| 1. |
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| 2. |
- Ramdas, S., et al.
(författare)
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A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
- 2022
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 109:8, s. 1366-1387
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
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| 3. |
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| 4. |
- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 5. |
- Bouyoucef, S E, et al.
(författare)
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Poster Session 2 : Monday 4 May 2015, 08
- 2015
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Ingår i: European Heart Journal Cardiovascular Imaging. - : Oxford University Press (OUP). - 2047-2404 .- 2047-2412. ; 16 Suppl 1
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Tidskriftsartikel (refereegranskat)
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| 6. |
- Ederle, Joerg, et al.
(författare)
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Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial
- 2010
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Ingår i: The Lancet. - 1474-547X. ; 375:9719, s. 985-997
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Tidskriftsartikel (refereegranskat)abstract
- Background Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy. Methods The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470. Findings The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4.0%) events of disabling stroke or death in the stenting group compared with 27 (3.2%) events in the endarterectomy group (hazard ratio [HR] 1.28, 95% CI 0.77-2.11). The incidence of stroke, death, or procedural myocardial infarction was 8.5% in the stenting group compared with 5.2% in the endarterectomy group (72 vs 44 events; HR 1.69, 1.16-2.45, p=0.006), Risks of any stroke (65 vs 35 events; HR 1.92, 1.27-2.89) and all-cause death (19 vs seven events; HR 2.76, 1.16-6.56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0.0197). Interpretation Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery.
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| 7. |
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| 8. |
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| 9. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 10. |
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| 11. |
- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 12. |
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| 13. |
- Ferreira, Mjv, et al.
(författare)
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Poster Session 3 : Tuesday 5 May 2015, 08
- 2015
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Ingår i: European Heart Journal Cardiovascular Imaging. - : Oxford University Press (OUP). - 2047-2404 .- 2047-2412. ; 16 Suppl 1
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Tidskriftsartikel (refereegranskat)
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| 14. |
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| 15. |
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| 16. |
- Hop, Paul J., et al.
(författare)
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Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
- 2022
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 14:633
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
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| 17. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 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
- Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
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| 18. |
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| 19. |
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| 20. |
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| 21. |
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| 22. |
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| 23. |
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| 24. |
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| 25. |
- Yaghootkar, Hanieh, et al.
(författare)
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Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:12, s. 2806-2818
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Tidskriftsartikel (refereegranskat)abstract
- Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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| 26. |
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| 27. |
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| 28. |
- Arias, M., et al.
(författare)
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Low-frequency radio absorption in Cassiopeia A
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 612
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Tidskriftsartikel (refereegranskat)abstract
- Context. Cassiopeia A is one of the best-studied supernova remnants. Its bright radio and X-ray emission is due to shocked ejecta. Cas A is rather unique in that the unshocked ejecta can also be studied: through emission in the infrared, the radio-active decay of Ti-44, and the low-frequency free-free absorption caused by cold ionised gas, which is the topic of this paper. Aims. Free-free absorption processes are affected by the mass, geometry, temperature, and ionisation conditions in the absorbing gas. Observations at the lowest radio frequencies can constrain a combination of these properties. Methods. We used Low Frequency Array (LOFAR) Low Band Antenna observations at 30-77 MHz and Very Large Array (VLA) L-band observations at 1-2 GHz to fit for internal absorption as parametrised by the emission measure. We simultaneously fit multiple UV-matched images with a common resolution of 17 '' (this corresponds to 0.25 pc for a source at the distance of Cas A). The ample frequency coverage allows us separate the relative contributions from the absorbing gas, the unabsorbed front of the shell, and the absorbed back of the shell to the emission spectrum. We explored the effects that a temperature lower than the similar to 100-500 K proposed from infrared observations and a high degree of clumping can have on the derived physical properties of the unshocked material, such as its mass and density. We also compiled integrated radio flux density measurements, fit for the absorption processes that occur in the radio band, and considered their effect on the secular decline of the source. Results. We find a mass in the unshocked ejecta of M = 2.95 +/- 0.48 M-circle dot for an assumed gas temperature of T = 100 K. This estimate is reduced for colder gas temperatures and, most significantly, if the ejecta are clumped. We measure the reverse shock to have a radius of 114 '' +/- 6 '' and be centred at 23:23:26, +58:48:54 (J2000). We also find that a decrease in the amount of mass in the unshocked ejecta (as more and more material meets the reverse shock and heats up) cannot account for the observed low-frequency behaviour of the secular decline rate. Conclusions. To reconcile our low-frequency absorption measurements with models that reproduce much of the observed behaviour in Cas A and predict little mass in the unshocked ejecta, the ejecta need to be very clumped or the temperature in the cold gas needs to be low (similar to 10 K). Both of these options are plausible and can together contribute to the high absorption value that we find.
