| 1. |
- Roselli, Carolina, et al.
(författare)
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Multi-ethnic genome-wide association study for atrial fibrillation
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
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Tidskriftsartikel (refereegranskat)abstract
- Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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| 2. |
- van de Vegte, Yordi, et al.
(författare)
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Genetic insights into resting heart rate and its role in cardiovascular disease
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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| 3. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 4. |
- Lind, Mikael, et al.
(författare)
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Sea Traffic Management - Beneficial for all Maritime Stakeholders
- 2016
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Ingår i: Transportation Research Procedia. - : Elsevier BV. ; 14, s. 183-192
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Konferensbidrag (refereegranskat)abstract
- Sea Traffic Management is the idea of sharing information and collaborating to optimise the maritime transport chain while increasing safety and sustainability. The digital information on-board and on shore is abundant; however, the interconnection today is point-to-point and proprietary and stops the industry becoming more efficient. We will discuss how Sea Traffic Management will help the industry achieve improved predictability by introducing standards for key information and supplying an infrastructure for information exchange. This enables all actors involved in the transport to plan better and utilise their resources more efficiently. Shorter routes, just-in-time arrivals, shorter port calls are factors that will strengthen the competitiveness of the maritime sector. Improved situational awareness on the bridge and knowledge of planned routes will help optimised planning as well as reducing the number of incidents and accidents. The standard route exchange format submitted by the EU-financed MONALISA 2.0 project partners in 2014 is included in the current edition of the IEC standard, which was launched in August 2015. Solutions using that standard will start realising the benefits already next year. We will describe an infrastructure, which could work in a centralised manner but also has the flexibility to be organised in a more federative manner, similar to how the maritime world works in many aspects. Some key components are: a unique identifier for each voyage; that the information publisher controls who can access the data; that updated information should be made available in real-time; and that subscription to updated data will be the main trigger for many systems and processes. We will also describe the outcomes of the test beds in the MONALISA 2.0 project - The Sound: how shore and vessel can interact better in order improve safety in dense traffic areas; Port of Gothenburg and Port of Valencia - how collaborative decision making can improve operations for all involved actors; European Maritime Simulator Network - how new solutions can be tested in complex traffic situations and areas with real people on a large number of bridges, without risk. How large of an impact will all this have on the maritime transport industry? Based on a study from Linköping University, we believe that the number €1 billion/year in Europe due to shorter routes is only the tip of the benefit iceberg. In the study ship operators and society split the benefit 50/50. Ship operators save on fuel and other cost, society saves on reduced emissions, and other actors associated to maritime operations benefit from a higher degree of infrastructural use. We will also present results from other business cases developed during 2015, in which the benefits of Sea Traffic Management are elaborated on main stakeholders.
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| 5. |
- Möller, Peter, et al.
(författare)
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Unga vuxna i Dalarna 2008 : En regional kartläggning av unga vuxnas livsvillkor
- 2008
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Unga vuxna är en mycket viktig men också sårbar grupp. Unga representerar på ett mycket påtagligt sätt framtiden, samtidigt som det faktum att de ännu inte hunnit etablera sig fullt ut i samhället gör dem särskilt utsatta. Flera nationella undersökningar visar att åldersgruppen 19-25 år upplevt försämringar under senare tid, bland annat i form av ökad psykisk ohälsa och försämrad ekonomi. Mest utsatta vad gäller ökad psykisk ohälsa och stress är unga kvinnor. Unga kvinnor uttrycker också i högre grad än unga män en känsla av otrygghet i offentliga miljöer, och då i synnerhet kvällstid. Kön är dock inte den enda faktor som bidrar till att skapa skillnader mellan olika kategorier av unga. Social bakgrund, etnicitet, personliga förutsättningar och tidigare erfarenheter bidrar på olika sätt till att forma unga människors möte med arbetsmarknaden och steget in i vuxenlivet. Den fysiska plats där man bor påverkar också i stor utsträckning hur ens sociala parametrar kommer att samspela med samhället. Vi vet att gruppen unga vuxna lever under andra villkor än för bara ett par decennier sedan. Kunskap har dock saknats om hur det ser ut i Dalarna. För att kunna stärka unga vuxnas position och ta vara på dem som den resurs de är för regionens utveckling behöver vi veta mera. Under 2006 tog Dalarnas forskningsråd initiativ till att samla en rad organisationer med särskilt intresse för gruppen unga vuxna. En arbetsgrupp bildades och ett samtal om unga vuxnas förändrade livsvillkor inleddes. Diskussionerna mynnade ut i ett beslut att låta göra en postenkät för att kartlägga unga vuxnas livsvillkor i Dalarna. Under hösten 2007 skickades enkäter ut till 3000 slumpmässigt utvalda 19–25-åringar i Dalarna; omkring 200 i var och en av Dalarnas 15 kommuner. Det är resultatet av den kartläggningen som presenteras i den här rapporten.
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| 6. |
- Pattaro, Cristian, et al.
(författare)
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Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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| 7. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 8. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 9. |
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| 10. |
- Ahlén, Elsa, 1990, et al.
(författare)
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Glycemic control, renal complications, and current smoking in relation to excess risk of mortality in persons with type 1 diabetes
- 2016
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Ingår i: Journal of Diabetes Science and Technology. - : SAGE Publications. - 1932-2968. ; 10:5, s. 1006-1014
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Background: A substantial excess risk of mortality still exists in persons with type 1 diabetes. The aim of this study was to evaluate the excess risk of mortality in persons with type 1 diabetes without renal complications who target goals for glycemic control and are nonsmokers. Furthermore, we evaluated risk factors of death due to hypoglycemia or ketoacidosis in young adults with type 1 diabetes. Methods: We evaluated a cohort based on 33 915 persons with type 1 diabetes and 169 249 randomly selected controls from the general population matched on age, sex, and county followed over a mean of 8.0 and 8.3 years, respectively. Hazard ratios (HRs) for all-cause and cardiovascular disease (CVD) mortality for persons with type 1 diabetes versus controls were estimated. Results: The adjusted HRs for all-cause and CVD mortality for persons with type 1 diabetes without renal complications (normoalbuminuria and eGFR ≥ 60 ml/min) and HbA1c ≤ 6.9% (52 mmol/mol) compared to controls were 1.22 (95% CI 0.98-1.52) and 1.03 (95% CI 0.66-1.60), respectively. The HRs increased with higher updated mean HbA1c. For nonsmokers in this group, the HRs for all-cause and CVD mortality were somewhat lower: 1.11 (95% CI 0.87-1.42) and 0.89 (95% CI 0.53-1.48) at updated mean HbA1c ≤ 6.9% (52 mmol/mol). HRs for significant predictors for deaths due to hypoglycemia or ketoacidosis in persons < 50 years were male sex 2.40 (95% CI 1.27-4.52), smoking 2.86 (95% CI 1.57-5.22), lower educational level 3.01 (95% CI 1.26-7.22), albuminuria or advanced kidney disease 2.83 (95% CI 1.63-4.93), earlier hospital diagnosis of hypoglycemia or ketoacidosis 2.30 (95% CI 1.20-4.42), and earlier diagnosis of intoxication 2.53 (95% CI 1.06-6.04). Conclusions: If currently recommended HbA1c targets can be reached, renal complications and smoking avoided in persons with type 1 diabetes, the excess risk of mortality will likely converge substantially to that of the general population.
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