| 1. |
- Walters, G. B., et al.
(författare)
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MAP1B mutations cause intellectual disability and extensive white matter deficit
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Discovery of coding variants in genes that confer risk of neurodevelopmental disorders is an important step towards understanding the pathophysiology of these disorders. Wholegenome sequencing of 31,463 Icelanders uncovers a frameshift variant (E712KfsTer10) in microtubule-associated protein 1B (MAP1B) that associates with ID/low IQ in a large pedigree (genome-wide corrected P = 0.022). Additional stop-gain variants in MAP1B (E1032Ter and R1664Ter) validate the association with ID and IQ. Carriers have 24% less white matter (WM) volume (beta = -2.1SD, P = 5.1 x 10(-8)), 47% less corpus callosum (CC) volume (beta = -2.4SD, P = 5.5 x 10(-10)) and lower brain-wide fractional anisotropy (P = 6.7 x 10(-4)). In summary, we show that loss of MAP1B function affects general cognitive ability through a profound, brain-wide WM deficit with likely disordered or compromised axons.
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| 2. |
- Gretarsdottir, Solveig, et al.
(författare)
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Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:8, s. 71-692
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Tidskriftsartikel (refereegranskat)abstract
- We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 x 10(-10). In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 x 10(-5)), peripheral arterial disease (OR = 1.14, P = 3.9 x 10(-5)) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases-that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.
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| 3. |
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| 4. |
- Gislason, S.R., et al.
(författare)
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Environmental pressure from the 2014–15 eruption of Bárðarbunga volcano, Iceland
- 2015
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Ingår i: Geochemical Perspectives Letters. - : European Association of Geochemistry. - 2410-3403 .- 2410-339X. ; 1:2015, s. 84 - 93
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Tidskriftsartikel (refereegranskat)abstract
- The effusive six months long 2014-2015 Bárðarbunga eruption (31 August-27 February) was the largest in Iceland for more than 200 years, producing 1.6 ± 0.3 km3 of lava. The total SO2 emission was 11 ± 5 Mt, more than the amount emitted from Europe in 2011. The ground level concentration of SO2 exceeded the 350 μg m−3 hourly average health limit over much of Iceland for days to weeks. Anomalously high SO2 concentrations were also measured at several locations in Europe in September. The lowest pH of fresh snowmelt at the eruption site was 3.3, and 3.2 in precipitation 105 km away from the source. Elevated dissolved H2SO4, HCl, HF, and metal concentrations were measured in snow and precipitation. Environmental pressures from the eruption and impacts on populated areas were reduced by its remoteness, timing, and the weather. The anticipated primary environmental pressure is on the surfacewaters, soils, and vegetation of Iceland.
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| 5. |
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| 6. |
- Stacey, Simon N, et al.
(författare)
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A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:11, s. 1098-103
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Tidskriftsartikel (refereegranskat)abstract
- To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).
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| 7. |
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| 8. |
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| 9. |
- Manojlovic, M., et al.
(författare)
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Microparticles expressing myeloperoxidase as potential biomarkers in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV)
- 2020
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Ingår i: Journal of Molecular Medicine. - : SPRINGER HEIDELBERG. - 0946-2716 .- 1432-1440. ; 98:9, s. 1279-1286
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Tidskriftsartikel (refereegranskat)abstract
- To investigate presence of circulating myeloperoxidase-positive microparticles (MPO(+)MPs) in relation to disease activity in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Forty-six patients with AAV and 23 age- and sex-matched healthy controls were included. Vasculitis disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). MPs were analyzed in citrate plasma by flow cytometry and phenotyped based on MPO expression and co-expression of pentraxin-3 (PTX3), high mobility group box 1 protein (HMGB1), and tumor necrosis factor-like weak inducer of apoptosis (TWEAK). Serum levels of PTX3, sTWEAK, and HMGB1 were also determined. Twenty-three patients had active vasculitis (BVAS >= 1). Concentrations of MPO(+)MPs expressing PTX3, HMGB1, and TWEAK were significantly higher in patients compared to healthy controls (p< 0.001,p< 0.01,p< 0.001, respectively), while concentrations of PTX3(+)and HMGB1(+)MPO(+)MPs were significantly higher in active AAV compared to patients in remission. MPO(+)MPs expressing either PTX3 or HMGB1 were associated with BVAS (r= 0.5,p< 0.001;r= 0.3,p= 0.04, respectively). Significantly higher serum PTX3 levels were found in active- than in inactive AAV (p< 0.001), correlating strongly with BVAS (r= 0.7,p< 0.001). Serum levels of sTWEAK and HMGB1 did not differ between patients and controls. Concentration of MPO(+)MPs is increased in plasma from AAV patients compared to healthy individuals. PTX3 in serum as well as PTX3 and HMGB1 expressed on MPO(+)MPs were associated with disease activity in the investigated patients. Key messages Myeloperoxidase-positive microparticles (MPO+MPs) are increased in plasma from patients with ANCA-associated vasculitis. Concentrations of MPO+MPs expressing PTX3, HMGB1, and TWEAK were significantly higher in patients compared to healthy controls. MPO+MPs expressing PTX3 and HMGB1 are associated with disease activity in ANCA-associated vasculitis.
