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- Lambert, J-C, et al.
(författare)
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Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease
- 2013
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 18:4, s. 461-470
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Tidskriftsartikel (refereegranskat)abstract
- Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n = 2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 x 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and A beta plasma concentrations in three independent non-demented populations (n = 2579). We reported that polymorphisms were associated with plasma A beta 42/A beta 40 ratio (best signal, P=5.4 x 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.
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- Oei, L., et al.
(författare)
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Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus
- 2014
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 59, s. 20-27
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Tidskriftsartikel (refereegranskat)abstract
- Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fracture applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5 x 10(-8). In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 x 10(-8). However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% Cl: 0.98-1.14; p = 0.17), displaying high degree of heterogeneity (I-2= 57%; Q(het)p = 0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures. (C) 2013 Elsevier Inc. All rights reserved.
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- Estrada, Karol, et al.
(författare)
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
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Tidskriftsartikel (refereegranskat)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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- Frasinski, L. J., et al.
(författare)
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Dynamics of Hollow Atom Formation in Intense X-Ray Pulses Probed by Partial Covariance Mapping
- 2013
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 111:7, s. 073002-
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Tidskriftsartikel (refereegranskat)abstract
- When exposed to ultraintense x-radiation sources such as free electron lasers (FELs) the innermost electronic shell can efficiently be emptied, creating a transient hollow atom or molecule. Understanding the femtosecond dynamics of such systems is fundamental to achieving atomic resolution in flash diffraction imaging of noncrystallized complex biological samples. We demonstrate the capacity of a correlation method called partial covariance mapping'' to probe the electron dynamics of neon atoms exposed to intense 8 fs pulses of 1062 eV photons. A complete picture of ionization processes competing in hollow atom formation and decay is visualized with unprecedented ease and the map reveals hitherto unobserved nonlinear sequences of photoionization and Auger events. The technique is particularly well suited to the high counting rate inherent in FEL experiments.
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- Moayyeri, Alireza, et al.
(författare)
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Genetic determinants of heel bone properties : genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:11, s. 3054-3068
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Tidskriftsartikel (refereegranskat)abstract
- Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
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- Zhaunerchyk, Vitali, et al.
(författare)
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Using covariance mapping to investigate the dynamics of multi-photon ionization processes of Ne atoms exposed to X-FEL pulses
- 2013
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Ingår i: Journal of Physics B. - : IOP Publishing. - 0953-4075 .- 1361-6455. ; 46:16, s. 164034-
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Tidskriftsartikel (refereegranskat)abstract
- We report on a detailed investigation into the electron emission processes of Ne atoms exposed to intense femtosecond x-ray pulses, provided by the Linac Coherent Light Source Free Electron Laser (FEL) at Stanford. The covariance mapping technique is applied to analyse the data, and the capability of this approach to disentangle both linear and nonlinear correlation features which may be hidden on coincidence maps of the same data set is demonstrated. Different correction techniques which enable improvements on the quality of the spectral features extracted from the covariance maps are explored. Finally, a method for deriving characteristics of the x-ray FEL pulses based on covariance mapping in combination with model simulations is presented.
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- Zitnik, M, et al.
(författare)
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High resolution multiphoton spectroscopy by a tunable free-electron-laser light.
- 2014
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Ingår i: Physical Review Letters. - 1079-7114 .- 0031-9007. ; 113:19
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Tidskriftsartikel (refereegranskat)abstract
- Seeded free electron lasers theoretically have the intensity, tunability, and resolution required for multiphoton spectroscopy of atomic and molecular species. Using the seeded free electron laser FERMI and a novel detection scheme, we have revealed the two-photon excitation spectra of dipole-forbidden doubly excited states in helium. The spectral profiles of the lowest (-1,0)^{+1} ^{1}S^{e} and (0,1)^{0} ^{1}D^{e} resonances display energy shifts in the meV range that depend on the pulse intensity. The results are explained by an effective two-level model based on calculated Rabi frequencies and decay rates.
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- Fang, L., et al.
(författare)
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Multiple Ionization and Double Core-hole Production in Molecules using the LCLS X-ray FEL
- 2012
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Ingår i: Journal of Physics, Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 388:3, s. 032028-
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Tidskriftsartikel (refereegranskat)abstract
- We used the world's first hard x-ray FEL to investigate the response of molecular systems to the ultra-intense, femtosecond x-ray radiation. We report sequential multiphoton ionization, frustrated absorption and double core hole production mechanisms.