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| 29. |
- Bouter, K. E. C., et al.
(författare)
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Differential metabolic effects of oral butyrate treatment in lean versus metabolic syndrome subjects article
- 2018
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Ingår i: Clinical and Translational Gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 2155-384X. ; 9:5
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Gut microbiota-derived short-chain fatty acids (SCFAs) have been associated with beneficial metabolic effects. However, the direct effect of oral butyrate on metabolic parameters in humans has never been studied. In this first in men pilot study, we thus treated both lean and metabolic syndrome male subjects with oral sodium butyrate and investigated the effect on metabolism. Methods: Healthy lean males (n = 9) and metabolic syndrome males (n = 10) were treated with oral 4 g of sodium butyrate daily for 4 weeks. Before and after treatment, insulin sensitivity was determined by a two-step hyperinsulinemic euglycemic clamp using [6,6-2H2]-glucose. Brown adipose tissue (BAT) uptake of glucose was visualized using 18F-FDG PET-CT. Fecal SCFA and bile acid concentrations as well as microbiota composition were determined before and after treatment. Results: Oral butyrate had no effect on plasma and fecal butyrate levels after treatment, but did alter other SCFAs in both plasma and feces. Moreover, only in healthy lean subjects a significant improvement was observed in both peripheral (median Rd: from 71 to 82 μmol/kg min, p < 0.05) and hepatic insulin sensitivity (EGP suppression from 75 to 82% p < 0.05). Although BAT activity was significantly higher at baseline in lean (SUVmax: 12.4 ± 1.8) compared with metabolic syndrome subjects (SUVmax: 0.3 ± 0.8, p < 0.01), no significant effect following butyrate treatment on BAT was observed in either group (SUVmax lean to 13.3 ± 2.4 versus metabolic syndrome subjects to 1.2 ± 4.1). Conclusions: Oral butyrate treatment beneficially affects glucose metabolism in lean but not metabolic syndrome subjects, presumably due to an altered SCFA handling in insulin-resistant subjects. Although preliminary, these first in men findings argue against oral butyrate supplementation as treatment for glucose regulation in human subjects with type 2 diabetes mellitus. © 2018 The Author(s).
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| 30. |
- Dahmen, J., et al.
(författare)
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Osteochondral Lesions of the Tibial Plafond and Ankle Instability With Ankle Cartilage Lesions: Proceedings of the International Consensus Meeting on Cartilage Repair of the Ankle
- 2022
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Ingår i: Foot & Ankle International. - : SAGE Publications. - 1071-1007 .- 1944-7876. ; 43:3, s. 448-452
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Tidskriftsartikel (refereegranskat)abstract
- Background: An international consensus group of experts was convened to collaboratively advance toward consensus opinions based on the best available evidence on key topics within cartilage repair of the ankle. The purpose of this article is to present the consensus statements on osteochondral lesions of the tibial plafond (OLTP) and on ankle instability with ankle cartilage lesions developed at the 2019 International Consensus Meeting on Cartilage Repair of the Ankle. Methods: Forty-three experts in cartilage repair of the ankle were convened and participated in a process based on the Delphi method of achieving consensus. Questions and statements were drafted within 4 working groups focusing on specific topics within cartilage repair of the ankle, after which a comprehensive literature review was performed and the available evidence for each statement was graded. Discussion and debate occurred in cases where statements were not agreed on in unanimous fashion within the working groups. A final vote was then held. Results: A total of 11 statements on OLTP reached consensus. Four achieved unanimous support and 7 reached strong consensus (greater than 75% agreement). A total of 8 statements on ankle instability with ankle cartilage lesions reached consensus during the 2019 International Consensus Meeting on Cartilage Repair of the Ankle. One achieved unanimous support, and seven reached strong consensus (greater than 75% agreement). Conclusions: These consensus statements may assist clinicians in the management of these difficult clinical pathologies.
