Genetic architecture of ambulatory blood pressure in the general population: insights from cardiovascular gene-centric array.

Genetic determinants of blood pressure are poorly defined. We undertook a large-scale, gene-centric analysis to identify loci and pathways associated with ambulatory systolic and diastolic blood pressure. We measured 24-hour ambulatory blood pressure in 2020 individuals from 520 white European nuclear families (the Genetic Regulation of Arterial Pressure of Humans in the Community Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array, which contains ≈50 000 single nucleotide polymorphisms in >2000 cardiovascular candidate loci. We found a strong association between rs13306560 polymorphism in the promoter region of MTHFR and CLCN6 and mean 24-hour diastolic blood pressure; each minor allele copy of rs13306560 was associated with 2.6 mm Hg lower mean 24-hour diastolic blood pressure (P=1.2×10(-8)). rs13306560 was also associated with clinic diastolic blood pressure in a combined analysis of 8129 subjects from the Genetic Regulation of Arterial Pressure of Humans in the Community Study, the CoLaus Study, and the Silesian Cardiovascular Study (P=5.4×10(-6)). Additional analysis of associations between variants in gene ontology-defined pathways and mean 24-hour blood pressure in the Genetic Regulation of Arterial Pressure of Humans in the Community Study showed that cell survival control signaling cascades could play a role in blood pressure regulation. There was also a significant overrepresentation of rare variants (minor allele frequency: <0.05) among polymorphisms showing at least nominal association with mean 24-hour blood pressure indicating that a considerable proportion of its heritability may be explained by uncommon alleles. Through a large-scale gene-centric analysis of ambulatory blood pressure, we identified an association of a novel variant at the MTHFR/CLNC6 locus with diastolic blood pressure and provided new insights into the genetic architecture of blood pressure.

Defining the role of common variation in the genomic and biological architecture of adult human height.

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Enterprise Architecture Principles in Research and Practice: Insights from an Exploratory Analysis

Even though architecture principles were first discussed in the 1990s, they are still perceived as an underexplored topic in enterprise architecture management research. By now, there is an increasing consensus about EA principles' nature, as well as guidelines for their formulation. However, the extant literature remains vague about what can be considered suitable EA design and evolution guidance principles. In addition, empirical insights regarding their role and usefulness in practice are still lacking. Accordingly, this research seeks to address three questions: (1) What are suitable principles to guide EA design and evolution? (2) What usage do EA principles have for practitioners? (3) Which propositions can be derived regarding EA principles' role and application? Opting for exploratory research, we apply a research process covering critical analysis of current publications as well as capturing experts' perceptions. Our research ontologically distinguishes between principles from nonprinciples, proposes a validated set of meta-principles, and clarifies principles' application, role, and usefulness in practice. The explored insights can be used as guidelines in defining suitable principles and turning them into an effective bridge between strategy and design and a guide in design decisions.

Trabecular bone score (TBS) the new parameter of 2D texture analysis for the evaluation of 3D bone micro architecture status

X-ray is a technology that is used for numerous applications in the medical field. The process of X-ray projection gives a 2-dimension (2D) grey-level texture from a 3- dimension (3D) object. Until now no clear demonstration or correlation has positioned the 2D texture analysis as a valid indirect evaluation of the 3D microarchitecture. TBS is a new texture parameter based on the measure of the experimental variogram. TBS evaluates the variation between 2D image grey-levels. The aim of this study was to evaluate existing correlations between 3D bone microarchitecture parameters - evaluated from μCT reconstructions - and the TBS value, calculated on 2D projected images. 30 dried human cadaveric vertebrae were acquired on a micro-scanner (eXplorer Locus, GE) at isotropic resolution of 93 μm. 3D vertebral body models were used. The following 3D microarchitecture parameters were used: Bone volume fraction (BV/TV), Trabecular thickness (TbTh), trabecular space (TbSp), trabecular number (TbN) and connectivity density (ConnD). 3D/2D projections has been done by taking into account the Beer-Lambert Law at X-ray energy of 50, 100, 150 KeV. TBS was assessed on 2D projected images. Correlations between TBS and the 3D microarchitecture parameters were evaluated using a linear regression analysis. Paired T-test is used to assess the X-ray energy effects on TBS. Multiple linear regressions (backward) were used to evaluate relationships between TBS and 3D microarchitecture parameters using a bootstrap process. BV/TV of the sample ranged from 18.5 to 37.6% with an average value at 28.8%. Correlations' analysis showedthat TBSwere strongly correlatedwith ConnD(0.856≤r≤0.862; p<0.001),with TbN (0.805≤r≤0.810; p<0.001) and negatively with TbSp (−0.714≤r≤−0.726; p<0.001), regardless X-ray energy. Results show that lower TBS values are related to "degraded" microarchitecture, with low ConnD, low TbN and a high TbSp. The opposite is also true. X-ray energy has no effect onTBS neither on the correlations betweenTBS and the 3Dmicroarchitecture parameters. In this study, we demonstrated that TBS was significantly correlated with 3D microarchitecture parameters ConnD and TbN, and negatively with TbSp, no matter what X-ray energy has been used. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared.

