| 1. |
- Eijsbouts, C., et al.
(författare)
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Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders
- 2021
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53:11, s. 1543-1552
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Tidskriftsartikel (refereegranskat)abstract
- Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS. © 2021, The Author(s).
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| 2. |
- Fritz, N., et al.
(författare)
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The serotonin receptor 3E variant is a risk factor for female IBS-D
- 2022
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Ingår i: Journal of Molecular Medicine-Jmm. - : Springer Science and Business Media LLC. - 0946-2716 .- 1432-1440. ; 100:11, s. 1617-1627
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Tidskriftsartikel (refereegranskat)abstract
- Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT3 receptor family. 5-HT(3)Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT3R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D.
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| 3. |
- Mohr, S., et al.
(författare)
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The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome
- 2021
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Ingår i: Journal of Cellular and Molecular Medicine. - : Wiley. - 1582-1838 .- 1582-4934. ; 25:16, s. 8047-8061
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Tidskriftsartikel (refereegranskat)abstract
- Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.
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| 4. |
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| 5. |
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| 6. |
- Colette, A., et al.
(författare)
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Future air quality in Europe: a multi-model assessment of projected exposure to ozone
- 2012
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Ingår i: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 12:21, s. 10613-10630
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Tidskriftsartikel (refereegranskat)abstract
- In order to explore future air quality in Europe at the 2030 horizon, two emission scenarios developed in the framework of the Global Energy Assessment including varying assumptions on climate and energy access policies are investigated with an ensemble of six regional and global atmospheric chemistry transport models. A specific focus is given in the paper to the assessment of uncertainties and robustness of the projected changes in air quality. The present work relies on an ensemble of chemistry transport models giving insight into the model spread. Both regional and global scale models were involved, so that the ensemble benefits from medium-resolution approaches as well as global models that capture long-range transport. For each scenario a whole decade is modelled in order to gain statistical confidence in the results. A statistical downscaling approach is used to correct the distribution of the modelled projection. Last, the modelling experiment is related to a hind-cast study published earlier, where the performances of all participating models were extensively documented. The analysis is presented in an exposure-based framework in order to discuss policy relevant changes. According to the emission projections, ozone precursors such as NOx will drop down to 30% to 50% of their current levels, depending on the scenario. As a result, annual mean O-3 will slightly increase in NOx saturated areas but the overall O-3 burden will decrease substantially. Exposure to detrimental O-3 levels for health (SOMO35) will be reduced down to 45% to 70% of their current levels. And the fraction of stations where present-day exceedences of daily maximum O-3 is higher than 120 mu g m(-3) more than 25 days per year will drop from 43% down to 2 to 8 %. We conclude that air pollution mitigation measures (present in both scenarios) are the main factors leading to the improvement, but an additional cobenefit of at least 40% (depending on the indicator) is brought about by the climate policy.
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| 7. |
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| 8. |
- Langner, J., et al.
(författare)
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A multi-model study of impacts of climate change on surface ozone in Europe
- 2012
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Ingår i: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 12:21, s. 10423-10440
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Tidskriftsartikel (refereegranskat)abstract
- The impact of climate change on surface ozone over Europe was studied using four offline regional chemistry transport models (CTMs) and one online regional integrated climate-chemistry model (CCM), driven by the same global projection of future climate under the SRES A1B scenario. Anthropogenic emissions of ozone precursors from RCP4.5 for year 2000 were used for simulations of both present and future periods in order to isolate the impact of climate change and to assess the robustness of the results across the different models. The sensitivity of the simulated surface ozone to changes in climate between the periods 20002009 and 2040-2049 differs by a factor of two between the models, but the general pattern of change with an increase in southern Europe is similar across different models. Emissions of isoprene differ substantially between different CTMs ranging from 1.6 to 8.0 Tg yr(-1) for the current climate, partly due to differences in horizontal resolution of meteorological input data. Also the simulated change in total isoprene emissions varies substantially across models explaining part of the different climate response on surface ozone. Ensemble mean changes in summer mean ozone and mean of daily maximum ozone are close to 1 ppb(v) in parts of the land area in southern Europe. Corresponding changes of 95-percentiles of hourly ozone are close to 2 ppb(v) in the same region. In northern Europe ensemble mean for mean and daily maximum show negative changes while there are no negative changes for the higher percentiles indicating that climate impacts on O-3 could be especially important in connection with extreme summer events.
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| 9. |
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| 10. |
- Gardiner, T., et al.
(författare)
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Trend analysis of greenhouse gases over Europe measured by a network of ground-based remote FTIR instruments
- 2008
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Ingår i: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 8:22, s. 6719-6727
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Tidskriftsartikel (refereegranskat)abstract
- This paper describes the statistical analysis of annual trends in long term datasets of greenhouse gas measurements taken over ten or more years. The analysis technique employs a bootstrap resampling method to determine both the long-term and intra-annual variability of the datasets, together with the uncertainties on the trend values. The method has been applied to data from a European network of ground-based solar FTIR instruments to determine the trends in the tropospheric, stratospheric and total columns of ozone, nitrous oxide, carbon monoxide, methane, ethane and HCFC-22. The suitability of the method has been demonstrated through statistical validation of the technique, and comparison with ground-based in-situ measurements and 3-D atmospheric models.
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