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- Davies, G., et al.
(författare)
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Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function
- 2018
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
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| 10. |
- Donkervoort, S., et al.
(författare)
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Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores
- 2020
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 107:6, s. 1078-1095
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Tidskriftsartikel (refereegranskat)abstract
- The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common UNC45B variant that acts as a complex hypomorph splice variant. Purified UNC-45B mutants showed changes in folding and solubility. In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants, which showed impaired myosin binding for one and defective muscle function for three. Together, our results demonstrate that UNC-45B impairment manifests as a chaperonopathy with progressive muscle pathology, which discovers the previously unknown conserved role of UNC-45B in myofibrillar organization.
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| 12. |
- Lacour, S., et al.
(författare)
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The mass of β Pictoris c from β Pictoris b orbital motion
- 2021
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 654
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Tidskriftsartikel (refereegranskat)abstract
- Aims. We aim to demonstrate that the presence and mass of an exoplanet can now be effectively derived from the astrometry of another exoplanet.Methods. We combined previous astrometry of β Pictoris b with a new set of observations from the GRAVITY interferometer. The orbital motion of β Pictoris b is fit using Markov chain Monte Carlo simulations in Jacobi coordinates. The inner planet, β Pictoris c, was also reobserved at a separation of 96 mas, confirming the previous orbital estimations.Results. From the astrometry of planet b only, we can (i) detect the presence of β Pictoris c and (ii) constrain its mass to 10.04(-3.10)(+4.53) M-Jup. If one adds the astrometry of β Pictoris c, the mass is narrowed down to 9.15(-1.06)(+1.08) M-Jup. The inclusion of radial velocity measurements does not affect the orbital parameters significantly, but it does slightly decrease the mass estimate to 8.89(-0.75)(+0.75) M-Jup. With a semimajor axis of 2.68 +/- 0.02 au, a period of 1221 +/- 15 days, and an eccentricity of 0.32 +/- 0.02, the orbital parameters of β Pictoris c are now constrained as precisely as those of β Pictoris b. The orbital configuration is compatible with a high-order mean-motion resonance (7:1). The impact of the resonance on the planets' dynamics would then be negligible with respect to the secular perturbations, which might have played an important role in the eccentricity excitation of the outer planet.
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| 13. |
- Lagrange, A. M., et al.
(författare)
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Unveiling the beta Pictoris system, coupling high contrast imaging, interferometric, and radial velocity data
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 642
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Tidskriftsartikel (refereegranskat)abstract
- Context. The nearby and young beta Pictoris system hosts a well resolved disk, a directly imaged massive giant planet orbiting at similar or equal to 9 au, as well as an inner planet orbiting at similar or equal to 2.7 au, which was recently detected through radial velocity (RV). As such, it offers several unique opportunities for detailed studies of planetary system formation and early evolution.Aims. We aim to further constrain the orbital and physical properties of beta Pictoris b and c using a combination of high contrast imaging, long base-line interferometry, and RV data. We also predict the closest approaches or the transit times of both planets, and we constrain the presence of additional planets in the system.Methods. We obtained six additional epochs of SPHERE data, six additional epochs of GRAVITY data, and five additional epochs of RV data. We combined these various types of data in a single Markov-chain Monte Carlo analysis to constrain the orbital parameters and masses of the two planets simultaneously. The analysis takes into account the gravitational influence of both planets on the star and hence their relative astrometry. Secondly, we used the RV and high contrast imaging data to derive the probabilities of presence of additional planets throughout the disk, and we tested the impact of absolute astrometry.Results. The orbital properties of both planets are constrained with a semi-major axis of 9.8 0.4 au and 2.7 +/- 0.02 au for b and c, respectively, and eccentricities of 0.09 +/- 0.1 and 0.27 +/- 0.07, assuming the HIPPARCOS distance. We note that despite these low fitting error bars, the eccentricity of beta Pictoris c might still be over-estimated. If no prior is provided on the mass of beta Pictoris b, we obtain a very low value that is inconsistent with what is derived from brightness-mass models. When we set an evolutionary model motivated prior to the mass of beta Pictoris b, we find a solution in the 10-11 M-Jup range. Conversely, beta Pictoris c's mass is well constrained, at 7.8 +/- 0.4 M-Jup, assuming both planets are on coplanar orbits. These values depend on the assumptions on the distance of the beta Pictoris system. The absolute astrometry HIPPARCOS-Gaia data are consistent with the solutions presented here at the 2 sigma level, but these solutions are fully driven by the relative astrometry plus RV data. Finally, we derive unprecedented limits on the presence of additional planets in the disk. We can now exclude the presence of planets that are more massive than about 2.5 M-Jup closer than 3 au, and more massive than 3.5 M-Jup between 3 and 7.5 au. Beyond 7.5 au, we exclude the presence of planets that are more massive than 1-2 M-Jup.Conclusions. Combining relative astrometry and RVs allows one to precisely constrain the orbital parameters of both planets and to give lower limits to potential additional planets throughout the disk. The mass of beta Pictoris c is also well constrained, while additional RV data with appropriate observing strategies are required to properly constrain the mass of beta Pictoris b.
