| 1. |
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| 2. |
- Lango Allen, Hana, et al.
(författare)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Tidskriftsartikel (refereegranskat)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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| 3. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 4. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 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
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 5. |
- 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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| 6. |
- Mazaheri, Mehdi, et al.
(författare)
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High-Temperature Mechanical Spectroscopy of Nitrogen-Rich Ca-alpha-SiAlON Ceramics
- 2011
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Ingår i: Journal of The American Ceramic Society. - : Wiley. - 0002-7820 .- 1551-2916. ; 94:5, s. 1536-1545
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Tidskriftsartikel (refereegranskat)abstract
- Nitrogen-rich Ca-alpha-SiAlON ceramics made with different starting powder compositions have been studied by high-temperature mechanical spectroscopy in parallel with compressive deformation in a spark plasma sintering equipment. The mechanical loss spectra measured upon heating show a relaxation peak at about 1150 K and a high-temperature exponential background at higher temperatures (> 1400 K), which are attributed to the alpha-relaxation in the glassy phase and to grain-boundary sliding, respectively. A theoretical interpretation of the results shows that the peak position is mainly a function of glass viscosity. The amplitude of the peak is not only affected by the glassy phase quantity but also depends on the restoring force due to grain elasticity. Therefore, despite a higher amount of glassy phase specimens containing elongated grains may show a lower peak. The amplitude of the internal friction peak corresponding to alpha-relaxation can be used to predict the compression creep of silicon-nitride-based ceramics.
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| 7. |
- Nakanishi, Tomoko, et al.
(författare)
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Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality
- 2021
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Ingår i: Journal of Clinical Investigation. - : American Society For Clinical Investigation. - 0021-9738 .- 1558-8238. ; 131:23
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. There is considerable variability in COVID-19 outcomes among younger adults, and some of this variation may be due to genetic predisposition. METHODS. We combined individual level data from 13,888 COVID-19 patients (n = 7185 hospitalized) from 17 cohorts in 9 countries to assess the association of the major common COVID-19 genetic risk factor (chromosome 3 locus tagged by rs10490770) with mortality, COVID-19-related complications, and laboratory values. We next performed metaanalyses using FinnGen and the Columbia University COVID-19 Biobank. RESULTS. We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (HR, 1.4; 95% CI, 1.2-1.7). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (OR, 2.1; 95% CI, 1.6-2.6), venous thromboembolism (OR, 1.7; 95% CI, 1.2-2.4), and hepatic injury (OR, 1.5; 95% CI, 1.2-2.0). Risk allele carriers age 60 years and younger had higher odds of death or severe respiratory failure (OR, 2.7; 95% CI, 1.8-3.9) compared with those of more than 60 years (OR, 1.5; 95% CI, 1.2-1.8; interaction, P = 0.038). Among individuals 60 years and younger who died or experienced severe respiratory failure, 32.3% were risk-variant carriers compared with 13.9% of those not experiencing these outcomes. This risk variant improved the prediction of death or severe respiratory failure similarly to, or better than, most established clinical risk factors. CONCLUSIONS. The major common COVID-19 genetic risk factor is associated with increased risks of morbidity and mortality, which are more pronounced among individuals 60 years or younger. The effect was similar in magnitude and more common than most established clinical risk factors, suggesting potential implications for future clinical risk management.
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| 8. |
- Yildiz, Ahmet Bahadir, 1989-
(författare)
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Neutron scattering studies of hard metals
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Since their discovery about 100 years ago, tools made of hard metals have been the enablers of development in various areas: from drilling subway lines for more sustainable cities to the machining of complex next-generation airplane engine parts for reduced CO2 emissions. An increase in properties of hard metals thus leads to efficient operations with shorter lead-time, less environmental footprint, and reduced cost. To tailor the as-sintered hard metal structure with desired properties and develop reliable modelling tools, it is critical to have statistically representative experimental data acquired in conditions mimicking the real processes for hard metals. However, to date, nano- and microstructural investigations of hard metals and related systems have been mainly focused on the lab-scale techniques, limiting the bulk-scale in-situ investigations. This thesis focuses on neutron scattering techniques and demonstrates how the utilization of small angle neutron scattering (SANS) techniques and neutron diffraction (ND) in a complementary manner with lab-scale techniques and computational tools can enhance the mechanistic understanding during processing of hard metals and related systems. Some of the presented information within the thesis is unique to neutron scattering experiments.SANS experiments are used for the quantification of nano- and microstructural features including Co-rich binder pocket size, WC grain size, and size and volume fraction of (V,W)Cx interfacial layers. The quantitative data enables