1. |
- Lango Allen, Hana, et al.
(author)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Journal article (peer-reviewed)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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2. |
- Calves, G. M., et al.
(author)
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Observations and analysis of phase scintillation of spacecraft signal on the interplanetary plasma
- 2014
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 564
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Journal article (peer-reviewed)abstract
- Aims. The phase scintillation of the European Space Agency's Venus Express (VEX) spacecraft telemetry signal was observed at X-band (lambda = 3.6 cm) with a number of radio telescopes of the European Very Long Baseline Interferometry (VLBI) Network in the period 2009-2013. Methods. We found a phase fluctuation spectrum along the Venus orbit with a nearly constant spectral index of -2.42 +/- 0.25 over the full range of solar elongation angles from 0 degrees to 45 degrees, which is consistent with Kolmogorov turbulence. Radio astronomical observations of spacecraft signals within the solar system give a unique opportunity to study the temporal behaviour of the signal's phase fluctuations caused by its propagation through the interplanetary plasma and the Earth's ionosphere. This gives complementary data to the classical interplanetary scintillation (IPS) study based on observations of the flux variability of distant natural radio sources. Results. We present here our technique and the results on IPS. We compare these with the total electron content for the line of sight through the solar wind. Finally, we evaluate the applicability of the presented technique to phase-referencing VLBI and Doppler observations of currently operational and prospective space missions.
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3. |
- Fernandez, J. L. Abelleira, et al.
(author)
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A Large Hadron Electron Collider at CERN
- 2012
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In: Journal of Physics G. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 39:7
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Journal article (peer-reviewed)
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4. |
- Liaset, B, et al.
(author)
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Nutritional Regulation of Bile Acid Metabolism Is Associated with Improved Pathological Characteristics of the Metabolic Syndrome
- 2011
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In: JOURNAL OF BIOLOGICAL CHEMISTRY. - 0021-9258. ; 286:32, s. 28382-28395
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Journal article (peer-reviewed)abstract
- Abstract Bile acids (BAs) are powerful regulators of metabolism, and mice treated orally with cholic acid are protected from diet-induced obesity, hepatic lipid accumulation, and increased plasma triacylglycerol (TAG) and glucose levels. Here, we show that plasma BA concentration in rats was elevated by exchanging the dietary protein source from casein to salmon protein hydrolysate (SPH). Importantly, the SPH-treated rats were resistant to diet-induced obesity. SPH-treated rats had reduced fed state plasma glucose and TAG levels and lower TAG in liver. The elevated plasma BA concentration was associated with induction of genes involved in energy metabolism and uncoupling, Dio2, Pgc-1α, and Ucp1, in interscapular brown adipose tissue. Interestingly, the same transcriptional pattern was found in white adipose tissue depots of both abdominal and subcutaneous origin. Accordingly, rats fed SPH-based diet exhibited increased whole body energy expenditure and heat dissipation. In skeletal muscle, expressions of the peroxisome proliferator-activated receptor β/δ target genes (Cpt-1b, Angptl4, Adrp, and Ucp3) were induced. Pharmacological removal of BAs by inclusion of 0.5 weight % cholestyramine to the high fat SPH diet attenuated the reduction in abdominal obesity, the reduction in liver TAG, and the decrease in nonfasted plasma TAG and glucose levels. Induction of Ucp3 gene expression in muscle by SPH treatment was completely abolished by cholestyramine inclusion. Taken together, our data provide evidence that bile acid metabolism can be modulated by diet and that such modulation may prevent/ameliorate the characteristic features of the metabolic syndrome.
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5. |
- Yaghootkar, Hanieh, et al.
(author)
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Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes.
- 2013
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 62:10, s. 3589-3598
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Journal article (peer-reviewed)abstract
- Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI -0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95% CI -0.38 to -0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: -0.03 SD; 95% CI -0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.
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6. |
- Blombach, Fabian, et al.
