causation of dyslexia. Kiaa0319 was among the candidate dyslexia susceptibility genes that were ascertained. KIAA0319 is located on Chromosome 6p22.2-22.3 and has been found to exhibit differential spatial-temporal expression patterns in the brain throughout development, which suggests that the polycystic kidney disease (PKD) domain encoded by KIAA0319 facilitates cell-cell adhesion to enable neuronal precursors to crawl up the radial glia during neuronal migration. With the knowledge of KIAA0319 involvement in early neurogenesis, we were interested in determining how different KIAA0319 expression may impact cortical neurons in layer II and III during early adulthood. We show that KIAA0319 knockdown in cortical pyramidal neurons significantly reduces the dendritic spine density. Studies have shown that changes in dendritic spine morphology and density affect properties of neural circuitry. Henceforth, this finding may reveal a link between the Kiaa0319 gene and the deficit of the neural processing task of reading due to reduced spines density. Finding a correlation between Kiaa0319 expression and its influence on dendritic spine development may lead to a greater insight of a direct link between the dyslexia susceptibility gene and the biological mechanism that causes dyslexia.

Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis

Over 2 billion people are estimated to be infected with virulent Mycobacterium tuberculosis, yet fewer than 10% progress to clinical tuberculosis within their lifetime. Twin studies and variations in the outcome of tuberculosis infection after exposure to similar environmental risks suggest genetic heterogeneity among individuals in their susceptibility to disease. In a mouse model of tuberculosis, we have established that resistance and susceptibility to virulent M. tuberculosis is a complex genetic trait. A new locus with a major effect on tuberculosis susceptibility, designated sst1 (susceptibility to tuberculosis 1), was mapped to a 9-centimorgan (cM) interval on mouse chromosome 1. It is located 10–19 cM distal to a previously identified gene, Nramp1, that controls the innate resistance of mice to the attenuated bacillus Calmette–Guérin vaccine strain. The phenotypic expression of the newly identified locus is distinct from that of Nramp1 in that sst1 controls progression of tuberculosis infection in a lung-specific manner. Mice segregating at the sst1 locus exhibit marked differences in the growth rates of virulent tubercle bacilli in the lungs. Lung lesions in congenic sst1-susceptible mice are characterized by extensive necrosis and unrestricted extracellular multiplication of virulent mycobacteria, whereas sst1-resistant mice develop interstitial granulomas and effectively control multiplication of the bacilli. The resistant allele of sst1, although powerful in controlling infection, is not sufficient to confer full protection against virulent M. tuberculosis, indicating that other genes located outside of the sst1 locus are likely also to be important for controlling tuberculosis infection.

New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study

Rheumatoid arthritis (RA), the most common autoimmune disease, is associated in families with other autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM). Its genetic component has been suggested by familial aggregation (λs = 5), twin studies, and segregation analysis. HLA, which is the only susceptibility locus known, has been estimated to account for one-third of this component. The aim of this paper was to identify new RA loci. A genome scan was performed with 114 European Caucasian RA sib pairs from 97 nuclear families. Linkage was significant only for HLA (P < 2.5⋅10−5) and nominal for 19 markers in 14 other regions (P < 0.05). Four of the loci implicated in IDDM potentially overlap with these regions: the putative IDDM6, IDDM9, IDDM13, and DXS998 loci. The first two of these candidate regions, defined in the RA genome scan by the markers D18S68-D18S61-D18S469 (18q22–23) and D3S1267 (3q13), respectively, were studied in 194 additional RA sib pairs from 164 nuclear families. Support for linkage to chromosome 3 only was extended significantly (P = 0.002). The analysis of all 261 families provided a linkage evidence of P = 0.001 and suggested an interaction between this putative RA locus and HLA. This locus could account for 16% of the genetic component of RA. Candidate genes include those coding for CD80 and CD86, molecules involved in antigen-specific T cell recognition. In conclusion, this first genome scan in RA Caucasian families revealed 14 candidate regions, one of which was supported further by the study of a second set of families.

