| 1. |
- Saevarsdottir, S., et al.
(författare)
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Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
- 2022
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:8
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
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| 2. |
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| 3. |
- Maes, S.L., et al.
(författare)
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Environmental drivers of increased ecosystem respiration in a warming tundra
- 2024
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 629:8010, s. 105-113
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Tidskriftsartikel (refereegranskat)abstract
- Arctic and alpine tundra ecosystems are large reservoirs of organic carbon. Climate warming may stimulate ecosystem respiration and release carbon into the atmosphere. The magnitude and persistency of this stimulation and the environmental mechanisms that drive its variation remain uncertain. This hampers the accuracy of global land carbon–climate feedback projections. Here we synthesize 136 datasets from 56 open-top chamber in situ warming experiments located at 28 arctic and alpine tundra sites which have been running for less than 1 year up to 25 years. We show that a mean rise of 1.4 °C [confidence interval (CI) 0.9–2.0 °C] in air and 0.4 °C [CI 0.2–0.7 °C] in soil temperature results in an increase in growing season ecosystem respiration by 30% [CI 22–38%] (n = 136). Our findings indicate that the stimulation of ecosystem respiration was due to increases in both plant-related and microbial respiration (n = 9) and continued for at least 25 years (n = 136). The magnitude of the warming effects on respiration was driven by variation in warming-induced changes in local soil conditions, that is, changes in total nitrogen concentration and pH and by context-dependent spatial variation in these conditions, in particular total nitrogen concentration and the carbon:nitrogen ratio. Tundra sites with stronger nitrogen limitations and sites in which warming had stimulated plant and microbial nutrient turnover seemed particularly sensitive in their respiration response to warming. The results highlight the importance of local soil conditions and warming-induced changes therein for future climatic impacts on respiration.
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| 4. |
- Rixen, C., et al.
(författare)
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Winters are changing: snow effects on Arctic and alpine tundra ecosystems
- 2022
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Ingår i: Arctic Science. - : Canadian Science Publishing. - 2368-7460. ; 8:3, s. 572-608
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Tidskriftsartikel (refereegranskat)abstract
- Snow is an important driver of ecosystem processes in cold biomes. Snow accumulation determines ground temperature, light conditions, and moisture availability during winter. It also affects the growing season's start and end, and plant access to moisture and nutrients. Here, we review the current knowledge of the snow cover's role for vegetation, plant-animal interactions, permafrost conditions, microbial processes, and biogeochemical cycling. We also compare studies of natural snow gradients with snow experimental manipulation studies to assess time scale difference of these approaches. The number of tundra snow studies has increased considerably in recent years, yet we still lack a comprehensive overview of how altered snow conditions will affect these ecosystems. Specifically, we found a mismatch in the timing of snowmelt when comparing studies of natural snow gradients with snow manipulations. We found that snowmelt timing achieved by snow addition and snow removal manipulations (average 7.9 days advance and 5.5 days delay, respectively) were substantially lower than the temporal variation over natural spatial gradients within a given year (mean range 56 days) or among years (mean range 32 days). Differences between snow study approaches need to be accounted for when projecting snow dynamics and their impact on ecosystems in future climates.
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| 5. |
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| 6. |
- Steinthorsdottir, V, et al.
(författare)
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Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 5976-
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Tidskriftsartikel (refereegranskat)abstract
- Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.
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| 7. |
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| 8. |
- Collins, C. G., et al.
(författare)
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Experimental warming differentially affects vegetative and reproductive phenology of tundra plants
- 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
- Rapid climate warming is altering Arctic and alpine tundra ecosystem structure and function, including shifts in plant phenology. While the advancement of green up and flowering are well-documented, it remains unclear whether all phenophases, particularly those later in the season, will shift in unison or respond divergently to warming. Here, we present the largest synthesis to our knowledge of experimental warming effects on tundra plant phenology from the International Tundra Experiment. We examine the effect of warming on a suite of season-wide plant phenophases. Results challenge the expectation that all phenophases will advance in unison to warming. Instead, we find that experimental warming caused: (1) larger phenological shifts in reproductive versus vegetative phenophases and (2) advanced reproductive phenophases and green up but delayed leaf senescence which translated to a lengthening of the growing season by approximately 3%. Patterns were consistent across sites, plant species and over time. The advancement of reproductive seasons and lengthening of growing seasons may have significant consequences for trophic interactions and ecosystem function across the tundra. It is unclear whether climate driven phenological shifts of tundra plants are consistent across the plant growing season. Here the authors analyse data from a network of field warming experiments in Arctic and alpine tundra, finding that warming differentially affects the timing and duration of reproductive and vegetative phenology.