Strategic Enterprise Architecture Management - Challenges, Best Practices, and Future Developments

The discipline of Enterprise Architecture Management (EAM) deals with the alignment of business and information systems architectures. While EAM has long been regarded as a discipline for IT managers this book takes a different stance: It explains how top executives can use EAM for leveraging their strategic planning and controlling processes and how EAM can contribute to sustainable competitive advantage. Based on the analysis of best practices from eight leading European companies from various industries the book presents crucial elements of successful EAM. It outlines what executives need to do in terms of governance, processes, methodologies and culture in order to bring their management to the next level. Beyond this, the book points how EAM might develop in the next decade allowing today's managers to prepare for the future of architecture management.

Effects of antiresorptive agents on bone micro-architecture assessed by Trabecular Bone Score in women age 50 and older. The Manitoba Prospective Study

Antiresorptive agents such as bisphosphonates induce a rapid increase of BMD during the 1st year of treatment and a partial maintenance of bone architecture. Trabecular Bone Score (TBS), a new grey-level texture measurement that can be extracted from the DXA image, correlates with 3D parameters of bone micro-architecture. Aim: To evaluate the longitudinal effect of antiresorptive agents on spine BMD and on site-matched spine microarchitecture as assessed by TBS. Methods: From the BMD database for Province of Manitoba, Canada, we selected women age >50 with paired baseline and follow up spine DXA examinations who had not received any prior HRT or other antiresorptive drug.Women were divided in two subgroups: (1) those not receiving any HRT or antiresorptive drug during follow up (=non-users) and (2) those receiving non-HRT antiresorptive drug during follow up (=users) with high adherence (medication possession ratio >75%) from a provincial pharmacy database system. Lumbar spine TBS was derived by the Bone Disease Unit, University of Lausanne, for each spine DXA examination using anonymized files (blinded from clinical parameters and outcomes). Effects of antiresorptive treatment for users and non-users on TBS and BMD at baseline and during mean 3.7 years follow-up were compared. Results were expressed % change per year. Results: 1150 non-users and 534 users met the inclusion criteria. At baseline, users and non-users had a mean age and BMI of [62.2±7.9 vs 66.1±8.0 years] and [26.3±4.7 vs 24.7±4.0 kg/m²] respectively. Antiresorptive drugs received by users were bisphosphonates (86%), raloxifene (10%) and calcitonin (4%). Significant differences in BMD change and TBS change were seen between users and nonusers during follow-up (p<0.0001). Significant decreases in mean BMD and TBS (−0.36± 0.05% per year; −0.31±0.06% per year) were seen for non-users compared with baseline (p<0.001). A significant increase in mean BMD was seen for users compared with baseline (+1.86±0.0% per year, p<0.0018). TBS of users also increased compared with baseline (+0.20±0.08% per year, p<0.001), but more slowly than BMD. Conclusion: We observed a significant increase in spine BMD and a positive maintenance of bone micro-architecture from TBS with antiresorptive treatment, whereas the treatment naïve group lost both density and micro-architecture. TBS seems to be responsive to treatment and could be suitable for monitoring micro-architecture. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: M.-A. Krieg: None declared, A. Goertzen: None declared, W. Leslie: None declared, D. Hans Consulting fees from Medimaps.

