| 1. |
- Lango Allen, Hana, et al.
(författare)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Tidskriftsartikel (refereegranskat)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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| 2. |
- Almroth Rosell, Elin, 1977, et al.
(författare)
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Effects of simulated natural and massive resuspension on benthic oxygen, nutrient and dissolved inorganic carbon fluxes in Loch Creran, Scotland
- 2012
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Ingår i: Journal of Sea Research. - : Elsevier BV. - 1385-1101. ; 72, s. 38-48
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Tidskriftsartikel (refereegranskat)abstract
- The effect of repeated natural resuspension on benthic oxygen consumption and the effect of natural and massive resuspension on oxygen consumption and fluxes of phosphate, silicate, ammonium and dissolved inorganic carbon (DIC) were studied at two stations (S1 and S2) in a Scottish sea loch. Station S11 had organically enriched sediment and station S1 had lower organic content in the sediment. The fluxes were measured in situ using the Göteborg benthic lander. Natural resuspension, simulating resuspension events due to strong wind, waves or currents, and massive resuspension, simulating resuspension due to e.g. trawling or dredging, were created inside the incubation chambers by regulating the stirring of the incubated overlying water or by retracting and shaking the incubated sediment. Natural resuspension showed clear effects on the oxygen consumption at station S11, where it increased with an average of 12.8 (standard error (s.e.) 0.17) and 7.7 (s.e. 0.12) mmol m− 2 d− 1 during the first and second incubations, respectively. At station S1 there was no clear effect of natural resuspension on the oxygen consumption. Massive resuspension increased the oxygen consumption on S1 with an average of 608 (standard deviation (sd) 366) mmol m− 2 d− 1 and on S11 with an average of 2396 (sd 2265) mmol m− 2 d− 1. The fluxes of ammonium, phosphate and silicate were affected by the massive resuspension in 50, 14 and 33% of the chambers, respectively, on station S11. However, in the majority of the cases there were no effects on the nutrient and DIC fluxes of massive resuspension. The absolute concentrations of DIC, ammonium and silicate did however instantly increase with an average of 419 (sd 297), 48 (sd 27) and 6.9 (sd 3.7) μM, respectively, at S11 upon massive resuspension. The concentrations of phosphate decreased instantly with an average of 0.2 (sd 0.1) μM. On station S1 there were effects only on the ammonium and silicate concentrations, which increased with 0.8 (sd 0.3) and 1.13 (sd 0.36) μM, respectively. The large increase in oxygen consumption due to massive resuspension indicates that activities like e.g. trawling and dredging that take place in areas where water exchange occurs infrequently may lead to oxygen depletion in bottom water, which in turn might affect the ecological balance. Silicate, ammonium and DIC can be released due to massive resuspension and contribute to increased algal blooms in surface waters.
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| 3. |
- Almroth Rosell, Elin, 1977, et al.
(författare)
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Transport of fresh and resuspended particulate organic material in the Baltic Sea — a model study
- 2011
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Ingår i: Journal of Marine Systems. - : Elsevier BV. - 0924-7963. ; 87:1, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- A fully coupled high-resolution 3-dimensional biogeochemical–physical ocean model including an empirical wave model was used to investigate the long-term average (1970–2007) distributions and transports of resuspended matter and other types of suspended organic matter in the Baltic Sea. Modelled bottom types were compared to observations and the results showed that the model successfully managed to capture the horizontal, as well as the vertical, distribution of the different bottom types: accumulation, transport and erosion bottoms. The model also captured well the nutrient element contents in the sediments. On average the largest contribution of resuspended organic carbon to the transport of total organic carbon is found at erosion and transport bottoms. Although the relative transport of resuspended organic carbon at deeper accumulation bottoms in general is low (< 10% of total), the central parts of the sub-basins act on average as sinks that import organic matter while the more shallow areas and the coastal regions acts as sources of organic carbon in the water column. This indicates that the particulate organic matter produced in erosion and transport areas might be kept in suspension long enough to be transported and settle in less energetic areas, i.e. on accumulation bottoms.
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| 4. |
- Cathalot, C., et al.
