Comparing strategies for association mapping in samples with related individuals

In this paper, different strategies to test for association in samples with related individuals designed for linkage studies are compared. Because no independent controls are available, a family-based association test and case-control tests corrected for the presence of related individuals in which unaffected relatives are used as controls were tested. When unrelated controls are available, additional strategies including selection of a single case per family considering either all families or a subset of linked families, are also considered. Analyses are performed on the simulated dataset, blind to the answers. The case-control test corrected for the presence of related individuals is the most powerful strategy to detect three loci associated with the disease under study. Using a correction factor for the case-control test performed conditional on the marker information rather than unconditional does not impact the power significantly

Impact of the diagnosis definition on linkage detection

Previous genome scan linkage analyses of the disease Kofendrerd Personality Disorder (KPD) with microsatellites led to detect some regions on chromosomes 1, 3, 5, and 9 that were identical for the three populations AI, KA, and DA but with large differences in significance levels. These differences in results may be explained by the different diagnosis definitions depending on the presence/absence of 12 traits that were used in the 3 populations AI, KA, and DA. Heterogeneity of linkage was thus investigated here according to the absence/presence of each of the 12 traits in the 3 populations. For this purpose, two methods, the triangle test statistic and the predivided sample test were applied to search for genetic heterogeneity. Three regions with a strong heterogeneity of linkage were detected: the region on chromosome 1 according to the presence/absence of the traits a and b, the region on chromosome 3 for the trait b, and the region on chromosome 9 for the traits k and l. These 3 regions were the same as those detected by linkage analyses. No novel region was detected by the heterogeneity tests. Concerning chromosome 1, linkage analyses showed a much stronger evidence of linkage for traits a and b and for a combination of these traits than for KPD. Moreover, there was no indication of linkage to any of the other traits used to define the diagnosis of KPD. A genetic factor located on the chromosome 1 may have been detected here which would be involved specifically in traits a and b or in a combination of these traits

Barriers to staff adoption of a surgical safety checklist

International audienceObjective: Implementation of a surgical checklist depends on many organisational factors and on socio-cultural patterns. The objective of this study was to identify barriers to effective implementation of a surgical checklist and to develop a best use strategy.Setting: 18 cancer centres in France.Design: The authors first assessed use compliance and completeness rates of the surgical checklist on a random sample of 80 surgical procedures performed under general or loco-regional anaesthesia in each of the 18 centres. They then developed a typology of the organisational and cultural barriers to effective checklist implementation and defined each barrier's contents using data from collective and semi-structured individual interviews of key staff, the results of an email questionnaire sent to the 18 centres, and direct observations over 20 h in two centres.Results: The study consisted of 1440 surgical procedures, 1299 checklists, and 28 578 items. The mean compliance rate was 90.2% (0, 100). The mean completion rate was 61% (0, 84). 11 barriers to effective checklist implementation were identified. Their incidence varied widely across centres. The main barriers were duplication of items within existing checklists (16/18 centres), poor communication between surgeon and anaesthetist (10/18), time spent completing the checklist for no perceived benefit, and lack of understanding and timing of item checks (9/18), ambiguity (8/18), unaccounted risks (7/18) and a time-honoured hierarchy (6/18).Conclusions: Several of the barriers to the successful implementation of the surgical checklist depended on organisational and cultural factors within each centre. The authors propose a strategy for change for checklist design, use and assessment, which could be used to construct a feedback loop for local team organisation and national initiatives

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

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

Early Development of Mouse Embryos Null Mutant for the Cyclin A2 Gene Occurs in the Absence of Maternally Derived Cyclin A2 Gene Products

AbstractProgression through the mammalian cell cycle is regulated by the sequential activation and inactivation of the cyclin-dependent kinases. In adult cells, cyclin A2-dependent kinases are required for entry into S and M phases, completion of S phase, and centrosome duplication. However, mouse embryos lacking the cyclin A2 gene nonetheless complete preimplantation development, but die soon after implantation. In this report, we investigated whether a contribution of maternal cyclin A2 mRNA and protein to early embryonic cell cycles might explain these conflicting observations. Our data show that a maternal stock of cyclin A2 mRNA is present in the oocyte and persists after fertilization until the second mitotic cell cycle, when it is degraded to undetectable levels coincident with transcriptional activation of the zygotic genome. A portion of maternally derived cyclin A2 protein is stable during the first mitosis and persists in the cytoplasm, but is completely degraded at the second mitosis. The ability of cyclin A2-null mutants to develop normally from the four-cell to the postimplantation stage in the absence of detectable cyclin A2 gene product indicates therefore that cyclin A2 is dispensable for cellular progression during the preimplantation nongrowth period of mouse embryo development

Geneva Statement on Heritable Human Genome Editing: The Need for Course Correction

As public interest advocates, policy experts, bioethicists, and scientists, we call for a course correction in public discussions about heritable human genome editing. Clarifying misrepresentations, centering societal consequences and concerns, and fostering public empowerment will support robust, global public engagement and meaningful deliberation about altering the genes of future generations

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

De la génétique clinique à la médecine génomique. Enjeux d’une « démocratisation » de l’accès aux technologies génomiques en contexte de soin

International audienceBy supporting genomic medicine, public policies aim to generalize the use of genetic testing in medical care. This text analyzes the conditions and effects of what is presented as an attempt to “democratize” the access to genomic technologies. Starting with clinical genetics, the paper describes the shifts in knowledge, practices and regulations implied by the current evolution. It argues that the discontinuities between clinical genetics and genomic medicine are important and that the diffusion of genomics cannot be reduced to a problem of technology transfer from research to the clinic. The text insists on the double complexification that characterizes this process – the complexification of the network of actors concerned by genomics and the complexification of the epistemological modalities through which the genetic explanation is mobilized. In addition to the threshold effects associated with the change of scale occurring in the use of genetic testing, notable displacements also result from the diversification of the social worlds concerned by genomics.En soutenant la médecine génomique, les politiques publiques ambitionnent de généraliser le recours à la génétique dans les prises en charge médicales. Pour analyser les conditions et les effets de ce qui s’affiche comme une « démocratisation » de l’accès aux technologies génomiques, ce texte part de la génétique clinique pour décrire les déplacements de savoirs, de pratiques et de régulations que cette évolution implique. Il défend l’idée que les discontinuités entre génétique clinique et médecine génomique sont fortes et que la généralisation du recours à la génomique n’est pas réductible à un problème de transfert de technologies depuis la recherche vers la clinique. Il insiste sur le double mouvement de complexification qui accompagne la massification du recours à ces technologies – complexification du réseau d’acteurs concernés et complexification des modalités épistémologiques de convocation de l’explication génétique. Aux effets de seuils liés au changement d’échelle, s’ajoutent ainsi des évolutions fortes résultant de la diversification des mondes sociaux concerné