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- Boxall, A. B. A., et al.
(författare)
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Pharmaceuticals and Personal Care Products in the Environment: What Are the Big Questions?
- 2012
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Ingår i: Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 120:9, s. 1221-1229
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Over the past 10-15 years, a substantial amount of work has been done by the scientific, regulatory, and business communities to elucidate the effects and risks of pharmaceuticals and personal care products (PPCPs) in the environment. OBJECTIVE: This review was undertaken to identify key outstanding issues regarding the effects of PPCPs on human and ecological health in order to ensure that future resources will be focused on the most important areas. DATA SOURCES: To better understand and manage the risks of PPCPs in the environment, we used the "key question" approach to identify the principle issues that need to be addressed. Initially, questions were solicited from academic, government, and business communities around the world. A list of 101 questions was then discussed at an international expert workshop, and a top-20 list was developed. Following the workshop, workshop attendees ranked the 20 questions by importance. DATA SYNTHESIS: The top 20 priority questions fell into seven categories: a) prioritization of substances for assessment, b) pathways of exposure, c) bioavailability and uptake, a effects characterization, e) risk and relative risk, f) antibiotic resistance, and g) risk management. CONCLUSIONS: A large body of information is now available on PPCPs in the environment. This exercise prioritized the most critical questions to aid in development of future research programs on the topic.
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| 18. |
- Garatti, A. Caratti o., et al.
(författare)
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The GRAVITY young stellar object survey: II. First spatially resolved observations of the CO bandhead emission in a high-mass YSO
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 635
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Tidskriftsartikel (refereegranskat)abstract
- Context. The inner regions of the discs of high-mass young stellar objects (HMYSOs) are still poorly known due to the small angular scales and the high visual extinction involved. Aims. We deploy near-infrared spectro-interferometry to probe the inner gaseous disc in HMYSOs and investigate the origin and physical characteristics of the CO bandhead emission (2.3-2.4 m). Methods. We present the first GRAVITY/VLTI observations at high spectral (R = 4000) and spatial (mas) resolution of the CO overtone transitions in NGC2024 IRS 2. Results. The continuum emission is resolved in all baselines and is slightly asymmetric, displaying small closure phases (8). Our best ellipsoid model provides a disc inclination of 34 1, a disc major axis position angle (PA) of 166 1, and a disc diameter of 3:99 0:09 mas (or 1.69 0.04 au, at a distance of 423 pc). The small closure phase signals in the continuum are modelled with a skewed rim, originating from a pure inclination effect. For the first time, our observations spatially and spectrally resolve the first four CO bandheads. Changes in visibility, as well as differential and closure phases across the bandheads are detected. Both the size and geometry of the CO-emitting region are determined by fitting a bidimensional Gaussian to the continuum-compensated CO bandhead visibilities. The CO-emitting region has a diameter of 2.740:08 0:07 mas (1.16 0.03 au), and is located in the inner gaseous disc, well within the dusty rim, with inclination and PA matching the dusty disc geometry, which indicates that both dusty and gaseous discs are coplanar. Physical and dynamical gas conditions are inferred by modelling the CO spectrum. Finally, we derive a direct measurement of the stellar mass of M 14:7 M by combining our interferometric and spectral modelling results.