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- Larsson, Mats, et al.
(författare)
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Double core-hole formation in small molecules at the LCLS free electron laser
- 2013
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Ingår i: Journal of Physics B. - : IOP Publishing. - 0953-4075 .- 1361-6455. ; 46:16, s. 164030-
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated nonlinear processes in small molecules by x-ray photoelectron spectroscopy using the Linac Coherent Light Source free electron laser, and by simulations. The main focus of the experiments was the formation of the two-site double core-hole (tsDCH) states in the molecules CO2, N2O and N-2. These experiments are described in detail and the results are compared with simulations of the photoelectron spectra. The double core-hole states, and in particular the tsDCH states, have been predicted to be highly sensitive to the chemical environment. The theory behind this chemical sensitivity is validated by the experiments. Furthermore, our simulations of the relative integrated intensities of the peaks associated with the nonlinear processes show that this type of simulation, in combination with experimental data, provides a useful tool for estimating the duration of ultra-short x-ray pulses.
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- Sahlén, Martin, et al.
(författare)
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Experimental Verification of the Chemical Sensitivity of Two-Site Double Core-Hole States Formed by an X-Ray Free-Electron Laser
- 2012
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 108:15, s. 153003-
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Tidskriftsartikel (refereegranskat)abstract
- We have performed x-ray two-photon photoelectron spectroscopy using the Linac Coherent Light Source x-ray free-electron laser in order to study double core-hole (DCH) states of CO2, N2O, and N-2. The experiment verifies the theory behind the chemical sensitivity of two-site DCH states by comparing a set of small molecules with respect to the energy shift of the two-site DCH state and by extracting the relevant parameters from this shift.
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- Saleacuten, P., et al.
(författare)
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X-ray FEL-induced Double Core-Hole Formation in Polyatomic Molecules
- 2012
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Ingår i: Journal of Physics, Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 388:2, s. 022083-
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Tidskriftsartikel (refereegranskat)abstract
- We use extremely intense, ultrashort soft X-Ray pulses generated by the LCLS X-Ray Free Electron Laser to investigate the production of molecular double core-hole states by sequential two-photon X-Ray absorption. The effect of critical LCLS parameters such as the number of photons per pulse, the pulse duration, and the focal spot size on the photoelectron and Auger spectra is modeled in detail and the results of these simulations are used as an aid in the interpretation of the experimental spectra obtained. The emphasis is on double core-hole formation in small polyatomic molecules such as CO2.
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- Yusuf, D, et al.
(författare)
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The transcription factor encyclopedia
- 2012
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906. ; 13:3, s. R24-
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Tidskriftsartikel (refereegranskat)
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- Braam, A. W., et al.
(författare)
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Depression, subthreshold depression and comorbid anxiety symptoms in older Europeans: Results from the EURODEP concerted action
- 2014
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Ingår i: Journal of Affective Disorders. - : Elsevier BV. - 0165-0327. ; 155, s. 266-272
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Tidskriftsartikel (refereegranskat)abstract
- Background: In the epidemiology of late life depression, few insights are available on the co-occurrence of subthreshold depression and comorbicl symptoms of anxiety. The current study aims to describe prevalence patterns of comorbid anxiety symptoms across different levels of depression in old age, and to describe the burden of depressive symptoms and functional disability across patterns of comorbidity. Methods: Respondents were older adults in the community, age 65-104 (N=14,200), from seven European countries, with in total nine study centres, collaborating in the EURODEP concerted action. Depression and anxiety were assessed using the Geriatric Mental State examination (GMS-AGECAT package), providing subthreshold level and case level diagnoses. Presence of anxiety symptoms was defined as at least three distinct symptoms of anxiety. Number of depressive symptoms was assessed with the EURO-D scale. Results: The prevalence of anxiety symptoms amounts to 32% for respondents without depression, 67% for those with subthreshold depression, and 87% for those with case level depression. The number of depressive symptoms is similar for those with subthreshold level depression with cornorbid anxiety, compared to case level depression without symptoms of anxiety. In turn, at case level, comorbid symptoms of anxiety are associated with higher levels of depressive symptoms and more functional disability. Limitations: GMS-AGECAT is insufficiently cciuipped with diagnostic procedures to identify specific types of anxiety disorders. conclusions: Anxiety symptoms in late life depression are highly prevalent, and are likely to contribute to the burden of symptoms of the depression, even at subthreshold level. (C) 2013 Elsevier By. All rights reserved.
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