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| 9. |
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| 10. |
- Sarneel, Judith M., et al.
(författare)
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Reading tea leaves worldwide : decoupled drivers of initial litter decomposition mass-loss rate and stabilization
- 2024
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Ingår i: Ecology Letters. - : John Wiley & Sons. - 1461-023X .- 1461-0248. ; 27:5
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Tidskriftsartikel (refereegranskat)abstract
- The breakdown of plant material fuels soil functioning and biodiversity. Currently, process understanding of global decomposition patterns and the drivers of such patterns are hampered by the lack of coherent large-scale datasets. We buried 36,000 individual litterbags (tea bags) worldwide and found an overall negative correlation between initial mass-loss rates and stabilization factors of plant-derived carbon, using the Tea Bag Index (TBI). The stabilization factor quantifies the degree to which easy-to-degrade components accumulate during early-stage decomposition (e.g. by environmental limitations). However, agriculture and an interaction between moisture and temperature led to a decoupling between initial mass-loss rates and stabilization, notably in colder locations. Using TBI improved mass-loss estimates of natural litter compared to models that ignored stabilization. Ignoring the transformation of dead plant material to more recalcitrant substances during early-stage decomposition, and the environmental control of this transformation, could overestimate carbon losses during early decomposition in carbon cycle models.
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| 11. |
- Hollister, R. D., et al.
(författare)
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A review of open top chamber (OTC) performance across the ITEX Network
- 2023
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Ingår i: Arctic Science. - : Canadian Science Publishing. - 2368-7460. ; 9:2, s. 331-344
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Tidskriftsartikel (refereegranskat)abstract
- Open top chambers (OTCs) were adopted as the recommended warming mechanism by the International Tundra Experiment network in the early 1990s. Since then, OTCs have been deployed across the globe. Hundreds of papers have reported the im-pacts of OTCs on the abiotic environment and the biota. Here, we review the impacts of the OTC on the physical environment, with comments on the appropriateness of using OTCs to characterize the response of biota to warming. The purpose of this review is to guide readers to previously published work and to provide recommendations for continued use of OTCs to under -stand the implications of warming on low stature ecosystems. In short, the OTC is a useful tool to experimentally manipulate temperature; however, the characteristics and magnitude of warming varies greatly in different environments; therefore, it is important to document chamber performance to maximize the interpretation of biotic response. When coupled with long-term monitoring, warming experiments are a valuable means to understand the impacts of climate change on natural ecosystems.
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| 12. |
- Jónsdóttir, I. S., et al.
(författare)
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Intraspecific trait variability is a key feature underlying high Arctic plant community resistance to climate warming
- 2022
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Ingår i: Ecological Monographs. - : Wiley. - 0012-9615 .- 1557-7015.