Is cannabis a gateway drug? Testing hypotheses about the relationship between cannabis use and the use of other illicit drugs

We outline and evaluate competing explanations of three relationships that have consistently been found between cannabis use and the use of other illicit drugs, namely, ( 1) that cannabis use typically precedes the use of other illicit drugs; and that ( 2) the earlier cannabis is used, and ( 3) the more regularly it is used, the more likely a young person is to use other illicit drugs. We consider three major competing explanations of these patterns: ( 1) that the relationship is due to the fact that there is a shared illicit market for cannabis and other drugs which makes it more likely that other illicit drugs will be used if cannabis is used; ( 2) that they are explained by the characteristics of those who use cannabis; and ( 3) that they reflect a causal relationship in which the pharmacological effects of cannabis on brain function increase the likelihood of using other illicit drugs. These explanations are evaluated in the light of evidence from longitudinal epidemiological studies, simulation studies, discordant twin studies and animal studies. The available evidence indicates that the association reflects in part but is not wholly explained by: ( 1) the selective recruitment to heavy cannabis use of persons with pre-existing traits ( that may be in part genetic) that predispose to the use of a variety of different drugs; ( 2) the affiliation of cannabis users with drug using peers in settings that provide more opportunities to use other illicit drugs at an earlier age; ( 3) supported by socialisation into an illicit drug subculture with favourable attitudes towards the use of other illicit drugs. Animal studies have raised the possibility that regular cannabis use may have pharmacological effects on brain function that increase the likelihood of using other drugs. We conclude with suggestions for the type of research studies that will enable a decision to be made about the relative contributions that social context, individual characteristics, and drug effects make to the relationship between cannabis use and the use of other drugs.

Genetic and environmental influences on extreme personality dispositions in adolescent female twins

Background: The objective was to determine whether the pattern of environmental and genetic influences on deviant personality scores differs from that observed for the normative range of personality, comparing results in adolescent and adult female twins. Methods: A sample of 2,796 female adolescent twins ascertained from birth records provided Junior Eysenck Personality Questionnaire data. The average age of the sample was 17.0 years ( S. D. 2.3). Genetic analyses of continuous and extreme personality scores were conducted. Results were compared for 3,178 adult female twins. Results: Genetic analysis of continuous traits in adolescent female twins were similar to findings in adult female twins, with genetic influences accounting for between 37% and 44% of the variance in Extraversion (Ex), Neuroticism (N), and Social Non-Conformity (SNC), with significant evidence of shared environmental influences (19%) found only for SNC in the adult female twins. Analyses of extreme personality characteristics, defined categorically, in the adolescent data and replicated in the adult female data, yielded estimates for high N and high SNC that deviated substantially (p < .05) from those obtained in the continuous trait analyses, and provided suggestive evidence that shared family environment may play a more important role in determining personality deviance than has been previously found when personality is viewed continuously. However, multiple-threshold models that assumed the same genetic and environmental determinants of both normative range variation and extreme scores gave acceptable fits for each personality dimension. Conclusions: The hypothesis of differences in genetic or environmental factors responsible for N and SNC among female twins with scores in the extreme versus normative ranges was partially supported, but not for Ex.

Handedness in twins: Joint analysis of data from 35 samples

Simultaneous analysis of handedness data from 35 samples of twins (with a combined sample size of 21,127 twin pairs) found a small but significant additive genetic effect accounting for 25.47% of the variance (95% confidence interval [CI] 15.69-29.51%). No common environmental influences were detected (C = 0.00; 95% Cl 0.00-7.67%), with the majority of the variance, 74.53%, explained by factors unique to the individual (95% Cl 70.49-78.67%). No significant heterogeneity was observed within studies that used similar methods to assess handedness, or across studies that used different methods. At an individual level the majority of studies had insufficient power to reject a purely unique environmental model due to insufficient power to detect familial aggregation. This lack of power is seldom mentioned within studies, and has contributed to the misconception that twin studies of handedness are not informative.

Myopia:precedents for research in the twenty-first century

The myopic eye is generally considered to be a vulnerable eye and, at levels greater than 6 D, one that is especially susceptible to a range of ocular pathologies. There is concern therefore that the prevalence of myopia in young adolescent eyes has increased substantially over recent decades and is now approaching 10-25% and 60-80%, respectively, in industrialized societies of the West and East. Whereas it is clear that the major structural correlate of myopia is longitudinal elongation of the posterior vitreous chamber, other potential correlates include profiles of lenticular and corneal power, the relationship between longitudinal and transverse vitreous chamber dimensions and ocular volume. The most potent predictors for juvenile-onset myopia continue to be a refractive error ≤+0.50 D at 5 years of age and family history. Significant and continuing progress is being made on the genetic characteristics of high myopia with at least four chromosomes currently identified. Twin studies and genetic modelling have computed a heritability index of at least 80% across the whole ametropic continuum. The high index does not, however, preclude an environmental precursor, sustained near work with high cognitive demand being the most likely. The significance of associations between accommodation, oculomotor dysfunction and human myopia is equivocal despite animal models that have demonstrated that sustained hyperopic defocus can induce vitreous chamber growth. Recent optical and pharmaceutical approaches to the reduction of myopia progression in children are likely precedents for future research, for example progressive addition spectacle lens trials and the use of the topical MI muscarinic antagonist pirenzepine.