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| 19. |
- Garcia-Lopez, R., et al.
(författare)
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A measure of the size of the magnetospheric accretion region in TW Hydrae
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 584:7822, s. 547-550
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Tidskriftsartikel (refereegranskat)abstract
- Stars form by accreting material from their surrounding disks. There is a consensus that matter flowing through the disk is channelled onto the stellar surface by the stellar magnetic field. This is thought to be strong enough to truncate the disk close to the corotation radius, at which the disk rotates at the same rate as the star. Spectro-interferometric studies in young stellar objects show that hydrogen emission (a well known tracer of accretion activity) mostly comes from a region a few milliarcseconds across, usually located within the dust sublimation radius1–3. The origin of the hydrogen emission could be the stellar magnetosphere, a rotating wind or a disk. In the case of intermediate-mass Herbig AeBe stars, the fact that Brackett γ (Brγ) emission is spatially resolved rules out the possibility that most of the emission comes from the magnetosphere4–6 because the weak magnetic fields (some tenths of a gauss) detected in these sources7,8 result in very compact magnetospheres. In the case of T Tauri sources, their larger magnetospheres should make them easier to resolve. The small angular size of the magnetosphere (a few tenths of a milliarcsecond), however, along with the presence of winds9,10 make the interpretation of the observations challenging. Here we report optical long-baseline interferometric observations that spatially resolve the inner disk of the T Tauri star TW Hydrae. We find that the near-infrared hydrogen emission comes from a region approximately 3.5 stellar radii across. This region is within the continuum dusty disk emitting region (7 stellar radii across) and also within the corotation radius, which is twice as big. This indicates that the hydrogen emission originates in the accretion columns (funnel flows of matter accreting onto the star), as expected in magnetospheric accretion models, rather than in a wind emitted at much larger distance (more than one astronomical unit).
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| 20. |
- Guergueltcheva, V., et al.
(författare)
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Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations
- 2012
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Ingår i: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 259:5, s. 838-850
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Tidskriftsartikel (refereegranskat)abstract
- Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of inherited disorders of the neuromuscular junction. A difficult to diagnose subgroup of CMS is characterised by proximal muscle weakness and fatigue while ocular and facial involvement is only minimal. DOK7 mutations have been identified as causing the disorder in about half of the cases. More recently, using classical positional cloning, we have identified mutations in a previously unrecognised CMS gene, GFPT1, in a series of DOK7-negative cases. However, detailed description of clinical features of GFPT1 patients has not been reported yet. Here we describe the clinical picture of 24 limb-girdle CMS (LG-CMS) patients and pathological findings of 18 of them, all carrying GFPT1 mutations. Additional patients with CMS, but without tubular aggregates, and patients with non-fatigable weakness with tubular aggregates were also screened. In most patients with GFPT1 mutations, onset of the disease occurs in the first decade of life with characteristic limb-girdle weakness and fatigue. A common feature was beneficial and sustained response to acetylcholinesterase inhibitor treatment. Most of the patients who had a muscle biopsy showed tubular aggregates in myofibers. Analysis of endplate morphology in one of the patients revealed unspecific abnormalities. Our study delineates the phenotype of CMS associated with GFPT1 mutations and expands the understanding of neuromuscular junction disorders. As tubular aggregates in context of a neuromuscular transmission defect appear to be highly indicative, we suggest calling this condition congenital myasthenic syndrome with tubular aggregates (CMS-TA).
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| 21. |
- Koutoulaki, M., et al.