(författare)
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Spatial and Temporal Variability of Benthic Respiration in a Scottish Sea Loch Impacted by Fish Farming: A Combination of In Situ Techniques
- 2012
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Ingår i: Aquatic geochemistry. - : Springer Science and Business Media LLC. - 1380-6165 .- 1573-1421. ; 18:6, s. 515-541
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Tidskriftsartikel (refereegranskat)abstract
- The effects of fish farm activities on sediment biogeochemistry were investigated in Loch Creran (Western Scotland) from March to October 2006. Sediment oxygen uptake rates (SOU) were estimated along an organic matter gradient generated from an Atlantic salmon farm using a combination of in situ techniques: microelectrodes, planar optode and benthic chamber incubations. Sulphide (H2S) and pH distributions in sediment porewater were also measured using in situ microelectrodes, and dissolved inorganic carbon (DIC) fluxes were measured in situ using benthic chambers. Relationships between benthic fluxes, vertical distribution of oxidants and reduced compounds in the sediment were examined as well as bacterial abundance and biomass. Seasonal variations in SOU were relatively low and mainly driven by seasonal temperature variations. The effect of the fish farm on sediment oxygen uptake rate was clearly identified by higher total and diffusive oxygen uptake rates (TOU and DOU, respectively) on impacted stations (TOU: 70 ± 25 mmol O2 m-2 day-1; DOU: 70 ± 32 mmol O2 m-2 day-1 recalculated at the summer temperature), compared with the reference station (TOU: 28.3 ± 5.5 mmol O2 m-2 day-1; DOU: 21.5 ± 4.5 mmol O2 m-2 day-1). At the impacted stations, planar optode images displayed high centimetre scale heterogeneity in oxygen distribution underlining the control of oxygen dynamics by small-scale processes. The organic carbon enrichment led to enhanced sulphate reduction as demonstrated by large vertical H2S concentration gradients in the porewater (from 0 to 1,000 lM in the top 3 cm) at the most impacted site. The impact on ecosystem functions such as bioirrigation was evidenced by a decreasing TOU/DOU ratio, from 1.7 in the non-impacted sediments to 1 in the impacted zone. This trend was related to a shift in the macrofaunal assemblage and an increase in sediment bacterial population. The turnover time of the organic load of the sediment was estimated to be over 6 years.
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| 5. |
- Dayeh, Tasnim, et al.
(författare)
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Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion.
- 2014
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- Impaired insulin secretion is a hallmark of type 2 diabetes (T2D). Epigenetics may affect disease susceptibility. To describe the human methylome in pancreatic islets and determine the epigenetic basis of T2D, we analyzed DNA methylation of 479,927 CpG sites and the transcriptome in pancreatic islets from T2D and non-diabetic donors. We provide a detailed map of the global DNA methylation pattern in human islets, β- and α-cells. Genomic regions close to the transcription start site showed low degrees of methylation and regions further away from the transcription start site such as the gene body, 3'UTR and intergenic regions showed a higher degree of methylation. While CpG islands were hypomethylated, the surrounding 2 kb shores showed an intermediate degree of methylation, whereas regions further away (shelves and open sea) were hypermethylated in human islets, β- and α-cells. We identified 1,649 CpG sites and 853 genes, including TCF7L2, FTO and KCNQ1, with differential DNA methylation in T2D islets after correction for multiple testing. The majority of the differentially methylated CpG sites had an intermediate degree of methylation and were underrepresented in CpG islands (∼7%) and overrepresented in the open sea (∼60%). 102 of the differentially methylated genes, including CDKN1A, PDE7B, SEPT9 and EXOC3L2, were differentially expressed in T2D islets. Methylation of CDKN1A and PDE7B promoters in vitro suppressed their transcriptional activity. Functional analyses demonstrated that identified candidate genes affect pancreatic β- and α-cells as Exoc3l silencing reduced exocytosis and overexpression of Cdkn1a, Pde7b and Sept9 perturbed insulin and glucagon secretion in clonal β- and α-cells, respectively. Together, our data can serve as a reference methylome in human islets. We provide new target genes with altered DNA methylation and expression in human T2D islets that contribute to perturbed insulin and glucagon secretion. These results highlight the importance of epigenetics in the pathogenesis of T2D.
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| 6. |
- Dekker Nitert, Marloes, et al.
(författare)
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Impact of an Exercise Intervention on DNA Methylation in Skeletal Muscle From First-Degree Relatives of Patients With Type 2 Diabetes.
- 2012
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797.
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Tidskriftsartikel (refereegranskat)abstract
- To identify epigenetic patterns, which may predispose to type 2 diabetes (T2D) due to a family history (FH) of the disease, we analyzed DNA methylation genome-wide in skeletal muscle from individuals with (FH(+)) or without (FH(-)) an FH of T2D. We found differential DNA methylation of genes in biological pathways including mitogen-activated protein kinase (MAPK), insulin, and calcium signaling (P ≤ 0.007) and of individual genes with known function in muscle, including MAPK1, MYO18B, HOXC6, and the AMP-activated protein kinase subunit PRKAB1 in skeletal muscle of FH(+) compared with FH(-) men. We further validated our findings from FH(+) men in monozygotic twin pairs discordant for T2D, and 40% of 65 analyzed genes exhibited differential DNA methylation in muscle of both FH(+) men and diabetic twins. We further examined if a 6-month exercise intervention modifies the genome-wide DNA methylation pattern in skeletal muscle of the FH(+) and FH(-) individuals. DNA methylation of genes in retinol metabolism and calcium signaling pathways (P < 3 × 10(-6)) and with known functions in muscle and T2D including MEF2A, RUNX1, NDUFC2, and THADA decreased after exercise. Methylation of these human promoter regions suppressed reporter gene expression in vitro. In addition, both expression and methylation of several genes, i.e., ADIPOR1, BDKRB2, and TRIB1, changed after exercise. These findings provide new insights into how genetic background and environment can alter the human epigenome.