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| 31. |
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| 33. |
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| 35. |
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| 36. |
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| 37. |
- Mahajan, Anubha, et al.
(författare)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Tidskriftsartikel (refereegranskat)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 38. |
- Menkveld, Albert J., et al.
(författare)
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Nonstandard Errors
- 2024
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Ingår i: JOURNAL OF FINANCE. - : Wiley-Blackwell. - 0022-1082 .- 1540-6261. ; 79:3, s. 2339-2390
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Tidskriftsartikel (refereegranskat)abstract
- In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty-nonstandard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for more reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants.
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| 39. |
- Miao, X. F., et al.
(författare)
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Short-range magnetic correlations and spin dynamics in the paramagnetic regime of (Mn,Fe)2(P,Si)
- 2016
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Ingår i: PHYSICAL REVIEW B. - 2469-9950. ; 94:1
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Tidskriftsartikel (refereegranskat)abstract
- The spatial and temporal correlations of magnetic moments in the paramagnetic regime of (Mn,Fe)(2)(P,Si) have been investigated by means of polarized neutron diffraction and muon-spin relaxation techniques. Short-range magnetic correlations are present at temperatures far above the ferromagnetic transition temperature (T-C). This leads to deviations of paramagnetic susceptibility from Curie-Weiss behavior. These short-range magnetic correlations extend in space, slow down with decreasing temperature, and finally develop into long-range magnetic order at T-C.
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| 40. |
- Porcu, E, et al.
(författare)
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Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3300-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits.
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| 41. |
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| 42. |
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| 43. |
- Spracklen, Cassandra N., et al.
(författare)
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Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology
- 2019
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Ingår i: American Journal of Human Genetics. - : CELL PRESS. - 0002-9297 .- 1537-6605. ; 105:1, s. 15-28
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Tidskriftsartikel (refereegranskat)abstract
- Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 x 10(-7)). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r(2) > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 x 10(-4)) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.
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| 44. |
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| 45. |
- van Eck, C. F., et al.
(författare)
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"Anatomic" anterior cruciate ligament reconstruction: a systematic review of surgical techniques and reporting of surgical data
- 2010
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Ingår i: Arthroscopy. - : Elsevier BV. - 1526-3231. ; 26:9 Suppl
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The aim of this systematic review was to evaluate studies published on anatomic double-bundle anterior cruciate ligament (ACL) reconstruction. METHODS: A systematic electronic search was performed by use of the Medline and Embase databases. Studies that were published from January 1995 to April 2009 were included. The selection criteria were studies that reported on a surgical technique for "anatomic double-bundle ACL reconstruction" on skeletally mature living human subjects and were written in English. Data collected and analyzed included a variety of surgical data. Tables were created to provide an overview of surgical techniques for anatomic ACL reconstruction. RESULTS: Seventy-four studies were included in this review. Some surgical factors were adequately reported in the majority of the articles: visualizing the native ACL insertion sites, placing the tunnels in the footprint, graft type, and fixation method. However; ACL insertion site measurement, femoral intercondylar notch measurement, individualization of surgery, and intraoperative/postoperative imaging were poorly reported. The most variety was seen in knee flexion angle during femoral tunnel drilling and tensioning pattern of the grafts. CONCLUSIONS: For most surgical data, there was a gross under-reporting of specific operative technique data. We believe that the details of an "anatomic" operative technique are crucial for the valid interpretations of the outcomes. Thus we encourage authors to report their surgical technique in a specific and standardized fashion.
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| 46. |
- Adage, Tiziana, et al.