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| 10. |
- Jonasdottir, A. D., et al.
(författare)
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Pentraxin-3-a potential biomarker in ANCA-associated vasculitis
- 2023
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Ingår i: Scandinavian Journal of Rheumatology. - : Taylor & Francis Ltd. - 0300-9742 .- 1502-7732. ; 52:3, s. 293-301
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Tidskriftsartikel (refereegranskat)abstract
- Objective The aim of this study was to investigate pentraxin-3 (PTX3) as a potential biomarker of inflammatory activity in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) at baseline and 6 month follow-up in a longitudinal cohort. Method Plasma PTX3 levels were measured in 79 newly diagnosed or relapsing AAV patients at baseline and 6 month follow-up, and in 23 healthy controls. Urinary PTX3 levels were measured in 34 of the patients. C-reactive protein (CRP), creatinine, and albuminuria were measured and the cumulative glucocorticoid dose at inclusion was calculated. The Birmingham Vasculitis Activity Score (BVAS) was assessed at baseline and follow-up. Results Plasma PTX3 levels were significantly higher at baseline than at 6 months (2.85 vs 1.23 ng/mL, p < 0.001). Plasma and urinary PTX3 levels correlated with BVAS at baseline (rho = 0.45, p < 0.001, and rho = 0.49, p = 0.008, respectively). A significant correlation between both plasma and urinary PTX3 levels and estimated glomerular filtration rate and albuminuria was found. However, there was no correlation between plasma and urinary PTX3 levels. At baseline, plasma and urinary PTX3 levels were significantly higher in patients with kidney involvement. PTX3 levels did not correlate with CRP, nor was there a correlation between CRP levels and BVAS at baseline. Conclusion Plasma and urinary PTX3 seem to reflect disease activity in AAV better than the commonly used CRP. PTX3 may have a potential role as a biomarker in monitoring disease activity in AAV patients, particularly in patients with kidney involvement.
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| 11. |
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| 12. |
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| 13. |
- Kumar, R, et al.
(författare)
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AUTOREACTIVE CD4+T CELLS AND THEIR TCR REPERTOIRE IN PR3-ANCA ASSOCIATED VASCULITIS
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 1-1
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- ANCA-associated vasculitis (AAV) with proteinase 3 (PR3) ANCA is genetically associated with HLA-DP [1], is often relapsing in nature, and has a predisposition for kidneys, lungs and ear-nose-throat involvement [2]. Despite the presence of PR3+ANCA, indicating CD4+T-cell help in the disease, the knowledge about autoreactive CD4+T cells is scarce. Activated T cells have been shown at site of inflammation [3] and involvement of proinflammatory cytokines in circulation is also reported [4, 5].Objectives:Identification of autoreactive T cells may help to identify the drivers of the immune responses and chronicity. We therefore aimed to investigate PR3-specific CD4+T-cell responses in peripheral blood of AAV patients with a focus on both phenotype and T-cell receptor (TCR) repertoires.Methods:The study included sixty-six patients: 26 with active PR3 autoantibody+ AAV, 21 with inactive but PR3+ AAV and 19 with inactive PR3- AAV. In-vitro cultures with PR3 protein were established to assess antigen-specific cytokine responses in a 3-color fluorospot assay. Deep immunophenotyping was performed by flow cytometry. Antigen-responsive CD4+ T cells were isolated and single cell TCRαβ sequences were generated and analyzed from PR3+ AAV patients (n=5) using a previously published protocol [6].Results:PBMCs from AAV patients demonstrated an HLA-DP associated cytokine responses to PR3 stimulation including IFN-γ and IL-10, but not IL-17A. This T-cell autoreactivity was found to be confined to a highly differentiated CD4+ T cell population characterized by perforin and GPR56 expression, implicating a cytotoxic feature of the response. Active disease involved a reduction in expression of several markers associated with cytotoxicity amongst the CD4+GPR56+ T cells. Their frequency was also negatively associated with the doses of prednisolone. A similar phenotype was shared with T cells activated by human cytomegalovirus (HCMV) peptides in the same patient cohort. Single cell sequencing of paired alpha beta T-cell receptors (TCRs) revealed different patterns of gene usage between PR3 and HCMV reactive T cells. Moreover, we could identify shared (public) PR3-reactive T-cell clones between different HLA-DPB1*04:01+ patients.Conclusion:PR3 is an autoantigen which provokes ANCA responses in AAV patients. Our study identified PR3-reactive CD4+ T cells at the level of their phenotype and TCR repertoire. The autoreactive CD4+ T cells, present in both active and inactive disease, implicate chronic antigen exposure and the persistence of long-lived T-cell clones. The presence of public autoreactive clones between HLA-DPB1*04:01+ patients suggests an active role for these cells in pathogenesis of AAV and validates the link with predisposed genotype.References:[1]Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DR, et al. Genetically distinct subsets within ANCA-associated vasculitis. New England Journal of Medicine. 