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Tidskriftsartikel (refereegranskat)abstract
- In the high Arctic, plant community species composition generally responds slowly to climate warming, whereas less is known about the community functional trait responses and consequences for ecosystem functioning. Slow species turnover and large distribution ranges of many Arctic plant species suggest a significant role of intraspecific trait variability in functional responses to climate change. Here, we compare taxonomic and functional community compositional responses to a long-term (17years) warming experiment in Svalbard, replicated across three major high Arctic habitats shaped by topography and contrasting snow regimes. We observed taxonomic compositional changes in all plant communities over time. Still, responses to experimental warming were minor and most pronounced in the drier habitats with relatively early snowmelt timing and long growing seasons (Cassiope and Dryas heaths). The habitats were clearly separated in functional trait space, defined by twelve size- and leaf economics-related traits, primarily due to interspecific trait variation. Functional traits also responded to experimental warming, most prominently in the Dryas heath and mostly due to intraspecific trait variation. Leaf area and leaf mass increased, and leaf δ15N decreased in response to the warming treatment. Intraspecific trait variability ranged between 30% and 71% of the total trait variation, reflecting functional resilience of those communities, dominated by long-lived plants, due to either phenotypic plasticity or genotypic variation that most likely underlies the observed resistance of high Arctic vegetation to climate warming. We further explored the consequences of trait variability for ecosystem functioning by measuring peak season CO2 fluxes. Together, environmental, taxonomic, and functional trait variables explained a large proportion of the variation in net ecosystem exchange (NEE), which increased when intraspecific trait variation was accounted for. In contrast, even though ecosystem respiration and gross ecosystem production both increased in response to warming across habitats, they were mainly driven by the direct kinetic impacts of temperature on plant physiology and biochemical processes. Our study shows that long-term experimental warming has a modest but significant effect on plant community functional trait composition and suggests that intraspecific trait variability is a key feature underlying high Arctic ecosystem resistance to climate warming.
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| 13. |
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| 14. |
- Mikaelsdottir, E, et al.
(författare)
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Genetic variants associated with platelet count are predictive of human disease and physiological markers
- 2021
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 4:1, s. 1132-
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Tidskriftsartikel (refereegranskat)abstract
- Platelets play an important role in hemostasis and other aspects of vascular biology. We conducted a meta-analysis of platelet count GWAS using data on 536,974 Europeans and identified 577 independent associations. To search for mechanisms through which these variants affect platelets, we applied cis-expression quantitative trait locus, DEPICT and IPA analyses and assessed genetic sharing between platelet count and various traits using polygenic risk scoring. We found genetic sharing between platelet count and counts of other blood cells (except red blood cells), in addition to several other quantitative traits, including markers of cardiovascular, liver and kidney functions, height, and weight. Platelet count polygenic risk score was predictive of myeloproliferative neoplasms, rheumatoid arthritis, ankylosing spondylitis, hypertension, and benign prostate hyperplasia. Taken together, these results advance understanding of diverse aspects of platelet biology and how they affect biological processes in health and disease.
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| 15. |
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| 16. |
- Sonderby, Ida E., et al.
(författare)
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Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia
- 2020
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:3, s. 584-602
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Tidskriftsartikel (refereegranskat)abstract
- Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
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| 17. |
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| 18. |
- Barrio, I. C., et al.
(författare)
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Developing common protocols to measure tundra herbivory across spatial scales
- 2022
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Ingår i: Arctic Science. - : Canadian Science Publishing. - 2368-7460. ; 8:3, s. 638-679
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Tidskriftsartikel (refereegranskat)abstract
- Understanding and predicting large-scale ecological responses to global environmental change requires comparative studies across geographic scales with coordinated efforts and standardized methodologies. We designed, applied, and assessed standardized protocols to measure tundra herbivory at three spatial scales: plot, site (habitat), and study area (landscape). The plot-and site-level protocols were tested in the field during summers 2014–2015 at 11 sites, nine of them consisting of warming experimental plots included in the International Tundra Experiment (ITEX). The study area protocols were assessed during 2014–2018 at 24 study areas across the Arctic. Our protocols provide comparable and easy to implement methods for assessing the intensity of invertebrate herbivory within ITEX plots and for characterizing vertebrate herbivore communities at larger spatial scales. We discuss methodological constraints and make recommendations for how these protocols can be used and how sampling effort can be optimized to obtain comparable estimates of herbivory, both at ITEX sites and at large landscape scales. The application of these protocols across the tundra biome will allow characterizing and comparing herbivore communities across tundra sites and at ecologically relevant spatial scales, providing an important step towards a better understanding of tundra ecosystem responses to large-scale environmental change.
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| 19. |
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| 20. |
- Saevarsdottir, KS, et al.