(author)
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Archaeal MBF1 binds to 30S and 70S ribosomes via its helix-turn-helix domain
- 2014
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In: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 462, s. 373-384
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Journal article (peer-reviewed)abstract
- MBF1 (multi-protein bridging factor 1) is a protein containing a conserved HTH (helix-turn-helix) domain in both eukaryotes and archaea. Eukaryotic MBF1 has been reported to function as a transcriptional co-activator that physically bridges transcription regulators with the core transcription initiation machinery of RNA polymerase II. In addition, MBF1 has been found to be associated with polyadenylated mRNA in yeast as well as in mammalian cells. aMBF1 (archaeal MBF1) is very well conserved among most archaeal lineages; however, its function has so far remained elusive. To address this, we have conducted a molecular characterization of this aMBF1. Affinity purification of interacting proteins indicates that aMBF1 binds to ribosomal subunits. On sucrose density gradients, aMBF1 co-fractionates with free 30S ribosomal subunits as well as with 70S ribosomes engaged in translation. Binding of aMBF1 to ribosomes does not inhibit translation. Using NMR spectroscopy, we show that aMBF1 contains a long intrinsically disordered linker connecting the predicted N-terminal zinc-ribbon domain with the C-terminal HTH domain. The HTH domain, which is conserved in all archaeal and eukaryotic MBF1 homologues, is directly involved in the association of aMBF1 with ribosomes. The disordered linker of the ribosome-bound aMBF1 provides the N-terminal domain with high flexibility in the aMBF1 ribosome complex. Overall, our findings suggest a role for aMBF1 in the archaeal translation process.
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7. |
- Christian, Parul, et al.
(author)
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Risk of childhood undernutrition related to small-for-gestational age and preterm birth in low- and middle-income countries
- 2013
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In: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 42:5, s. 1340-1355
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Journal article (peer-reviewed)abstract
- BACKGROUND:Low- and middle-income countries continue to experience a large burden of stunting; 148 million children were estimated to be stunted, around 30-40% of all children in 2011. In many of these countries, foetal growth restriction (FGR) is common, as is subsequent growth faltering in the first 2 years. Although there is agreement that stunting involves both prenatal and postnatal growth failure, the extent to which FGR contributes to stunting and other indicators of nutritional status is uncertain.METHODS:Using extant longitudinal birth cohorts (n = 19) with data on birthweight, gestational age and child anthropometry (12-60 months), we estimated study-specific and pooled risk estimates of stunting, wasting and underweight by small-for-gestational age (SGA) and preterm birth.RESULTS:We grouped children according to four combinations of SGA and gestational age: adequate size-for-gestational age (AGA) and preterm; SGA and term; SGA and preterm; and AGA and term (the reference group). Relative to AGA and term, the OR (95% confidence interval) for stunting associated with AGA and preterm, SGA and term, and SGA and preterm was 1.93 (1.71, 2.18), 2.43 (2.22, 2.66) and 4.51 (3.42, 5.93), respectively. A similar magnitude of risk was also observed for wasting and underweight. Low birthweight was associated with 2.5-3.5-fold higher odds of wasting, stunting and underweight. The population attributable risk for overall SGA for outcomes of childhood stunting and wasting was 20% and 30%, respectively.CONCLUSIONS:This analysis estimates that childhood undernutrition may have its origins in the foetal period, suggesting a need to intervene early, ideally during pregnancy, with interventions known to reduce FGR and preterm birth.
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10. |
- Hao, G. Z., et al.
(author)
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Effect of Trapped Energetic Particles on the Resistive Wall Mode
- 2011
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In: Physical Review Letters. ; 107, s. 015001-
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Journal article (peer-reviewed)abstract
- A stability analysis for the resistive wall mode is studied in the presence of trapped energetic particles (EPs). When the EPs’ beta exceeds a critical value, a fishbonelike bursting mode (FLM) with an external kink eigenstructure can exist. This offers the first analytic interpretation of the experimental observations [ Phys. Rev. Lett. 103 045001 (2009)]. The mode-particle resonances for the FLM and the q=1 fishbone occur in different regimes of the precession frequency of EPs. In certain ranges of the plasma rotation speed and the EPs’ beta, a mode conversion can occur between the resistive wall mode and FLM.
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