| 1. |
- Okada, Yukinori, et al.
(författare)
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Genetics of rheumatoid arthritis contributes to biology and drug discovery
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 506:7488, s. 376-381
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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| 2. |
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| 3. |
- Forabosco, P., et al.
(författare)
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Meta-analysis of genome-wide linkage studies of systemic lupus erythematosus
- 2006
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Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 7:7, s. 609-614
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Tidskriftsartikel (refereegranskat)abstract
- A genetic contribution to the development of systemic lupus erythematosus (SLE) is well established. Several genome-wide linkage scans have identified a number of putative susceptibility loci for SLE, some of which have been replicated in independent samples. This study aimed to identify the regions showing the most consistent evidence for linkage by applying the genome scan meta-analysis (GSMA) method. The study identified two genome-wide suggestive regions on 6p21.1-q15 and 20p11-q13.13 (P-value=0.0056 and P-value=0.0044, respectively) and a region with P-value<0.01 on 16p13-q12.2.The region on chromosome 6 contains the human leukocyte antigen cluster, and the chromosome 16 and 20 regions have been replicated in several cohorts. The potential importance of the identified genomic regions are also highlighted. These results, in conjunction with data emerging from dense single nucleotide polymorphism typing of specific regions or future genome-wide association studies will help guide efforts to identify the actual predisposing genetic variation contributing to this complex genetic disease.
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| 4. |
- Abdelhameed, A. H., et al.
(författare)
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Cryogenic characterization of a LiAlO2 crystal and new results on spin-dependent dark matter interactions with ordinary matter: CRESST Collaboration
- 2020
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 80:9
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Tidskriftsartikel (refereegranskat)abstract
- In this work, a first cryogenic characterization of a scintillating LiAlO2 single crystal is presented. The results achieved show that this material holds great potential as a target for direct dark matter search experiments. Three different detector modules obtained from one crystal grown at the Leibniz-Institut fur Kristallzuchtung (IKZ) have been tested to study different properties at cryogenic temperatures. Firstly, two 2.8 g twin crystals were used to build different detector modules which were operated in an above-ground laboratory at the Max Planck Institute for Physics (MPP) in Munich, Germany. The first detector module was used to study the scintillation properties of LiAlO2 at cryogenic temperatures. The second achieved an energy threshold of (213.02 +/- 1.48) eV which allows setting a competitive limit on the spin-dependent dark matter particle-proton scattering cross section for dark matter particle masses between 350 MeV/c2 and 1.50 GeV/c2. Secondly, a detector module with a 373 g LiAlO2 crystal as the main absorber was tested in an underground facility at the Laboratori Nazionali del Gran Sasso (LNGS): from this measurement it was possible to determine the radiopurity of the crystal and study the feasibility of using this material as a neutron flux monitor for low-background experiments.
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| 5. |
- Abdelhameed, A. H., et al.
(författare)
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First results from the CRESST-III low-mass dark matter program
- 2019
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Ingår i: Physical Review D. - 2470-0010 .- 2470-0029. ; 100:10
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Tidskriftsartikel (refereegranskat)abstract
- The CRESST experiment is a direct dark matter search which aims to measure interactions of potential dark matter particles in an Earth-bound detector. With the current stage, CRESST-III, we focus on a low energy threshold for increased sensitivity towards light dark matter particles. In this paper we describe the analysis of one detector operated in the first run of CRESST-III (05/2016-02/2018) achieving a nuclear recoil threshold of 30.1 eV. This result was obtained with a 23.6 g CaWO4 crystal operated as a cryogenic scintillating calorimeter in the CRESST setup at the Laboratori Nazionali del Gran Sasso (LNGS). Both the primary phonon (heat) signal and the simultaneously emitted scintillation light, which is absorbed in a separate silicon-on-sapphire light absorber, are measured with highly sensitive transition edge sensors operated at similar to 15 mK. The unique combination of these sensors with the light element oxygen present in our target yields sensitivity to dark matter particle masses as low as 160 MeV/c(2).
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| 6. |
- Abdelhameed, A. H., et al.
(författare)
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First results on sub-GeV spin-dependent dark matter interactions with Li-7
- 2019
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 79:7
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Tidskriftsartikel (refereegranskat)abstract
- In this work, we want to highlight the potential of lithium as a target for spin-dependent dark matter search in cryogenic experiments, with a special focus on the low-mass region of the parameter space. We operated a prototype detector module based on a Li2MoO4 target crystal in an above-ground laboratory. Despite the high background environment, the detector sets a competitive limit on spin-dependent interactions of dark matter particles with protons and neutrons for masses between 1.5 GeV/c(2).
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| 7. |
- Abdelhameed, A. H., et al.
(författare)
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Geant4-based electromagnetic background model for the CRESST dark matter experiment
- 2019
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 79:10
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Tidskriftsartikel (refereegranskat)abstract
- The CRESST (Cryogenic Rare Event Search with Superconducting Thermometers) dark matter search experiment aims for the detection of dark matter particles via elastic scattering off nuclei in CaWO4 crystals. To understand the CRESST electromagnetic background due to the bulk contamination in the employed materials, a model based on Monte Carlo simulations was developed using the Geant4 simulation toolkit. The results of the simulation are applied to the TUM40 detector module of CRESST-II phase 2. We are able to explain up to (68 +/- 16)% of the electromagnetic background in the energy range between 1 and 40 keV.
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| 8. |
- Bertoldo, E., et al.
(författare)
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Lithium-Containing Crystals for Light Dark Matter Search Experiments
- 2020
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Ingår i: Journal of Low Temperature Physics. - : Springer Science and Business Media LLC. - 0022-2291 .- 1573-7357. ; 199:1-2, s. 510-518
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Tidskriftsartikel (refereegranskat)abstract
- In the current direct dark matter search landscape, the leading experiments in the sub-GeV mass region mostly rely on cryogenic techniques which employ crystalline targets. One attractive type of crystals for these experiments is those containing lithium, due to the fact that 7Li is an ideal candidate to study spin-dependent dark matter interactions in the low mass region. Furthermore, 6Li can absorb neutrons, a challenging background for dark matter experiments, through a distinctive signature which allows the monitoring of the neutron flux directly on site. In this work, we show the results obtained with three different detectors based on LiAlO 2, a target crystal never used before in cryogenic experiments.
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| 9. |
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| 10. |
- Chung, Sharon A., et al.
(författare)
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Differential Genetic Associations for Systemic Lupus Erythematosus Based on Anti-dsDNA Autoantibody Production
- 2011
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:3, s. e1001323-
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, n = 811) and anti-dsDNA autoantibody negative (anti-dsDNA -, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, p = 2.0E-20) compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, p = 2.4E-04), with (Pheterogeneity)<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti-dsDNA + SLE and were not associated with anti-dsDNA - SLE. In conclusion, we identified differential genetic associations with SLE based on anti-dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti-dsDNA - SLE.
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