(författare)
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Hypothalamic, metabolic, and behavioral responses to pharmacological inhibition of CNS melanocortin signaling in rats
- 2001
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 21:10, s. 3639-3645
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Tidskriftsartikel (refereegranskat)abstract
- The CNS melanocortin (MC) system is implicated as a mediator of the central effects of leptin, and reduced activity of the CNS MC system promotes obesity in both rodents and humans. Because activation of CNS MC receptors has direct effects on autonomic outflow and metabolism, we hypothesized that food intake- independent mechanisms contribute to development of obesity induced by pharmacological blockade of MC receptors in the brain and that changes in hypothalamic neuropeptidergic systems known to regulate weight gain [i. e., corticotropin-releasing hormone (CRH), cocaine- amphetamine- related transcript (CART), proopiomelanocortin (POMC), and neuropeptide Y (NPY)] would trigger this effect. Relative to vehicle- treated controls, third intracerebroventricular (i3vt) administration of the MC receptor antagonist SHU9119 to rats for 11 d doubled food and water intake (toward the end of treatment) and increased body weight (similar to 14%) and fat content (similar to 90%), hepatic glycogen content (similar to 40%), and plasma levels of cholesterol (similar to 48%), insulin (similar to 259%), glucagon (similar to 80%), and leptin (similar to 490%), whereas spontaneous locomotor activity and body temperature were reduced. Pair- feeding of i3vt SHU9119- treated animals to i3vt vehicle- treated controls normalized plasma levels of insulin, glucagon, and hepatic glycogen content, but only partially reversed the elevations of plasma cholesterol (similar to 31%) and leptin (similar to 104%) and body fat content (similar to 27%). Reductions in body temperature and locomotor activity induced by i3vt SHU9119 were not reversed by pair feeding, but rather were more pronounced. None of the effects found can be explained by peripheral action of the compound. The obesity effects occurred despite a lack in neuropeptide expression responses in the neuroanatomical range selected across the arcuate (i. e., CART, POMC, and NPY) and paraventricular (i. e., CRH) hypothalamus. The results indicate that reduced activity of the CNS MC pathway promotes fat deposition via both food intake- dependent and -independent mechanisms.
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| 47. |
- Beck, Hylke E., et al.
(författare)
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Global Fully Distributed Parameter Regionalization Based on Observed Streamflow From 4,229 Headwater Catchments
- 2020
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Ingår i: Journal of Geophysical Research - Atmospheres. - 2169-897X .- 2169-8996. ; 125:17
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Tidskriftsartikel (refereegranskat)abstract
- All hydrological models need to be calibrated to obtain satisfactory streamflow simulations. Here we present a novel parameter regionalization approach that involves the optimization of transfer equations linking model parameters to climate and landscape characteristics. The optimization was performed in a fully spatially distributed fashion at high resolution (0.05 degrees), instead of at lumped catchment scale, using an unprecedented database of daily observed streamflow from 4,229 headwater catchments (<5,000 km(2)) worldwide. The optimized equations were subsequently applied globally to produce parameter maps for the entire land surface including ungauged regions. The approach was evaluated using the Kling-Gupta efficiency (KGE) and a gridded version of the hydrological model HBV. Tenfold cross validation was used to evaluate the generalizability of the approach and to obtain an ensemble of parameter maps. For the 4,229 independent validation catchments, the regionalized parameters yielded a median KGE of 0.46. The median KGE improvement (relative to uncalibrated parameters) was 0.29, and improvements were obtained for 88% of the independent validation catchments. These scores compare favorably to those from previous large catchment sample studies. The degree of performance improvement due to the regionalized parameters did not depend on climate or topography. Substantial improvements were obtained even for independent validation catchments located far from the catchments used for optimization, underscoring the value of the derived parameters for poorly gauged regions. The regionalized parameters-available via -should be useful for hydrological applications requiring accurate streamflow simulations.
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| 48. |
- Boeije, M. F. J., et al.
(författare)
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On the phase stability of CaCu5-type compounds
- 2017
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Ingår i: Journal of Alloys and Compounds. - : Elsevier BV. - 0925-8388 .- 1873-4669. ; 722, s. 549-554
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Tidskriftsartikel (refereegranskat)abstract
- We present a hybrid method to inspect the phase stability of compounds having a CaCu5-type crystal structure. This is done using 2D stability plots using the Miedema parameters that are based on the work function and electron density of the constituent elements. Stable compounds are separated from unstable binary compounds, with a probability of 94%. For stable compounds, a linear relation is found, showing a constant ratio of charge transfer and electron density mismatch. DFT calculations show the same trend. Elements from the s, d, f-block are all reliably represented, elements from the p-block are still challenging.
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| 49. |
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| 50. |
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