Subjective mental time: the functional architecture of projecting the self to past and future.

Abstract Human experience takes place in the line of mental time (MT) created through 'self-projection' of oneself to different time-points in the past or future. Here we manipulated self-projection in MT not only with respect to one's life events but also with respect to one's faces from different past and future time-points. Behavioural and event-related functional magnetic resonance imaging activity showed three independent effects characterized by (i) similarity between past recollection and future imagination, (ii) facilitation of judgements related to the future as compared with the past, and (iii) facilitation of judgements related to time-points distant from the present. These effects were found with respect to faces and events, and also suggest that brain mechanisms of MT are independent of whether actual life episodes have to be re-experienced or pre-experienced, recruiting a common cerebral network including the anteromedial temporal, posterior parietal, inferior frontal, temporo-parietal and insular cortices. These behavioural and neural data suggest that self-projection in time is a fundamental aspect of MT, relying on neural structures encoding memory, mental imagery and self.

Bone mineral density (BMD), micro-architecture estimation (TBS) and vertebral fracture assessment (VFA) extracted from a single DXA device in combination with clinical risk factors improve significantly the identification of women at high risk of fracture.

Osteoporosis (OP) is a systemic skeletal disease characterized by a low bone mineral density (BMD) and a micro-architectural (MA) deterioration. Clinical risk factors (CRF) are often used as a MA approximation. MA is yet evaluable in daily practice by the trabecular bone score (TBS) measure. TBS is very simple to obtain, by reanalyzing a lumbar DXA-scan. TBS has proven to have diagnosis and prognosis values, partially independent of CRF and BMD. The aim of the OsteoLaus cohort is to combine in daily practice the CRF and the information given by DXA (BMD, TBS and vertebral fracture assessment (VFA)) to better identify women at high fracture risk. The OsteoLaus cohort (1400 women 50 to 80 years living in Lausanne, Switzerland) started in 2010. This study is derived from the cohort COLAUS who started in Lausanne in 2003. The main goal of COLAUS is to obtain information on the epidemiology and genetic determinants of cardiovascular risk in 6700 men and women. CRF for OP, bone ultrasound of the heel, lumbar spine and hip BMD, VFA by DXA and MA evaluation by TBS are recorded in OsteoLaus. Preliminary results are reported. We included 631 women: mean age 67.4 ± 6.7 years, BMI 26.1 ± 4.6, mean lumbar spine BMD 0.943 ± 0.168 (T-score − 1.4 SD), and TBS 1.271 ± 0.103. As expected, correlation between BMD and site matched TBS is low (r2 = 0.16). Prevalence of VFx grade 2/3, major OP Fx and all OP Fx is 8.4%, 17.0% and 26.0% respectively. Age- and BMI-adjusted ORs (per SD decrease) are 1.8 (1.2-2.5), 1.6 (1.2-2.1), and 1.3 (1.1-1.6) for BMD for the different categories of fractures and 2.0 (1.4-3.0), 1.9 (1.4-2.5), and 1.4 (1.1-1.7) for TBS respectively. Only 32 to 37% of women with OP Fx have a BMD < − 2.5 SD or a TBS < 1.200. If we combine a BMD < − 2.5 SD or a TBS < 1.200, 54 to 60% of women with an osteoporotic Fx are identified. As in the already published studies, these preliminary results confirm the partial independence between BMD and TBS. More importantly, a combination of TBS subsequent to BMD increases significantly the identification of women with prevalent OP Fx which would have been misclassified by BMD alone. For the first time we are able to have complementary information about fracture (VFA), density (BMD), micro- and macro architecture (TBS and HAS) from a simple, low ionizing radiation and cheap device: DXA. Such complementary information is very useful for the patient in the daily practice and moreover will likely have an impact on cost effectiveness analysis.