(författare)
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The GRAVITY young stellar object survey: IV. The CO overtone emission in 51 Oph at sub-au scales
- 2021
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 645
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Tidskriftsartikel (refereegranskat)abstract
- Context. 51 Oph is a Herbig Ae/Be star that exhibits strong near-infrared CO ro-vibrational emission at 2.3 μm, most likely originating in the innermost regions of a circumstellar disc. Aims. We aim to obtain the physical and geometrical properties of the system by spatially resolving the circumstellar environment of the inner gaseous disc. Methods. We used the second-generation Very Large Telescope Interferometer instrument GRAVITY to spatially resolve the continuum and the CO overtone emission. We obtained data over 12 baselines with the auxiliary telescopes and derive visibilities, and the differential and closure phases as a function of wavelength. We used a simple local thermal equilibrium ring model of the CO emission to reproduce the spectrum and CO line displacements. Results. Our interferometric data show that the star is marginally resolved at our spatial resolution, with a radius of ∼10.58 ± 2.65R·. The K-band continuum emission from the disc is inclined by 63° ± 1°, with a position angle of 116° ± 1°, and 4 ± 0.8 mas (0.5 ± 0.1 au) across. The visibilities increase within the CO line emission, indicating that the CO is emitted within the dust-sublimation radius. By modelling the CO bandhead spectrum, we derive that the CO is emitted from a hot (T = 1900-2800 K) and dense (NCO = (0.9-9) × 1021 cm-2) gas. The analysis of the CO line displacement with respect to the continuum allows us to infer that the CO is emitted from a region 0.10 ± 0.02 au across, well within the dust-sublimation radius. The inclination and position angle of the CO line emitting region is consistent with that of the dusty disc. Conclusions. Our spatially resolved interferometric observations confirm the CO ro-vibrational emission within the dust-free region of the inner disc. Conventional disc models exclude the presence of CO in the dust-depleted regions of Herbig AeBe stars. Ad hoc models of the innermost disc regions, that can compute the properties of the dust-free inner disc, are therefore required.
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| 23. |
- Senderek, J, et al.
(författare)
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Hexosamine Biosynthetic Pathway Mutations Cause Neuromuscular Transmission Defect
- 2011
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Ingår i: American journal of human genetics. - 0002-9297. ; 88:2, s. 162-172
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Tidskriftsartikel (refereegranskat)abstract
- Neuromuscular junctions (NMJs) are synapses that transmit impulses from motor neurons to skeletal muscle fibers leading to muscle contraction. Study of hereditary disorders of neuromusculartransmission, termed congenital myasthenic syndromes (CMS), has helped elucidate fundamental processes influencing development and function of the nerve-muscle synapse. Using genetic linkage, we find 18 different biallelic mutations in the gene encoding glutamine-fructose-6-phosphate transaminase 1 (GFPT1) in 13 unrelated families with an autosomal recessive CMS. Consistent with these data, downregulation of the GFPT1 ortholog gfpt1 in zebrafish embryos altered muscle fiber morphology and impaired neuromuscular junction development. GFPT1 is the key enzyme of the hexosaminepathway yielding the amino sugar UDP-N-acetylglucosamine, an essential substrate for protein glycosylation. Our findings provide further impetus to study the glycobiology of NMJ and synapses in general.
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| 26. |
- Balaz, M., et al.
(författare)
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Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation
- 2019
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 29:4
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Tidskriftsartikel (refereegranskat)abstract
- Recent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo, whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modulating brown adipocyte functionality and systemic metabolism.
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| 28. |
- Bladen, Catherine L., et al.
(författare)
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The TREAT-NMD Duchenne Muscular Dystrophy Registries : Conception, Design, and Utilization by Industry and Academia
- 2013
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 34:11, s. 1449-1457
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Tidskriftsartikel (refereegranskat)abstract
- Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence<5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardized patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here, we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organizations, and industry.
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| 30. |
- Düzel, E., et al.
