Modeling the effect of a genetic factor for a complex trait in a simulated population

Genetic Analysis Workshop 14 simulated data have been analyzed with MASC(marker association segregation chi-squares) in which we implemented a bootstrap procedure to provide the variation intervals of parameter estimates. We model here the effect of a genetic factor, S, for Kofendrerd Personality Disorder in the region of the marker C03R0281 for the Aipotu population. The goodness of fit of several genetic models with two alleles for one locus has been tested. The data are not compatible with a direct effect of a single-nucleotide polymorphism (SNP) (SNP 16, 17, 18, 19 of pack 153) in the region. Therefore, we can conclude that the functional polymorphism has not been typed and is in linkage disequilibrium with the four studied SNPs. We obtained very large variation intervals both of the disease allele frequency and the degree of dominance. The uncertainty of the model parameters can be explained first, by the method used, which models marginal effects when the disease is due to complex interactions, second, by the presence of different sub-criteria used for the diagnosis that are not determined by S in the same way, and third, by the fact that the segregation of the disease in the families was not taken into account. However, we could not find any model that could explain the familial segregation of the trait, namely the higher proportion of affected parents than affected sibs

Prognostic value of histopathology and trends in cervical cancer: a SEER population study

<p>Abstract</p> <p>Background</p> <p>Histopathology is a cornerstone in the diagnosis of cervical cancer but the prognostic value is controversial.</p> <p>Methods</p> <p>Women under active follow-up for histologically confirmed primary invasive cervical cancer were selected from the United States Surveillance, Epidemiology, and End Results (SEER) 9-registries public use data 1973–2002. Only histologies with at least 100 cases were retained. Registry area, age, marital status, race, year of diagnosis, tumor histology, grade, stage, tumor size, number of positive nodes, number of examined nodes, odds of nodal involvement, extent of surgery, and radiotherapy were evaluated in Cox models by stepwise selection using the Akaike Information Criteria.</p> <p>Results</p> <p>There were 30,989 records evaluable. From 1973 to 2002, number of cases dropped from 1,100 new cases/year to 900/year, but adenocarcinomas and adenosquamous carcinoma increased from 100/year to 235/year. Median age was 48 years. Statistically significant variables for both overall and cause-specific mortality were: age, year of diagnosis, race, stage, histology, grade, hysterectomy, radiotherapy, tumor size and nodal ratio. The histological types were jointly significant, P < 0.001. Cause-specific mortality hazard ratios by histological type relatively to non-microinvasive squamous cell carcinoma were: microinvasive squamous cell carcinoma 0.28 (95% confidence interval: 0.20–0.39), carcinoma not otherwise specified 0.91 (0.79–1.04), non-mucinous adenocarcinoma 1.06 (0.98–1.15), adenosquamous carcinoma 1.35 (1.20–1.51), mucinous adenocarcinoma 1.52 (1.23–1.88), small cell carcinoma 1.94 (1.58–2.39).</p> <p>Conclusion</p> <p>Small cell carcinoma and adenocarcinomas were associated with poorer survival. The incidental observation of increasing numbers of adenocarcinomas despite a general decline suggests the inefficiency of conventional screening for these tumors. Increased incidence of adenocarcinomas, their adverse prognosis, and the young age at diagnosis indicate the need to identify women who are at risk.</p

Progressive Retinal Atrophy in the Border Collie: A new XLPRA

<p>Abstract</p> <p>Background</p> <p>Several forms of progressive retinal atrophy (PRA) segregate in more than 100 breeds of dog with each PRA segregating in one or a few breeds. This breed specificity may be accounted for by founder effects and genetic drift, which have reduced the genetic heterogeneity of each breed, thereby facilitating the identification of causal mutations. We report here a new form of PRA segregating in the Border Collie breed. The clinical signs, including the loss of night vision and a progressive loss of day vision, resulting in complete blindness, occur at the age of three to four years and may be detected earlier through systematic ocular fundus examination and electroretinography (ERG).</p> <p>Results</p> <p>Ophthalmic examinations performed on 487 dogs showed that affected dogs present a classical form of PRA. Of those, 274 have been sampled for DNA extraction and 87 could be connected through a large pedigree. Segregation analysis suggested an X-linked mode of transmission; therefore both XLPRA1 and XLPRA2 mutations were excluded through the genetic tests.</p> <p>Conclusion</p> <p>Having excluded these mutations, we suggest that this PRA segregating in Border Collie is a new XLPRA (XLPRA3) and propose it as a potential model for the homologous human disease, X-Linked Retinitis Pigmentosa.</p

