| 1. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Jansson, Anna, 1985, et al.
(författare)
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Novel Method for Controlled Wetting of Materials in the Environmental Scanning Electron Microscope
- 2013
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Ingår i: Microscopy and Microanalysis. - 1435-8115 .- 1431-9276. ; 19:1, s. 30-37
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Tidskriftsartikel (refereegranskat)abstract
- Environmental scanning electron microscopy has been extensively used for studying the wetting properties of different materials. For some types of investigation, however, the traditional ways of conducting in situ dynamic wetting experiments do not offer sufficient control over the wetting process. Here, we present a novel method for controlled wetting of materials in the environmental scanning electron microscope (ESEM). It offers improved control of the point of interaction between the water and the specimen and renders it more accessible for imaging. It also enables the study of water transport through a material by direct imaging. The method is based on the use of a piezo-driven nanomanipulator to bring a specimen in contact with a water reservoir in the ESEM chamber. The water reservoir is established by local condensation on a Peltier-cooled surface. A fixture was designed to make the experimental setup compatible with the standard Peltier cooling stage of the microscope. The developed technique was successfully applied to individual cellulose fibers, and the absorption and transport of water by individual cellulose fibers were imaged.
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| 3. |
- Jansson, Anna, 1985, et al.
(författare)
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Novel Method for Visualizing Water Transport Through Phase-Separated Polymer Films
- 2014
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Ingår i: Microscopy and Microanalysis. - : Oxford University Press (OUP). - 1435-8115 .- 1431-9276. ; 20:2, s. 394-406
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Tidskriftsartikel (refereegranskat)abstract
- Drug release from oral pharmaceutical formulations can be modified by applying a polymeric coating film with controlled mass transport properties. Interaction of the coating film with water may crucially influence its composition and permeability to both water and drug. Understanding this interaction between film microstructure, wetting, and mass transport is important for the development of new coatings. We present a novel method for controlled wetting of polymer coating films in an environmental scanning electron microscope, providing direct visual information about the processes occurring as the film goes from dry to wet. Free films made of phase-separated blends of water-insoluble ethyl cellulose (EC) and water-soluble hydroxypropyl cellulose (HPC) were used as a model system, and the blend ratio was varied to study the effect on the water transport properties. Local variations in water transport through the EC/HPC films were directly observed, enabling the immediate analysis of the structure-mass transport relationships. The leaching of HPC could be studied by evaporating water from the films in situ. Significant differences were observed between films of varying composition. The method provides a valuable complement to the current approach of making distinct diffusion and microscopy experiments for studying the dynamic interaction of polymer films with water.
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| 4. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 5. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 6. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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