(författare)
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Illness severity and risk of mental morbidities among patients recovering from COVID-19: a cross-sectional study in the Icelandic population
- 2021
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 11:7, s. e049967-
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Tidskriftsartikel (refereegranskat)abstract
- To test if patients recovering from COVID-19 are at increased risk of mental morbidities and to what extent such risk is exacerbated by illness severity.DesignPopulation-based cross-sectional study.SettingIceland.ParticipantsA total of 22 861 individuals were recruited through invitations to existing nationwide cohorts and a social media campaign from 24 April to 22 July 2020, of which 373 were patients recovering from COVID-19.Main outcome measuresSymptoms of depression (Patient Health Questionnaire), anxiety (General Anxiety Disorder Scale) and posttraumatic stress disorder (PTSD; modified Primary Care PTSD Screen for DSM-5) above screening thresholds. Adjusting for multiple covariates and comorbidities, multivariable Poisson regression was used to assess the association between COVID-19 severity and mental morbidities.ResultsCompared with individuals without a diagnosis of COVID-19, patients recovering from COVID-19 had increased risk of depression (22.1% vs 16.2%; adjusted relative risk (aRR) 1.48, 95% CI 1.20 to 1.82) and PTSD (19.5% vs 15.6%; aRR 1.38, 95% CI 1.09 to 1.75) but not anxiety (13.1% vs 11.3%; aRR 1.24, 95% CI 0.93 to 1.64). Elevated relative risks were limited to patients recovering from COVID-19 that were 40 years or older and were particularly high among individuals with university education. Among patients recovering from COVID-19, symptoms of depression were particularly common among those in the highest, compared with the lowest tertile of influenza-like symptom burden (47.1% vs 5.8%; aRR 6.42, 95% CI 2.77 to 14.87), among patients confined to bed for 7 days or longer compared with those never confined to bed (33.3% vs 10.9%; aRR 3.67, 95% CI 1.97 to 6.86) and among patients hospitalised for COVID-19 compared with those never admitted to hospital (48.1% vs 19.9%; aRR 2.72, 95% CI 1.67 to 4.44).ConclusionsSevere disease course is associated with increased risk of depression and PTSD among patients recovering from COVID-19.
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| 21. |
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| 22. |
- Skuladottir, AT, et al.
(författare)
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A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 1598-
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Tidskriftsartikel (refereegranskat)abstract
- Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (48,843 cases and 1,190,837 controls), we found 53 sequence variants at 50 loci associated with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 × 10−24, OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate CTS risk and highlight the role of 19 CTS variants in the biology of the extracellular matrix. We show that the genetic component to the risk is higher in bilateral/recurrent/persistent cases than nonrecurrent/nonpersistent cases. Anthropometric traits including height and BMI are genetically correlated with CTS, in addition to early hormonal-replacement therapy, osteoarthritis, and restlessness. Our findings suggest that the components of the extracellular matrix play a key role in the pathogenesis of CTS.
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| 23. |
- Skuladottir, AT, et al.
(författare)
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A genome-wide meta-analysis uncovers six sequence variants conferring risk of vertigo
- 2021
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 4:1, s. 1148-
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Tidskriftsartikel (refereegranskat)abstract
- Vertigo is the leading symptom of vestibular disorders and a major risk factor for falls. In a genome-wide association study of vertigo (Ncases = 48,072, Ncontrols = 894,541), we uncovered an association with six common sequence variants in individuals of European ancestry, including missense variants in ZNF91, OTOG, OTOGL, and TECTA, and a cis-eQTL for ARMC9. The association of variants in ZNF91, OTOGL, and OTOP1 was driven by an association with benign paroxysmal positional vertigo. Using previous reports of sequence variants associating with age-related hearing impairment and motion sickness, we found eight additional variants that associate with vertigo. Although disorders of the auditory and the vestibular system may co-occur, none of the six genome-wide significant vertigo variants were associated with hearing loss and only one was associated with age-related hearing impairment. Our results uncovered sequence variants associating with vertigo in a genome-wide association study and implicated genes with known roles in inner ear development, maintenance, and disease.
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| 24. |
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| 25. |
- Dans, Madeline G., et al.
(författare)
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Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite’s lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action.
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