Genetics of VEGF Serum Variation in Human Isolated Populations of Cilento: Importance of VEGF Polymorphisms

Vascular Endothelial Growth Factor (VEGF) is the main player in angiogenesis. Because of its crucial role in this process, the study of the genetic factors controlling VEGF variability may be of particular interest for many angiogenesis-associated diseases. Although some polymorphisms in the VEGF gene have been associated with a susceptibility to several disorders, no genome-wide search on VEGF serum levels has been reported so far. We carried out a genome-wide linkage analysis in three isolated populations and we detected a strong linkage between VEGF serum levels and the 6p21.1 VEGF region in all samples. A new locus on chromosome 3p26.3 significantly linked to VEGF serum levels was also detected in a combined population sample. A sequencing of the gene followed by an association study identified three common single nucleotide polymorphisms (SNPs) influencing VEGF serum levels in one population (Campora), two already reported in the literature (rs3025039, rs25648) and one new signal (rs3025020). A fourth SNP (rs41282644) was found to affect VEGF serum levels in another population (Cardile). All the identified SNPs contribute to the related population linkages (35% of the linkage explained in Campora and 15% in Cardile). Interestingly, none of the SNPs influencing VEGF serum levels in one population was found to be associated in the two other populations. These results allow us to exclude the hypothesis that the common variants located in the exons, intron-exon junctions, promoter and regulative regions of the VEGF gene may have a causal effect on the VEGF variation. The data support the alternative hypothesis of a multiple rare variant model, possibly consisting in distinct variants in different populations, influencing VEGF serum levels

Correction: Exome Sequencing in an Admixed Isolated Population IndicatesNFXL1 Variants Confer a Risk for Specific Language Impairment

Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10–4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model

Clinique médicale, clinique psychologique

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René Major, entre résistance et désistance

International audiencePsychanalyste de renom, René Major est l'auteur d'une remarquable oeuvre de pensée qui a ouvert, notamment grâce aux Cahiers Confrontation, un espace de dialogue entre la psychanalyse, la philosophie et la littérature, en élargissant ces échanges aux discours des sciences humaines. Selon le voeu formulé lors de la création en 2003 de l'Institut des Hautes Etudes en Psychanalyse qu'il a présidé jusqu'en 2017, ses travaux ont relancé l'étude de la psychanalyse dans toutes ses composantes : cliniques, théoriques, éthiques. Lecteur éclairé des oeuvres de Freud, Lacan et Derrida, René Major se distingue par la portée politique de sa réflexion qui analyse les symptômes individuels et sociaux, les nouvelles formes de violence et de cruauté dans la société. Accordant une attention particulière à la pulsion de pouvoir, sa réflexion s'est incarnée dans des engagements concrets, qu'il s'agisse de la politique de la psychanalyse face à la dictature et la torture au Brésil, de la guerre au Moyen-Orient, des maux de l'économie néolibérale ou de l'organisation des Etats généraux de la psychanalyse en 2000.Cet ouvrage réunit pour la première fois autour de cette oeuvre unique psychanalystes, philosophes, historiens et critiques littéraires, qui entendent saluer le travail et l'enseignement de René Major, mais surtout penser avec lui cette "psychanalyse à venir" telle qu'il la rêve et l'imagine

Der Andere in sich oder die Frage des Doppelgangers bei einem Dichter

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De l'inaudible à l'inouï

Convoquant différentes scènes d'héritage, ces variations cliniques autour d'un texte important de Ferenczi entendent ré-ouvrir, à la lumière des pratiques actuelles, les redoutables questions qui divisent encore la communauté analytique : traumatisme, fantasme, pulsion de mort. Il nous faut déplier patiemment ce texte pour en entendre les résonances actuelles : aux limites de l'analysable, il s'agit parfois d'attendre de façon active pour pouvoir entendre, sinon l'inaudible, du moins l'inouï