| 1. |
- Albrechtsen, A., et al.
(author)
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Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes
- 2013
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 56:2, s. 298-310
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Journal article (peer-reviewed)abstract
- Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) > 1% with common metabolic phenotypes. The study comprised three stages. We performed medium-depth (8x) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI > 27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. Exome sequencing identified 70,182 polymorphisms with MAF > 1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 x 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 x 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 x 10(-10)). We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.
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| 2. |
- Reiling, E., et al.
(author)
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Genetic association analysis of LARS2 with type 2 diabetes
- 2010
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 53:1, s. 103-110
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Journal article (peer-reviewed)abstract
- LARS2 has been previously identified as a potential type 2 diabetes susceptibility gene through the low-frequency H324Q (rs71645922) variant (minor allele frequency [MAF] 3.0%). However, this association did not achieve genome-wide levels of significance. The aim of this study was to establish the true contribution of this variant and common variants in LARS2 (MAF > 5%) to type 2 diabetes risk. We combined genome-wide association data (n = 10,128) from the DIAGRAM consortium with independent data derived from a tagging single nucleotide polymorphism (SNP) approach in Dutch individuals (n = 999) and took forward two SNPs of interest to replication in up to 11,163 Dutch participants (rs17637703 and rs952621). In addition, because inspection of genome-wide association study data identified a cluster of low-frequency variants with evidence of type 2 diabetes association, we attempted replication of rs9825041 (a proxy for this group) and the previously identified H324Q variant in up to 35,715 participants of European descent. No association between the common SNPs in LARS2 and type 2 diabetes was found. Our replication studies for the two low-frequency variants, rs9825041 and H324Q, failed to confirm an association with type 2 diabetes in Dutch, Scandinavian and UK samples (OR 1.03 [95% CI 0.95-1.12], p = 0.45, n = 31,962 and OR 0.99 [0.90-1.08], p = 0.78, n = 35,715 respectively). In this study, the largest study examining the role of sequence variants in LARS2 in type 2 diabetes susceptibility, we found no evidence to support previous data indicating a role in type 2 diabetes susceptibility.
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| 3. |
- Timmermans, Anne, et al.
(author)
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Endometrial Thickness Measurement for Detecting Endometrial Cancer in Women With Postmenopausal Bleeding A Systematic Review and Meta-Analysis
- 2010
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In: Obstetrics and Gynecology. - 1873-233X. ; 116:1, s. 160-167
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Research review (peer-reviewed)abstract
- OBJECTIVE: To estimate the accuracy of endometrial thickness measurement in the detection of endometrial cancer among women with postmenopausal bleeding with individual patient data using different meta-analytic strategies. DATA SOURCES: Original data sets of studies detected after reviewing the included studies of three previous reviews on this subject. An additional literature search of published articles using MEDLINE databases was preformed from January 2000 to December 2006 to identify articles reporting on endometrial carcinoma and sonographic endometrial thickness measurement in women with postmenopausal bleeding. METHODS OF STUDY SELECTION: We identified 90 studies reporting on endometrial thickness measurements and endometrial carcinoma in women with postmenopausal bleeding. TABULATION, INTEGRATION, AND RESULTS: We contacted 79 primary investigators to obtain the individual patient data of their reported studies, of which 13 could provide data. Data on 2,896 patients, of which 259 had carcinoma, were included. Several approaches were used in the analyses of the acquired data. First, we performed receiver operator characteristics (ROC) analysis per study, resulting in a summary area under the ROC curve (AUC) calculated as a weighted mean of AUCs from original studies. Second, individual patient data were pooled and analyzed with ROC analyses irrespective of study with standardization of distributional differences across studies using multiples of the median and by random effects logistic regression. Finally, we also used a two-stage procedure, calculating sensitivities and specificities for each study and using the bivariate random effects model to estimate summary estimates for diagnostic accuracy. This resulted in rather comparable ROC curves with AUCs varying between 0.82 and 0.84 and summary estimates for sensitivity and specificity located along these curves. These curves indicated a lower AUC than previously reported meta-analyses using conventional techniques. CONCLUSION: Previous meta-analyses on endometrial thickness measurement probably have overestimated its diagnostic accuracy in the detection of endometrial carcinoma. We advise the use of cutoff level of 3 mm for exclusion of endometrial carcinoma in women with postmenopausal bleeding. (Obstet Gynecol 2010;116:160-7)
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| 4. |
- Chemissany, W., et al.
(author)
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Black holes in supergravity and integrability
- 2010
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In: Journal of High Energy Physics (JHEP). - 1126-6708 .- 1029-8479. ; :9, s. 80-
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Journal article (peer-reviewed)abstract
- Stationary black holes of massless supergravity theories are described by certain geodesic curves on the target space that is obtained after dimensional reduction over time. When the target space is a symmetric coset space we make use of the group-theoretical structure to prove that the second order geodesic equations are integrable in the sense of Liouville, by explicitly constructing the correct amount of Hamiltonians in involution. This implies that the Hamilton-Jacobi formalism can be applied, which proves that all such black hole solutions, including non-extremal solutions, possess a description in terms of a (fake) superpotential. Furthermore, we improve the existing integration method by the construction of a Lax integration algorithm that integrates the second order equations in one step instead of the usual two step procedure. We illustrate this technology with a specific example.
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| 5. |
- Chemissany, W., et al.
(author)
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Brane solutions and integrability: a status report
- 2011
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Conference paper (peer-reviewed)abstract
- We review the status of the integrability and solvability of the geodesics equations of motion on symmetric coset spaces that appear as sigma models of supergravity theories when reduced over respectively the timelike and spacelike direction. Such geodesic curves describe respectively timelike and spacelike brane solutions. We emphasize the applications to black holes.
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| 6. |
- Danielsson, Ulf H., et al.
(author)
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De Sitter hunting in a classical landscape
- 2011
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In: Fortschritte der Physik. - : Wiley. - 0015-8208 .- 1521-3978. ; 59:9
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Journal article (peer-reviewed)abstract
- We elaborate on the construction of de Sitter solutions from IIA orientifolds of SU(3)-structure manifolds that solve the 10-dimensional equations of motion at tree-level in the approximation of smeared sources. First we classify geometries that are orbifolds of a group manifold covering space which, upon the proper inclusion of O6 planes, can be described within the framework of N=1 supergravity in 4D. Then we scan systematically for de Sitter solutions, obtained as critical points of an effective 4D potential. Apart from finding many new solutions we emphasize the challenges in constructing explicit classical de Sitter vacua, which have sofar not been met. These challenges are interesting avenues for further research and include finding solutions that are perturbatively stable, satisfy charge and flux quantization, and have genuine localized (versus smeared) orientifold sources. This paper intends to be self-contained and pedagogical, and thus can serve as a guide to the necessary technical tools required for this line of research. In an appendix we explain how to study flux and charge quantization in the presence of a non-trivial H-field using twisted homology.
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