Beyond EA Frameworks: Towards an Understanding of the Adoption of Enterprise Architecture Management

Enterprise architectures (EA) are considered promising approaches to reduce the complexities of growing information technology (IT) environments while keeping pace with an ever-changing business environment. However, the implementation of enterprise architecture management (EAM) has proven difficult in practice. Many EAM initiatives face severe challenges, as demonstrated by the low usage level of enterprise architecture documentation and enterprise architects' lack of authority regarding enforcing EAM standards and principles. These challenges motivate our research. Based on three field studies, we first analyze EAM implementation issues that arise when EAM is started as a dedicated and isolated initiative. Following a design-oriented paradigm, we then suggest a design theory for architecture-driven IT management (ADRIMA) that may guide organizations to successfully implement EAM. This theory summarizes prescriptive knowledge related to embedding EAM practices, artefacts and roles in the existing IT management processes and organization.

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

High-density sex-specific linkage maps of a European tree frog (Hyla arborea) identify the sex chromosome without information on offspring sex.

Identifying homology between sex chromosomes of different species is essential to understanding the evolution of sex determination. Here, we show that the identity of a homomorphic sex chromosome pair can be established using a linkage map, without information on offspring sex. By comparing sex-specific maps of the European tree frog Hyla arborea, we find that the sex chromosome (linkage group 1) shows a threefold difference in marker number between the male and female maps. In contrast, the number of markers on each autosome is similar between the two maps. We also find strongly conserved synteny between H. arborea and Xenopus tropicalis across 200 million years of evolution, suggesting that the rate of chromosomal rearrangement in anurans is low. Finally, we show that recombination in males is greatly reduced at the centers of large chromosomes, consistent with previous cytogenetic findings. Our research shows the importance of high-density linkage maps for studies of recombination, chromosomal rearrangement and the genetic architecture of ecologically or economically important traits.