(författare)
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European Ultrahigh-Field Imaging Network for Neurodegenerative Diseases (EUFIND)
- 2019
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Ingår i: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - : Wiley. - 2352-8729. ; 11, s. 538-549
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The goal of European Ultrahigh-Field Imaging Network in Neurodegenerative Diseases (EUFIND) is to identify opportunities and challenges of 7 Tesla (7T) MRI for clinical and research applications in neurodegeneration. EUFIND comprises 22 European and one US site, including over 50 MRI and dementia experts as well as neuroscientists. Methods: EUFIND combined consensus workshops and data sharing for multisite analysis, focusing on 7 core topics: clinical applications/clinical research, highest resolution anatomy, functional imaging, vascular systems/vascular pathology, iron mapping and neuropathology detection, spectroscopy, and quality assurance. Across these topics, EUFIND considered standard operating procedures, safety, and multivendor harmonization. Results: The clinical and research opportunities and challenges of 7T MRI in each subtopic are set out as a roadmap. Specific MRI sequences for each subtopic were implemented in a pilot study presented in this report. Results show that a large multisite 7T imaging network with highly advanced and harmonized imaging sequences is feasible and may enable future multicentre ultrahigh-field MRI studies and clinical trials. Discussion: The EUFIND network can be a major driver for advancing clinical neuroimaging research using 7T and for identifying use-cases for clinical applications in neurodegeneration. © 2018 The Authors
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| 32. |
- Hellstrom, S., et al.
(författare)
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Beyond generalists: The Brassicaceae pollen specialist Osmia brevicornis as a prospective model organism when exploring pesticide risk to bees
- 2023
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Ingår i: Environmental and Sustainability Indicators. - : Elsevier BV. - 2665-9727. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Bees are under threat from agricultural intensification, and species which are pollen specialists (oligolectic) are thought to have declined disproportionately compared to pollen generalists (polylectic). When assessing the risks of dietary pesticide (plant protection products) exposure to non-target beneficial insects such as wild bees, effects on pollen specialist species have seldom been considered. Research and risk assessment on pesticide risk to bees mainly use a small selection of model species, only representing pollen generalist species. Moreover, the foraging preferences of the existing model species are not always adequately matched to the crops investigated, which may lead to incorrect conclusions regarding the risks posed by pesticides in pollen and nectar. Here, we propose Osmia brevicornis, an oligolectic European wild bee species specialized on Brassicaceae pollen, as a new model organism suitable for assessment of how pesticides can impact specialist pollinators, especially in oilseed rape, a mass flowering Brassicaceae crop. We demonstrate that O. brevicornis can be successfully reared in the field next to oilseed rape and that its nesting success and offspring numbers can be increased by setting out a starting population. In our field assay, nesting tube diameter affected occupation rate and the sex ratio of O. brevicornis offspring. We describe a method for housing and controlled oral administration of sucrose solution in the lab-oratory, facilitating future studies on pesticide exposure. We conclude that O. brevicornis is a feasible model for assessing the risk of pesticides in the laboratory and in the field, especially for those compounds used in oilseed rape cultivation, as well as for investigating the general ecology of pollen specialists. By suggesting O. brevicornis as a potential model species, we aim to encourage diversification of the species used in agricultural ecology, especially to consider pollen specialists, and encourage attention to the foraging preferences and dietary needs of selected model species when considering pesticide exposure risk and effects.
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| 43. |
- Lewis, Cathryn M, et al.
(författare)
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Genome scan meta-analysis of schizophrenia and bipolar disorder, part II : Schizophrenia
- 2003
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Ingår i: American Journal of Human Genetics. - 0002-9297 .- 1537-6605. ; 73:1, s. 34-48
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
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| 47. |
- Logroscino, G, et al.