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| 7. |
- Hall, Elin, et al.
(författare)
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DNA methylation of the glucagon-like peptide 1 receptor (GLP1R) in human pancreatic islets.
- 2013
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 14:Jul,23
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Tidskriftsartikel (refereegranskat)abstract
- Insulin secretion is enhanced upon the binding of Glucagon-like peptide-1 (GLP-1) to its receptor (GLP1R) in pancreatic β cells. Although a reduced expression of GLP1R in pancreatic islets from type 2 diabetic patients and hyperglycaemic rats has been established, it is still unknown if this is caused by differential DNA methylation of GLP1R in pancreatic islets of type 2 diabetic patients.
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| 8. |
- Hall, Elin, et al.
(författare)
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Effects of palmitate on genome-wide mRNA expression and DNA methylation patterns in human pancreatic islets.
- 2014
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Ingår i: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Circulating free fatty acids are often elevated in patients with type 2 diabetes (T2D) and obese individuals. Chronic exposure to high levels of saturated fatty acids has detrimental effects on islet function and insulin secretion. Altered gene expression and epigenetics may contribute to T2D and obesity. However, there is limited information on whether fatty acids alter the genome-wide transcriptome profile in conjunction with DNA methylation patterns in human pancreatic islets. To dissect the molecular mechanisms linking lipotoxicity to impaired insulin secretion, we investigated the effects of a 48 h palmitate treatment in vitro on genome-wide mRNA expression and DNA methylation patterns in human pancreatic islets.
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| 9. |
- Hall, Elin, et al.
(författare)
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Sex differences in the genome-wide DNA methylation pattern and impact on gene expression, microRNA levels and insulin secretion in human pancreatic islets
- 2014
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Ingår i: GenomeBiology. - : Springer Science and Business Media LLC. - 1465-6906. ; 15:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Epigenetic factors regulate tissue-specific expression and X-chromosome inactivation. Previous studies have identified epigenetic differences between sexes in some human tissues. However, it is unclear whether epigenetic modifications contribute to sex-specific differences in insulin secretion and metabolism. Here, we investigate the impact of sex on the genome-wide DNA methylation pattern in human pancreatic islets from 53 males and 34 females, and relate the methylome to changes in expression and insulin secretion. Results: Glucose-stimulated insulin secretion is higher in female versus male islets. Genome-wide DNA methylation data in human islets clusters based on sex. While the chromosome-wide DNA methylation level on the X-chromosome is higher in female versus male islets, the autosomes do not display a global methylation difference between sexes. Methylation of 8,140 individual X-chromosome sites and 470 autosomal sites shows sex-specific differences in human islets. These include sites in/near AR, DUSP9, HNF4A, BCL11A and CDKN2B. 61 X-chromosome genes and 18 autosomal genes display sex-specific differences in both DNA methylation and expression. These include NKAP, SPESP1 and APLN, which exhibited lower expression in females. Functional analyses demonstrate that methylation of NKAP and SPESP1 promoters in vitro suppresses their transcriptional activity. Silencing of Nkap or Apln in clonal beta-cells results in increased insulin secretion. Differential methylation between sexes is associated with altered levels of microRNAs miR-660 and miR-532 and related target genes. Conclusions: Chromosome-wide and gene-specific sex differences in DNA methylation associate with altered expression and insulin secretion in human islets. Our data demonstrate that epigenetics contribute to sex-specific metabolic phenotypes.
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| 10. |
- Jacobsen, S. C., et al.
(författare)
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Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men
- 2012
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 55:12, s. 3341-3349
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Tidskriftsartikel (refereegranskat)abstract
- Energy-dense diets that are high in fat are associated with a risk of metabolic diseases. The underlying molecular mechanisms could involve epigenetics, as recent data show altered DNA methylation of putative type 2 diabetes candidate genes in response to high-fat diets. We examined the effect of a short-term high-fat overfeeding (HFO) diet on genome-wide DNA methylation patterns in human skeletal muscle. Skeletal muscle biopsies were obtained from 21 healthy young men after ingestion of a short-term HFO diet and a control diet, in a randomised crossover setting. DNA methylation was measured in 27,578 CpG sites/14,475 genes using Illumina's Infinium Bead Array. Candidate gene expression was determined by quantitative real-time PCR. HFO introduced widespread DNA methylation changes affecting 6,508 genes (45%), with a maximum methylation change of 13.0 percentage points. The HFO-induced methylation changes were only partly and non-significantly reversed after 6-8 weeks. Alterations in DNA methylation levels primarily affected genes involved in inflammation, the reproductive system and cancer. Few gene expression changes were observed and these had poor correlation to DNA methylation. The genome-wide DNA methylation changes induced by the short-term HFO diet could have implications for our understanding of transient epigenetic regulation in humans and its contribution to the development of metabolic diseases. The slow reversibility suggests a methylation build-up with HFO, which over time may influence gene expression levels.
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