| 1. |
- Locke, Adam E, et al.
(author)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Journal article (peer-reviewed)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 2. |
- Ried, Janina S., et al.
(author)
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A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape
- 2016
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Journal article (peer-reviewed)abstract
- Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
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| 3. |
- Shungin, Dmitry, et al.
(author)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Journal article (peer-reviewed)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 6. |
- Williamson, Alice, et al.
(author)
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Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake
- 2023
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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:6, s. 973-983
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Journal article (peer-reviewed)abstract
- Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.
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| 7. |
- Bernhardt, Peter, 1966, et al.
(author)
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A novel quantitative image-based method for evaluating cranial symmetry and its usefulness in patients undergoing surgery for unicoronal synostosis.
- 2013
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In: The Journal of craniofacial surgery. - 1536-3732. ; 24:1, s. 166-9
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Journal article (peer-reviewed)abstract
- Background: Unicoronal synostosis presents with cranial asymmetry. Fixed points are difficult to identify; surgical results are therefore difficult to evaluate. The aim of this study was to develop a computer-based method for evaluation of forehead symmetry to enable evaluation of surgical results in unicoronal synostosis. Methods: The MATLAB tool was programmed to segment computed tomographic images, leaving the outermost contour. Cephalometric images were segmented manually due to lower contrast. A center-point (O) and an end-point were manually defined in the midline of the forehead and at the nonfused coronal suture, respectively. The program then found a point (p) on the fused side, at the same distance from the O as the end-point. The contours of the left and right side of the forehead were thereafter superimposed, and the position of minimal area mismatch of the sides was identified. To correct for growth between preoperative images and follow-up, the number of mismatching pixels was related to the area outlined by the contour of the forehead, the end-point and p. Two quantities, the relative symmetry change and the absolute symmetry change, were defined and evaluated by repeated measurements on spherical and elliptical phantoms and 15 patients. Results: Measurements with the MATLAB program were reliable with an SD of 0.26% to 5.39% for the expected range of differences. The SD was lower for measurements on computed tomographic images than for measurements on cephalometric images. The SD was also lower in patients with large surgical improvement than in patients with little improvement. The results support the use of relative symmetry change to evaluate surgical results. Conclusions: Our new computer-based method is capable of measuring forehead symmetry with good precision. This method can be used for systematic evaluation of surgical outcome for unicoronal synostosis and other asymmetric skull deformities.
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| 8. |
- Dahlström Wester, Maria, et al.
(author)
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Accumulation of boron in human malignant glioma cells in vitro is cell type dependent
- 2004
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In: Journal of Neuro-Oncology. - 0167-594X .- 1573-7373. ; 68:3, s. 199-205
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Journal article (peer-reviewed)abstract
- It has been shown that human malignant glioma tumours consist of several subpopulations of tumour cells. Due to heterogeneity and different degrees of vascularisation cell subpopulations possess varying resistance to chemo- or radiation therapy. Therefore, therapy is dependent on the ability to specifically target a tumour cell. Boron neutron capture therapy (BNCT) is a bimodal method, in radiation therapy, taking advantage of the ability of the stable isotope boron-10 to capture neutrons. It results in disintegration products depositing large amounts of energy within a short length, approximately one cell diameter. Thereby, selective irradiation of a target cell may be accomplished if a sufficient amount of boron has been accumulated and hence the cell-associated boron concentration is of critical importance. The accumulation of boron, boronophenylalanine (BPA), was investigated in two human glioma cell subpopulations and a human fibroblast cell line in vitro. The cells were incubated at low boron concentrations (0-5 microg B/ml). Oil filtration was then used for separation of extracellular and cell-associated boron. Inductively coupled plasma atomic emission spectroscopy (ICP-AES) was used for boron determination. Significant (P < 0.05) differences in accumulation ratio (relation between cell-associated and extracellular boron concentration) between human malignant glioma cell lines were found. Human fibroblasts, used to represent normal cells, showed a growth-dependent uptake and a lower accumulation ratio than the glioma cells. Our findings indicate that BPA concentration, incubation time and differences in boron uptake between cell subpopulations should be considered in BNCT.
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| 9. |
- Eklund, Lena K., et al.
(author)
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Mutation analysis of the human homologue of drosophila patched and the xeroderma pigmentosum complementation group A genes in squamous cell carcinomas of the skin
- 1998
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In: Molecular Carcinogenesis. - 0899-1987 .- 1098-2744. ; 21:2, s. 87-92
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Journal article (peer-reviewed)abstract
- The human homologue of Drosophila patched (PTCH), located at chromosome 9q22.3, was recently identified as a candidate tumor suppressor gene for familial and sporadic basal cell carcinomas. Squamous cell carcinomas (SCCs) of the skin display allelic loss in this chromosomal region, which, in addition to the PTCH gene, contains the DNA repair gene xeroderma pigmentosum complementation group A (XPA). Patients with xeroderma pigmentosum are predisposed to non-melanoma skin tumors because of deficient excision repair of ultraviolet-induced DNA damage. Mutation analysis by single-strand conformation analysis and direct DNA sequencing of all 23 exons of the PTCH gene and all six exons of the XPA gene in 14 SCCs did not reveal structural alterations in any of these genes. Additionally, analysis of PTCH expression by in situ hybridization in SCCs revealed no evidence of upregulation of PTCH mRNA, confirming the lack of mutations in this gene. These findings suggest that another, yet to be identified gene or genes on chromosome 9q are involved in SCC tumorigenesis.
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| 10. |
- Gärdenfors, Peter, et al.
(author)
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Understanding by experiencing patterns
- 2008
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In: A Smorgasbord of Cognitive Science. - 9789157805324
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Book chapter (pop. science, debate, etc.)abstract
- This chapter focuses on the cognitive and emotional mechanisms of understanding. We propose that understanding consists in seeing or, more generally, experiencing a pattern. Patterns can be experienced by all sensory modalities and in abstract thinking, but here the focus is primarily on the visual modality. We discuss how understanding by experiencing patterns can be achieved in learning processes. The goal of education should be that students understand the material they study. We propose that this is achieved by helping them to discover patterns that they cannot find on their own. We also highlight the role of emotions in understanding, especially the subjective experience of an aha-feeling, which occurs when a pattern suddenly falls into place. Finally, we present some educational techniques such as visualizations, simulations, and intelligent tutoring systems that can be used for pointing out salient features in a pattern.
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