us to draw conclusions regarding the mechanism of grain coarsening inhibition in V-doped hard metals at different V additions. The findings indicate that the grain coarsening inhibition in V-doped hard metals originates from reduced WC/Co interface mobility and total driving force for coarsening. The complex nature of structural evolution at sintering temperatures is further investigated by in-situ SANS up to 1500 oC. Our results show that the size and volume fraction of interfacial layers strongly depend on the presence of bulk (V,W)Cx precipitates and V activity in the binder phase.In-situ ND experiments during aging of (Ti,Zr)C-based systems provide time-resolved insights into the kinetics and structural evolution during phase separation at 1600 oC for 10 h. The results reveal that the decomposition of (Ti,Zr)C into TiC- and ZrC-rich phases can be significantly retarded by minor HfC or NbC additions. During decomposition, in line with the nucleation and growth process, no change is observed in the lattice parameter of ZrC-rich phase. In contrast, the lattice parameter of TiC-rich phase reduces with decomposition, resulting from TiC enrichment, i.e. it reaches equilibrium composition in the course of time. Furthermore, a novel multi-principal element carbide system (Ti,Zr,Hf,W)C with exceptional hardness is designed. Although the system has a miscibility gap, only minor decomposition is observed after 100 h aging at 1350 oC, where the formation of (Ti,W)C- and (Zr,Hf)C-rich decomposition products and WC precipitates occur. Such hindered decomposition enables the carbide system to preserve its high hardness.In summary, by using neutron scattering techniques, this thesis contributes to a better understanding of nano- and microstructural evolution in hard metals and related systems during their processing at elevated temperatures. The thesis and appended papers also guide readers regarding the planning, e.g. sample preparation and sample environment selection, and data analysis of neutron scattering experiments. The thesis can thus serve as a starting point for the more widespread utilization of neutron scattering techniques by the hard metal industry.
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| 9. |
- Östberg, Gustaf, 1971, et al.
(författare)
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Effect of TaC on plastic deformation of WC-Co and Ti(C,N)-WC-Co
- 2006
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Ingår i: International Journal of Refractory Metals and Hard Materials. - : Elsevier BV. - 0263-4368. ; 24:1-2, s. 145-154
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Tidskriftsartikel (refereegranskat)abstract
- The plastic deformation resistance of metal cutting inserts made from a WC–Co cemented carbide, a Ti(C, N)–WC–Co cermet and corresponding materials with additions of TaC has been studied. The cermets were produced with both high and low carbon activity, resulting in a total of six materials. Ab initio calculations of some WC/WC grain boundary geometries suggest that both Co and Ta segregate substitutionally to the boundary and improve the grain boundary strength when substituting carbon. However, only Co segregation was found experimentally, probably due to (Ta, W)C formation. Plastic deformation tests were performed with a turning operation under controlled conditions. For the WC–Co, the addition of Ta had a positive effect for lower cutting speeds but at higher speeds the effect was negative. Three-point bending tests indicated a beneficial effect of Ta in WC–Co, which was also confirmed by internal friction (IF) measurements. However, after thermal cycling, the effect of Ta could be smaller, or even negative. The Ta cermet produced with low carbon activity exhibited a better plastic deformation resistance during cutting but no apparent effects of Ta could be seen either in IF measurements or in three-point bending tests of the cermets. However, a correlation was found between plastic deformation during turning and IF spectra. In the cermet materials, binder phase lamella formation promotes grain boundary sliding at high temperatures.
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| 10. |
- Östberg, Gustaf, 1971, et al.
(författare)
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Mechanisms of plastic deformation of WC-Co and Ti(C,N)-WC-Co
- 2006
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Ingår i: Int. J. Refract. Hard Mater.. - : Elsevier BV. - 0263-4368. ; 24:1-2, s. 135-144
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Tidskriftsartikel (refereegranskat)abstract
- The deformation of the cutting edge of inserts made from WC–Co and Ti(C, N)–19%WC–Co upon radial turning was measured as a function of the cutting speed. Ab initio calculations of some grain boundary geometries in WC–Co indicated that Co segregates to WC/WC grain boundaries in submonolayer proportions and increases their strength and resistance to Co infiltration. This was also confirmed with TEM-EDX. SEM studies showed that during plastic deformation the hard phase skeletons in both materials were partly broken up and infiltrated by binder phase. TEM observations showed a considerable deformation of the WC grains and some infiltrated grain boundaries were facetted along low energy planes. In the cermet, no deformation of the hard phase grains could be seen. The plastic deformation at high temperatures observed by three-point bending corresponds to a number of relaxation processes, detected by internal friction, related to grain boundary sliding. Both materials deform by grain boundary sliding, accommodated in the cermet by Co diffusion and in the WC–Co by deformation of the hard phase and diffusion of Co.
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| 11. |
- Bravo, L, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 12. |
- Tabiri, S, et al.
(författare)
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- 2021
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swepub:Mat__t
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