2012; 367(3):214-223.[2]Kumar Sharma R, Lövström B, Gunnarsson I, Malmström V. Proteinase 3 autoreactivity in Anti-Neutrophil Cytoplasmic Antibody-associated vasculitis–immunological versus clinical features. Scandinavian Journal of Immunology. 2020:e12958.[3]Wilde B, Thewissen M, Damoiseaux J, van Paassen P, Witzke O, Tervaert JWCJAr, et al. T cells in ANCA-associated vasculitis: what can we learn from lesional versus circulating T cells? 2010; 12(1):204.[4]Hoffmann JC, Patschan D, Dihazi H, Müller C, Schwarze K, Henze E, et al. Cytokine profiling in anti neutrophil cytoplasmic antibody-associated vasculitis: a cross-sectional cohort study. Rheumatology international. 2019; 39(11):1907-1917.[5]Berti A, Warner R, Johnson K, Cornec D, Schroeder D, Kabat B, et al. Circulating Cytokine Profiles and ANCA Specificity in Patients with ANCA-Associated Vasculitis. Arthritis & rheumatology (Hoboken, NJ). 2018; 70(7):1114.[6]Han A, Glanville J, Hansmann L, Davis MM. Linking T-cell receptor sequence to functional phenotype at the single-cell level. Nature biotechnology. 2014; 32(7):684-692.Disclosure of Interests:None declared
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| 14. |
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| 15. |
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| 16. |
- Thorleifsson, Gudmar, et al.
(författare)
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Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:10, s. 906-909
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a genome-wide association study for primary open-angle glaucoma (POAG) in 1,263 affected individuals (cases) and 34,877 controls from Iceland. We identified a common sequence variant at 7q31 (rs4236601[ A], odds ratio (OR) = 1.36, P = 5.0 x 10(-10)). We then replicated the association in sample sets of 2,175 POAG cases and 2,064 controls from Sweden, the UK and Australia (combined OR = 1.18, P = 0.0015) and in 299 POAG cases and 580 unaffected controls from Hong Kong and Shantou, China (combined OR = 5.42, P = 0.0021). The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG.
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| 17. |
- Arnardottir, E. S., et al.
(författare)
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The Sleep Revolution project: the concept and objectives
- 2022
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Ingår i: Journal of Sleep Research. - : Wiley. - 0962-1105 .- 1365-2869. ; 31:4
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Tidskriftsartikel (refereegranskat)abstract
- Obstructive sleep apnea is linked to severe health consequences such as hypertension, daytime sleepiness, and cardiovascular disease. Nearly a billion people are estimated to have obstructive sleep apnea with a substantial economic burden. However, the current diagnostic parameter of obstructive sleep apnea, the apnea-hypopnea index, correlates poorly with related comorbidities and symptoms. Obstructive sleep apnea severity is measured by counting respiratory events, while other physiologically relevant consequences are ignored. Furthermore, as the clinical methods for analysing polysomnographic signals are outdated, laborious, and expensive, most patients with obstructive sleep apnea remain undiagnosed. Therefore, more personalised diagnostic approaches are urgently needed. The Sleep Revolution, funded by the European Union's Horizon 2020 Research and Innovation Programme, aims to tackle these shortcomings by developing machine learning tools to better estimate obstructive sleep apnea severity and phenotypes. This allows for improved personalised treatment options, including increased patient participation. Also, implementing these tools will alleviate the costs and increase the availability of sleep studies by decreasing manual scoring labour. Finally, the project aims to design a digital platform that functions as a bridge between researchers, patients, and clinicians, with an electronic sleep diary, objective cognitive tests, and questionnaires in a mobile application. These ambitious goals will be achieved through extensive collaboration between 39 centres, including expertise from sleep medicine, computer science, and industry and by utilising tens of thousands of retrospectively and prospectively collected sleep recordings. With the commitment of the European Sleep Research Society and Assembly of National Sleep Societies, the Sleep Revolution has the unique possibility to create new standardised guidelines for sleep medicine.
