| 1. |
- de Rojas, I., et al.
(författare)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 2. |
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| 3. |
- Ramdas, S., et al.
(författare)
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A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
- 2022
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 109:8, s. 1366-1387
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
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| 8. |
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| 10. |
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| 11. |
- Hempelmann, N., et al.
(författare)
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Locking the Spin Precession in a Storage Ring
- 2017
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Ingår i: Physical Review Letters. - : American Physical Society. - 0031-9007 .- 1079-7114. ; 119:1
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Tidskriftsartikel (refereegranskat)abstract
- This Letter reports the successful use of feedback from a spin polarization measurement to the revolution frequency of a 0.97 GeV= c bunched and polarized deuteron beam in the Cooler Synchrotron (COSY) storage ring in order to control both the precession rate (approximate to 121 kHz) and the phase of the horizontal polarization component. Real time synchronization with a radio frequency (rf) solenoid made possible the rotation of the polarization out of the horizontal plane, yielding a demonstration of the feedback method to manipulate the polarization. In particular, the rotation rate shows a sinusoidal function of the horizontal polarization phase (relative to the rf solenoid), which was controlled to within a 1 standard deviation range of sigma= 0.21 rad. The minimum possible adjustment was 3.7 mHz out of a revolution frequency of 753 kHz, which changes the precession rate by 26 mrad/s. Such a capability meets a requirement for the use of storage rings to look for an intrinsic electric dipole moment of charged particles.
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| 12. |
- Hempelmann, N., et al.
(författare)
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Phase measurement for driven spin oscillations in a storage ring
- 2018
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Ingår i: Physical Review Accelerators and Beams. - : American Physical Society. - 2469-9888. ; 21:4
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Tidskriftsartikel (refereegranskat)abstract
- This paper reports the first simultaneous measurement of the horizontal and vertical components of the polarization vector in a storage ring under the influence of a radio frequency (rf) solenoid. The experiments were performed at the Cooler Synchrotron COSY in Julich using a vector polarized, bunched 0.97 GeV/c deuteron beam. Using the new spin feedback system, we set the initial phase difference between the solenoid field and the precession of the polarization vector to a predefined value. The feedback system was then switched off, allowing the phase difference to change over time, and the solenoid was switched on to rotate the polarization vector. We observed an oscillation of the vertical polarization component and the phase difference. The oscillations can be described using an analytical model. The results of this experiment also apply to other rf devices with horizontal magnetic fields, such as Wien filters. The precise manipulation of particle spins in storage rings is a prerequisite for measuring the electric dipole moment (EDM) of charged particles.
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| 13. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 14. |
- Saleev, A., et al.
(författare)
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Spin tune mapping as a novel tool to probe the spin dynamics in storage rings
- 2017
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Ingår i: Physical Review Accelerators and Beams. - : American Physical Society. - 2469-9888. ; 20:7
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Tidskriftsartikel (refereegranskat)abstract
- Precision experiments, such as the search for electric dipole moments of charged particles using storage rings, demand for an understanding of the spin dynamics with unprecedented accuracy. The ultimate aim is to measure the electric dipole moments with a sensitivity up to 15 orders in magnitude better than the magnetic dipole moment of the stored particles. This formidable task requires an understanding of the background to the signal of the electric dipole from rotations of the spins in the spurious magnetic fields of a storage ring. One of the observables, especially sensitive to the imperfection magnetic fields in the ring is the angular orientation of stable spin axis. Up to now, the stable spin axis has never been determined experimentally, and in addition, the JEDI collaboration for the first time succeeded to quantify the background signals that stem from false rotations of the magnetic dipole moments in the horizontal and longitudinal imperfection magnetic fields of the storage ring. To this end, we developed a new method based on the spin tune response of a machine to artificially applied longitudinal magnetic fields. This novel technique, called spin tune mapping, emerges as a very powerful tool to probe the spin dynamics in storage rings. The technique was experimentally tested in 2014 using polarized deuterons stored in the cooler synchrotron COSY, and for the first time, the angular orientation of the stable spin axis at two different locations in the ring has been determined to an unprecedented accuracy of better than 2.8 mu rad.
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| 15. |
- Winkler, TW, et al.
(författare)
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Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals
- 2022
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 580-
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
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| 16. |
- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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| 17. |
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| 18. |
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| 19. |
- Evangelou, Evangelos, et al.
(författare)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 20. |
- Eversmann, D., et al.