GENETIC ARCHITECTURE, EVOLUTION AND MAINTENANCE OF A COLOR CLINE AT A CONTINENTAL SCALE

On a geological time scale the conditions on earth are very variable and biological patterns (for example the distributions of species) are very dynamic. Understanding large scale patterns of variation observed today thus requires a deep understanding of the historical factors that drove their evolution. In this thesis, we reevaluated the evolution and maintenance of a continental color cline observed in the European barn owl (Tyto alba) using population genetic tools. The colour cline spans from south-est Europe where most individual have pure white underparts to north and east Europe where most individuals have rufous-brown underparts. Our results globally showed that the old scenario, stipulating that the color cline evolved by secondary contact of two color morphs (white and rufous) that evolved in allopatry during the last ice age has to be revised. We collected samples of about 700 barn owls from the Western Palearctic to establish the first population genetic data set for this species. Individuals were genotyped at 22 microsatellites markers, at one mitochondrial gene, and at a candidate color gene. The color of each individuals was assessed and their sex determined by molecular methods. We first showed that the genetic variation in Western Europe is very limited compared to the heritable color variation. We found no evidences of different glacial lineages, and showed that selection must be involved in the maintenance of the color cline (chapter 1). Using computer simulations, we demonstrated that the post-glacial colonization of Europe occurred from the Iberian Peninsula and that the color cline could not have evolved by neutral demographic processes during this colonization (chapter 2). Finally we reevaluated the whole history of the establishment of the Western Palearctic variation of the barn owl (chapter 3): This study showed that all Western European barn owls descend from white barn owls phenotypes from the Middle East that colonized the Iberian Peninsula via North-Africa. Following the end of the last ice age (20'000 years ago), these white barn owls colonized Western Europe and under selection a novel rufous phenotype evolved (during or after the colonization). An important part of the color variation could be explained by a single mutation in the melanocortin-1-receptor (MC1R) gene that appeared during or after the colonization. The colonization of Europe reached until Greece, where the rufous birds encountered white ones (which reached Greece from the Middle East over the Bosporus) in a secondary contact zone. Our analyses show that white and rufous barn owls in Greece interbreed only to a limited extent. This suggests that barn owls are at the verge of becoming two species in Greece and demonstrates that European barn owls represent an incipient ring species around the Mediterranean. The revisited history of the establishment of the European barn owl color cline makes this model system remarkable for several aspects. It is a very clear example of strong local adaptation that can be achieved despite high gene flow (strong color and MC1R differentiation despite almost no neutral genetic differentiation). It also offers a wonderful model system to study the interactions between colonization processes and selection processes which have, for now, been remarkably understudied despite their potentially ubiquitous importance. Finally it represents a very interesting case in the speciation continuum and appeals for further studying the amount of gene flow that occurs between the color morphs in Greece. -- Sur l'échelle des temps géologiques, les conditions sur terre sont très variables et les patrons biologiques (telle que la distribution des espèces) sont très dynamiques. Si l'on veut comprendre des patrons que l'on peut observer à large échelle aujourd'hui, il est nécessaire de d'abord comprendre les facteurs historiques qui ont gouverné leur établissement. Dans cette thèse, nous allons réévaluer, grâce à des outils modernes de génétique des populations, l'évolution et la maintenance d'un cline de couleur continental observé chez l'effraie des clochers européenne (Tyto alba). Globalement, nos résultats montrent que le scenario accepté jusqu'à maintenant, qui stipule que le cline de couleur a évolué à partir du contact secondaire de deux morphes de couleur (blanches et rousses) ayant évolué en allopatrie durant les dernières glaciations, est à revoir. Afin de constituer le premier jeu de données de génétique des populations pour cette espèce, nous avons récolté des échantillons d'environ 700 effraies de l'ouest Paléarctique. Nous avons génotypé tous les individus à 22 loci microsatellites, sur un gène mitochondrial et sur un autre gène participant au déterminisme de la couleur. Nous avons aussi mesuré la couleur de tous les individus et déterminé leur sexe génétiquement. Nous avons tout d'abord pu montrer que la variation génétique neutre est négligeable en comparaison avec la variation héritable de couleur, qu'il n'existe qu'une seule lignée européenne et que de la sélection doit être impliquée dans le maintien du cline de couleur (chapitre 1). Grâce à des simulations informatiques, nous avons démontré que l'ensemble de l'Europe de l'ouest a été recolonisé depuis la Péninsule Ibérique après les dernières glaciations et que le cline de couleur ne peut pas avoir évolué par des processus neutre durant cette colonisation (chapitre 2). Finalement, nous avons réévalué l'ensemble de l'histoire postglaciaire de l'espèce dans l'ouest Paléarctique (chapitre 3): l'ensemble des effraies du Paléarctique descendent d'effraie claire du Moyen-Orient qui ont colonisé la péninsule ibérique en passant par l'Afrique du nord. Après la fin de la dernière glaciation (il y a 20'000 ans), ces effraies claires ont colonisé l'Europe de l'ouest et ont évolués par sélection le phénotype roux (durant ou après la colonisation). Une part importante de la variation de couleur peut être expliquée par une mutation sur le gène MC1R qui est apparue durant ou juste après la colonisation. Cette vague de colonisation s'est poursuivie jusqu'en Grèce où ces effraies rousses ont rencontré dans une zone de contact secondaire des effraies claires (qui sont remontées en Grèce depuis le Moyen-Orient via le Bosphore). Nos analyses montrent que le flux de gènes entre effraies blanches et rousses est limité en Grèce, ce qui suggère qu'elles sont en passe de former deux espèces et ce qui montre que les effraies constituent un exemple naissant de spéciation en anneaux autour de la Méditerranée. L'histoire revisitée des effraies des clochers de l'ouest Paléarctique en fait un système modèle remarquable pour plusieurs aspects. C'est un exemple très claire de forte adaptation locale maintenue malgré un fort flux de gènes (différenciation forte de couleur et sur le gène MC1R malgré presque aucune structure neutre). Il offre également un très bon système pour étudier l'interaction entre colonisation et sélection, un thème ayant été remarquablement peu étudié malgré son importance. Et il offre finalement un cas très intéressant dans le « continuum de spéciation » et il serait très intéressant d'étudier plus en détail l'importance du flux de gènes entre les morphes de couleur en Grèce.