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| 18. |
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| 19. |
- Pfeffer, M. A., et al.
(författare)
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Ground-Based measurements of the 2014-2015 holuhraun volcanic cloud (Iceland)
- 2018
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Ingår i: Geosciences (Switzerland). - : MDPI AG. - 2076-3263. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- The 2014-2015 Bárðarbunga fissure eruption at Holuhraun in central Iceland was distinguished by the high emission of gases, in total 9.6 Mt SO 2 , with almost no tephra. This work collates all ground-based measurements of this extraordinary eruption cloud made under particularly challenging conditions: remote location, optically dense cloud with high SO 2 column amounts, low UV intensity, frequent clouds and precipitation, an extensive and hot lava field, developing ramparts, and high-latitude winter conditions. Semi-continuous measurements of SO 2 flux with three scanning DOAS instruments were augmented by car traverses along the ring-road and along the lava. The ratios of other gases/SO 2 were measured by OP-FTIR, MultiGAS, and filter packs. Ratios of SO 2 /HCl = 30-110 and SO 2 /HF = 30-130 show a halogen-poor eruption cloud. Scientists on-site reported extremely minor tephra production during the eruption. OPC and filter packs showed low particle concentrations similar to non-eruption cloud conditions. Three weather radars detected a droplet-rich eruption cloud. Top of eruption cloud heights of 0.3-5.5 km agl were measured with ground-and aircraft-based visual observations, web camera and NicAIR II infrared images, triangulation of scanning DOAS instruments, and the location of SO 2 peaks measured by DOAS traverses. Cloud height and emission rate measurements were critical for initializing gas dispersal simulations for hazard forecasting.
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| 20. |
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| 21. |
- Stacey, Simon N, et al.
(författare)
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Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.
- 2010
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Ingår i: PLoS genetics. - : Public Library of Science. - 1553-7404. ; 6:7, s. e1001029-
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Tidskriftsartikel (refereegranskat)abstract
- We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor alpha (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case:control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2 x 10(-3)), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9 x 10(-4)) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9 x 10(-7)), was without significant heterogeneity between ancestries (P(het) = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.
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| 22. |
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| 23. |
- Styrkarsdottir, Unnur, et al.
(författare)
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Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:5, s. 801-805
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Tidskriftsartikel (refereegranskat)abstract
- We performed a genome-wide association study of total hip replacements, based on variants identified through whole-genome sequencing, which included 4,657 Icelandic patients and 207,514 population controls. We discovered two rare signals that strongly associate with osteoarthritis total hip replacement: a missense variant, c.1141G>C (p.Asp369His), in the COMP gene (allelic frequency = 0.026%, P = 4.0 × 10-12, odds ratio (OR) = 16.7) and a frameshift mutation, rs532464664 (p.Val330Glyfs∗106), in the CHADL gene that associates through a recessive mode of inheritance (homozygote frequency = 0.15%, P = 4.5 × 10-18, OR = 7.71). On average, c.1141G>C heterozygotes and individuals homozygous for rs532464664 had their hip replacement operation 13.5 years and 4.9 years earlier than others (P = 0.0020 and P = 0.0026), respectively. We show that the full-length CHADL transcript is expressed in cartilage. Furthermore, the premature stop codon introduced by the CHADL frameshift mutation results in nonsense-mediated decay of the mutant transcripts.
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| 24. |
- Thorleifsson, Gudmar, et al.
(författare)
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Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma
- 2007
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 317:5843, s. 1397-1400
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Tidskriftsartikel (refereegranskat)abstract
- Glaucoma is a leading cause of irreversible blindness. A genome-wide search yielded multiple single-nucleotide polymorphisms (SNPs) in the 15q24.1 region associated with glaucoma. Further investigation revealed that the association is confined to exfoliation glaucoma (XFG). Two nonsynonymous SNPs in exon 1 of the gene LOXL1 explain the association, and the data suggest that they confer risk of XFG mainly through exfoliation syndrome (XFS). About 25% of the general population is homozygous for the highest-risk haplotype, and their risk of suffering from XFG is more than 100 times that of individuals carrying only low-risk haplotypes. The population-attributable risk is more than 99%. The product of LOXL1 catalyzes the formation of elastin fibers found to be a major component of the lesions in XFG.
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| 25. |
- Jonsson, Stefan, et al.
(författare)
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Identification of sequence variants influencing immunoglobulin levels
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 49:8, s. 1182-1191
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Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10(-55), β = -0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10(-8), β = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity.
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