(författare)
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New Method for a Continuous Determination of the Spin Tune in Storage Rings and Implications for Precision Experiments
- 2015
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 115:9
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Tidskriftsartikel (refereegranskat)abstract
- A new method to determine the spin tune is described and tested. In an ideal planar magnetic ring, the spin tune-defined as the number of spin precessions per turn-is given by nu(s) = gamma G (gamma is the Lorentz factor, G the gyromagnetic anomaly). At 970 MeV/c, the deuteron spins coherently process at a frequency of approximate to 120 kHz in the Cooler Synchrotron COSY. The spin tune is deduced from the up-down asymmetry of deuteron-carbon scattering. In a time interval of 2.6 s, the spin tune was determined with a precision of the order 10(-8), and to 1 x 10(-10) for a continuous 100 s accelerator cycle. This renders the presented method a new precision tool for accelerator physics; controlling the spin motion of particles to high precision is mandatory, in particular, for the measurement of electric dipole moments of charged particles in a storage ring.
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| 21. |
- Guidoboni, G., et al.
(författare)
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How to Reach a Thousand-Second in-Plane Polarization Lifetime with 0.97-GeV/c Deuterons in a Storage Ring
- 2016
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Ingår i: Physical Review Letters. - : American Physical Society. - 0031-9007 .- 1079-7114. ; 117:5
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Tidskriftsartikel (refereegranskat)abstract
- We observe a deuteron beam polarization lifetime near 1000 s in the horizontal plane of a magnetic storage ring (COSY). This long spin coherence time is maintained through a combination of beam bunching, electron cooling, sextupole field corrections, and the suppression of collective effects through beam current limits. This record lifetime is required for a storage ring search for an intrinsic electric dipole moment on the deuteron at a statistical sensitivity level approaching 10(-29) e cm.
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| 22. |
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| 23. |
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| 24. |
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| 25. |
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| 26. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 27. |
- Augustyniak, W., et al.
(författare)
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Polarization of a stored beam by spin-filtering
- 2012
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Ingår i: Physics Letters B. - : Elsevier. - 0370-2693 .- 1873-2445. ; 718:1, s. 64-69
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Tidskriftsartikel (refereegranskat)abstract
- The PAX Collaboration has successfully performed a spin-filtering experiment with protons at the COSY-ring. The measurement allowed the determination of the spin-dependent polarizing cross section, that compares well with the theoretical prediction from the nucleon-nucleon potential. The test confirms that spin-filtering can be adopted as a method to polarize a stored beam and that the present interpretation of the mechanism in terms of the proton-proton interaction is correct. The outcome of the experiment is of utmost importance in view of the possible application of the method to polarize a beam of stored antiprotons.
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| 28. |
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| 29. |
- Guidoboni, G., et al.
(författare)
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Connection between zero chromaticity and long in-plane polarization lifetime in a magnetic storage ring
- 2018
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Ingår i: Physical Review Accelerators and Beams. - : American Physical Society. - 2469-9888. ; 21:2
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, we demonstrate the connection between a magnetic storage ring with additional sextupole fields set so that the x and y chromaticities vanish and the maximizing of the lifetime of in-plane polarization (IPP) for a 0.97-GeV/c deuteron beam. The IPP magnitude was measured by continuously monitoring the down-up scattering asymmetry (sensitive to sideways polarization) in an in-beam, carbontarget polarimeter and unfolding the precession of the IPP due to the magnetic anomaly of the deuteron. The optimum operating conditions for a long IPP lifetime were made by scanning the field of the storage ring sextupole magnet families while observing the rate of IPP loss during storage of the beam. The beam was bunched and electron cooled. The IPP losses appear to arise from the change of the orbit circumference, and consequently the particle speed and spin tune, due to the transverse betatron oscillations of individual particles in the beam. The effects of these changes are canceled by an appropriate sextupole field setting.
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| 30. |
- 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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| 31. |
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| 33. |
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| 34. |
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| 35. |
- Wain, Louise V., et al.
(författare)
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Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney
- 2017
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Ingår i: Hypertension. - 0194-911X .- 1524-4563. ; 70:3, s. e4-e19
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
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| 36. |
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| 37. |
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| 38. |
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| 39. |
- Chasman, Daniel I., et al.
(författare)
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Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function
- 2012
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:24, s. 5329-5343
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Tidskriftsartikel (refereegranskat)abstract
- In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5.6 10(9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 10(4)2.2 10(7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
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| 40. |
- Gorski, Mathias, et al.
