| 1. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)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. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)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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| 3. |
- Surakka, Ida, et al.
(författare)
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The impact of low-frequency and rare variants on lipid levels.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:6, s. 589-597
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Tidskriftsartikel (refereegranskat)abstract
- Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.
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| 4. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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| 5. |
- Pattaro, Cristian, et al.
(författare)
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Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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| 6. |
- Somani, M. C., et al.
(författare)
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Influence of composition and prior deformation on phase transformation temperatures and hardness in direct quenching using physical simulation
- 2015
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Ingår i: Materials Performance and Characterization. - : ASTM International. - 2379-1365 .- 2165-3992. ; 4:3, s. 341-364
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Tidskriftsartikel (refereegranskat)abstract
- For conventional reheated and quenched (RQ) steels, the level of alloying necessary to achieve a given hardenability and hardness can be estimated from calculated Jominy curves or ideal critical diameters (DI) given in ASTM A255-10(2014). However, for thermomechanically rolled direct quenched (DQ) steels, little data are available. In this study, the accuracy of the ASTM approach was estimated by designing an experiment to study the main effects of seven alloying elements (C, Mn, Cr, Ni, Mo, Nb, and V) at two levels with eight boron steels based on an eight-run resolution III partial factorial designed experiment. Continuous cooling transformation (CCT) diagrams covering cooling rates of 1.5°C/s-48°C/s were determined using Gleeble simulations with or without controlled deformation below Tnr. The effects of deformation below Tnr and the alloying elements were clearly revealed. In general, low temperature straining of the austenite led to higher levels of hardness than quenching from unstrained austenite. The start of the bainite transformation Ar3 (bainite) was modelled as a function of chemical composition and cooling rate. The data in the CCT diagrams were used to derive equivalent ideal critical diameters (DIB) for strained and unstrained prior austenite. The hardenability index DIB calculated from experimental Jominy curves generally agreed well with those of CCT data for unstrained austenite. In order to apply the ASTM A255 approach to the calculation of DIB, boron factors (BF) for steels with alloy factors (AFs) greater than 26 were estimated by extrapolating the ASTM data. However, this approach did not give satisfactory predictions for either strained or unstrained austenite. Preliminary analysis indicated that Cr, Mo, and V might be less effective at increasing hardenability than implied from their AFs. New formulae were given to allow estimations of the hardness to be expected in connection with direct quenching.
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| 7. |
- Woolway, R. Iestyn, et al.
(författare)
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Geographic and temporal variations in turbulent heat loss from lakes : A global analysis across 45 lakes
- 2018
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Ingår i: Limnology and Oceanography. - : WILEY. - 0024-3590 .- 1939-5590. ; 63:6, s. 2436-2449
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Tidskriftsartikel (refereegranskat)abstract
- Heat fluxes at the lake surface play an integral part in determining the energy budget and thermal structure in lakes, including regulating how lakes respond to climate change. We explore patterns in turbulent heat fluxes, which vary across temporal and spatial scales, using in situ high-frequency monitoring data from 45 globally distributed lakes. Our analysis demonstrates that some of the lakes studied follow a marked seasonal cycle in their turbulent surface fluxes and that turbulent heat loss is highest in larger lakes and those situated at low latitude. The Bowen ratio, which is the ratio of mean sensible to mean latent heat fluxes, is smaller at low latitudes and, in turn, the relative contribution of evaporative to total turbulent heat loss increases toward the tropics. Latent heat transfer ranged from similar to 60% to > 90% of total turbulent heat loss in the examined lakes. The Bowen ratio ranged from 0.04 to 0.69 and correlated significantly with latitude. The relative contributions to total turbulent heat loss therefore differ among lakes, and these contributions are influenced greatly by lake location. Our findings have implications for understanding the role of lakes in the climate system, effects on the lake water balance, and temperature-dependent processes in lakes.
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