(författare)
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Incidence of Syndromes Associated With Frontotemporal Lobar Degeneration in 9 European Countries
- 2023
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 80:3, s. 279-286
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Tidskriftsartikel (refereegranskat)abstract
- Diagnostic incidence data for syndromes associated with frontotemporal lobar degeneration (FTLD) in multinational studies are urgent in light of upcoming therapeutic approaches.ObjectiveTo assess the incidence of FTLD across Europe.Design, Setting, and ParticipantsThe Frontotemporal Dementia Incidence European Research Study (FRONTIERS) was a retrospective cohort study conducted from June 1, 2018, to May 31, 2019, using a population-based registry from 13 tertiary FTLD research clinics from the UK, the Netherlands, Finland, Sweden, Spain, Bulgaria, Serbia, Germany, and Italy and including all new FTLD-associated cases during the study period, with a combined catchment population of 11 023 643 person-years. Included patients fulfilled criteria for the behavioral variant of frontotemporal dementia (BVFTD), the nonfluent variant or semantic variant of primary progressive aphasia (PPA), unspecified PPA, progressive supranuclear palsy, corticobasal syndrome, or frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS). Data were analyzed from July 19 to December 7, 2021.Main Outcomes and MeasuresRandom-intercept Poisson models were used to obtain estimates of the European FTLD incidence rate accounting for geographic heterogeneity.ResultsBased on 267 identified cases (mean [SD] patient age, 66.70 [9.02] years; 156 males [58.43%]), the estimated annual incidence rate for FTLD in Europe was 2.36 cases per 100 000 person-years (95% CI, 1.59-3.51 cases per 100 000 person-years). There was a progressive increase in FTLD incidence across age, reaching its peak at the age of 71 years, with 13.09 cases per 100 000 person-years (95% CI, 8.46-18.93 cases per 100 000 person-years) among men and 7.88 cases per 100 000 person-years (95% CI, 5.39-11.60 cases per 100 000 person-years) among women. Overall, the incidence was higher among men (2.84 cases per 100 000 person-years; 95% CI, 1.88-4.27 cases per 100 000 person-years) than among women (1.91 cases per 100 000 person-years; 95% CI, 1.26-2.91 cases per 100 000 person-years). BVFTD was the most common phenotype (107 cases [40.07%]), followed by PPA (76 [28.46%]) and extrapyramidal phenotypes (69 [25.84%]). FTD-ALS was the rarest phenotype (15 cases [5.62%]). A total of 95 patients with FTLD (35.58%) had a family history of dementia. The estimated number of new FTLD cases per year in Europe was 12 057.Conclusions and RelevanceThe findings suggest that FTLD-associated syndromes are more common than previously recognized, and diagnosis should be considered at any age. Improved knowledge of FTLD incidence may contribute to appropriate health and social care planning and in the design of future clinical trials.
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| 50. |
- Oldfors Hedberg, Carola, 1969, et al.
(författare)
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Functional characterization of GYG1 variants in two patients with myopathy and glycogenin-1 deficiency
- 2019
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 29:12, s. 951-960
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Tidskriftsartikel (refereegranskat)abstract
- Glycogen storage disease XV is caused by variants in the glycogenin-1 gene, GYG1, and presents as a predominant skeletal myopathy or cardiomyopathy. We describe two patients with late-onset myopathy anti biallelic GYG1 variants. In patient 1, the novel c.144-2A>G splice acceptor variant and the novel frameshift variant c.631delG (p.Va1211Cysfs(star)30) were identified, and in patient 2, the previously described c.304G>C (p.Asp102His) and c.487deLG (p.Asp163Thrfs(star)5) variants were found. Protein analysis showed total absence of glycogenin-1 expression in patient 1, whereas in patient 2 there was reduced expression of glycogenin-1, with the residual protein being non-functional. Both patients showed glycogen and polyglucosan storage in their muscle fibers, as revealed by PAS staining and electron microscopy. Age at onset of the myopathy phenotype was 53 years and 70 years respectively, with the selective pattern of muscle involvement on MRI corroborating the pattern of weakness. Cardiac evaluation of patient 1 and 2 did not show any specific abnormalities linked to the glycogenin-1 deficiency. In patient 2, who was shown to express the p.Asp102His mutated glycogenin-1, cardiac evaluation was still normal at age 77 years. This contrasts with the association of the p.Asp102His variant in homozygosity with a severe cardiomyopathy in several cases with an onset age between 30 and 50 years. This finding might indicate that the level of p.Asp102His mutated glycogenin-1 determines if a patient will develop a cardiomyopathy. (C) 2019 Elsevier B.V. All rights reserved.
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