(författare)
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1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10(-8) previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.
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| 41. |
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| 42. |
- Huffman, Jennifer E., et al.
(författare)
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Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, P-inter= 2.6 x 10(-8)). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDAR-ADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10(-8)), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10(-8)), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10(-4)). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.
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| 43. |
- 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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| 44. |
- Oellers, D., et al.
(författare)
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New experimental upper limit of the electron-proton spin-flip cross-section
- 2014
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 759, s. 6-9
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Tidskriftsartikel (refereegranskat)abstract
- In a previous publication, measurements of the depolarization of a stored proton beam by interaction with a co-propagating unpolarized electron beam at low relative energy have been presented and an upper limit of about 3 x 10(7) b for the electron-proton spin flip cross-section was determined. A refined analysis presented in this paper reduces the previous upper limit by a factor of three by the introduction of a new procedure that, also makes use of non-identified particles.
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| 45. |
- O'Seaghdha, Conall M., et al.
(författare)
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Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations
- 2013
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 9:9, s. e1003796-
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Tidskriftsartikel (refereegranskat)abstract
- Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in <= 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
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| 46. |
- Parsa, Afshin, et al.
(författare)
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Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function
- 2013
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Ingår i: Journal of the American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 24:12, s. 2105-2117
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Tidskriftsartikel (refereegranskat)abstract
- Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
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| 47. |
- 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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| 48. |
- Pattaro, Cristian, et al.
(författare)
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Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function
- 2012
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 8:3, s. e1002584-
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genomewide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
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| 49. |
- Petrov, Dmitry, et al.
(författare)
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Machine Learning for Large-Scale Quality Control of 3D Shape Models in Neuroimaging
- 2017
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Ingår i: Machine learning in medical imaging. MLMI (Workshop). - Cham : Springer International Publishing. ; 10541, s. 371-378
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Tidskriftsartikel (refereegranskat)abstract
- As very large studies of complex neuroimaging phenotypes become more common, human quality assessment of MRI-derived data remains one of the last major bottlenecks. Few attempts have so far been made to address this issue with machine learning. In this work, we optimize predictive models of quality for meshes representing deep brain structure shapes. We use standard vertex-wise and global shape features computed homologously across 19 cohorts and over 7500 human-rated subjects, training kernelized Support Vector Machine and Gradient Boosted Decision Trees classifiers to detect meshes of failing quality. Our models generalize across datasets and diseases, reducing human workload by 30-70%, or equivalently hundreds of human rater hours for datasets of comparable size, with recall rates approaching inter-rater reliability.
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| 50. |
- Piras, F, et al.
(författare)
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White matter microstructure and its relation to clinical features of obsessive-compulsive disorder: findings from the ENIGMA OCD Working Group
- 2021
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1, s. 173-
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Tidskriftsartikel (refereegranskat)abstract
- Microstructural alterations in cortico-subcortical connections are thought to be present in obsessive–compulsive disorder (OCD). However, prior studies have yielded inconsistent findings, perhaps because small sample sizes provided insufficient power to detect subtle abnormalities. Here we investigated microstructural white matter alterations and their relation to clinical features in the largest dataset of adult and pediatric OCD to date. We analyzed diffusion tensor imaging metrics from 700 adult patients and 645 adult controls, as well as 174 pediatric patients and 144 pediatric controls across 19 sites participating in the ENIGMA OCD Working Group, in a cross-sectional case-control magnetic resonance study. We extracted measures of fractional anisotropy (FA) as main outcome, and mean diffusivity, radial diffusivity, and axial diffusivity as secondary outcomes for 25 white matter regions. We meta-analyzed patient-control group differences (Cohen’s d) across sites, after adjusting for age and sex, and investigated associations with clinical characteristics. Adult OCD patients showed significant FA reduction in the sagittal stratum (d = −0.21, z = −3.21, p = 0.001) and posterior thalamic radiation (d = −0.26, z = −4.57, p < 0.0001). In the sagittal stratum, lower FA was associated with a younger age of onset (z = 2.71, p = 0.006), longer duration of illness (z = −2.086, p = 0.036), and a higher percentage of medicated patients in the cohorts studied (z = −1.98, p = 0.047). No significant association with symptom severity was found. Pediatric OCD patients did not show any detectable microstructural abnormalities compared to controls. Our findings of microstructural alterations in projection and association fibers to posterior brain regions in OCD are consistent with models emphasizing deficits in connectivity as an important feature of this disorder.
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