| 11. |
- Koettgen, Anna, et al.
(författare)
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Genome-wide association analyses identify 18 new loci associated with serum urate concentrations
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:2, s. 145-154
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Tidskriftsartikel (refereegranskat)abstract
- Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SEMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
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| 12. |
- Rodriguez, D., et al.
(författare)
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MATS and LaSpec : High-precision experiments using ion traps and lasers at FAIR
- 2010
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Ingår i: The European physical journal. Special topics. - : Springer Science and Business Media LLC. - 1951-6355 .- 1951-6401. ; 183, s. 1-123
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Forskningsöversikt (refereegranskat)abstract
- Nuclear ground state properties including mass, charge radii, spins and moments can be determined by applying atomic physics techniques such as Penning-trap based mass spectrometry and laser spectroscopy. The MATS and LaSpec setups at the low-energy beamline at FAIR will allow us to extend the knowledge of these properties further into the region far from stability. The mass and its inherent connection with the nuclear binding energy is a fundamental property of a nuclide, a unique ""fingerprint"". Thus, precise mass values are important for a variety of applications, ranging from nuclear-structure studies like the investigation of shell closures and the onset of deformation, tests of nuclear mass models and mass formulas, to tests of the weak interaction and of the Standard Model. The required relative accuracy ranges from 10(-5) to below 10(-8) for radionuclides, which most often have half-lives well below 1 s. Substantial progress in Penning trap mass spectrometry has made this method a prime choice for precision measurements on rare isotopes. The technique has the potential to provide high accuracy and sensitivity even for very short-lived nuclides. Furthermore, ion traps can be used for precision decay studies and offer advantages over existing methods. With MATS (Precision Measurements of very short-lived nuclei using an Advanced Trapping System for highly-charged ions) at FAIR we aim to apply several techniques to very short-lived radionuclides: High-accuracy mass measurements, in-trap conversion electron and alpha spectroscopy, and trap-assisted spectroscopy. The experimental setup of MATS is a unique combination of an electron beam ion trap for charge breeding, ion traps for beam preparation, and a high-precision Penning trap system for mass measurements and decay studies. For the mass measurements, MATS offers both a high accuracy and a high sensitivity. A relative mass uncertainty of 10(-9) can be reached by employing highly-charged ions and a non-destructive Fourier-Transform Ion-Cyclotron-Resonance (FT-ICR) detection technique on single stored ions. This accuracy limit is important for fundamental interaction tests, but also allows for the study of the fine structure of the nuclear mass surface with unprecedented accuracy, whenever required. The use of the FT-ICR technique provides true single ion sensitivity. This is essential to access isotopes that are produced with minimum rates which are very often the most interesting ones. Instead of pushing for highest accuracy, the high charge state of the ions can also be used to reduce the storage time of the ions, hence making measurements on even shorter-lived isotopes possible. Decay studies in ion traps will become possible with MATS. Novel spectroscopic tools for in-trap high-resolution conversion-electron and charged-particle spectroscopy from carrier-free sources will be developed, aiming e. g. at the measurements of quadrupole moments and E0 strengths. With the possibility of both high-accuracy mass measurements of the shortest-lived isotopes and decay studies, the high sensitivity and accuracy potential of MATS is ideally suited for the study of very exotic nuclides that will only be produced at the FAIR facility. Laser spectroscopy of radioactive isotopes and isomers is an efficient and model-independent approach for the determination of nuclear ground and isomeric state properties. Hyperfine structures and isotope shifts in electronic transitions exhibit readily accessible information on the nuclear spin, magnetic dipole and electric quadrupole moments as well as root-mean-square charge radii. The dependencies of the hyperfine splitting and isotope shift on the nuclear moments and mean square nuclear charge radii are well known and the theoretical framework for the extraction of nuclear parameters is well established. These extracted parameters provide fundamental information on the structure of nuclei at the limits of stability. Vital information on both bulk and valence nuclear properties are derived and an exceptional sensitivity to changes in nuclear deformation is achieved. Laser spectroscopy provides the only mechanism for such studies in exotic systems and uniquely facilitates these studies in a model-independent manner. The accuracy of laser-spectroscopic-determined nuclear properties is very high. Requirements concerning production rates are moderate; collinear spectroscopy has been performed with production rates as few as 100 ions per second and laser-desorption resonance ionization mass spectroscopy (combined with beta-delayed neutron detection) has been achieved with rates of only a few atoms per second. This Technical Design Report describes a new Penning trap mass spectrometry setup as well as a number of complementary experimental devices for laser spectroscopy, which will provide a complete system with respect to the physics and isotopes that can be studied. Since MATS and LaSpec require high-quality low-energy beams, the two collaborations have a common beamline to stop the radioactive beam of in-flight produced isotopes and prepare them in a suitable way for transfer to the MATS and LaSpec setups, respectively.
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| 13. |
- Scott, Robert A., et al.
(författare)
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Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:9, s. 991-1005
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Tidskriftsartikel (refereegranskat)abstract
- Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
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| 14. |
- Asselbergs, Folkert W., et al.
(författare)
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Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci
- 2012
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 91:5, s. 823-838
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering similar to 2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
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| 15. |
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| 16. |
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| 17. |
- van der Harst, Pim, et al.
(författare)
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Seventy-five genetic loci influencing the human red blood cell
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 492:7429, s. 369-375
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Tidskriftsartikel (refereegranskat)abstract
- Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
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| 18. |
- Ganesh, Santhi K., et al.
(författare)
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Loci influencing blood pressure identified using a cardiovascular gene-centric array
- 2013
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:8, s. 1663-1678
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Tidskriftsartikel (refereegranskat)abstract
- Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped 50 000 single-nucleotide polymorphisms (SNPs) that capture variation in 2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P 2.4 10(6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
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| 19. |
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| 20. |
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