| 1. |
- 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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| 2. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 3. |
- Feng, Shaohong, et al.
(författare)
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Dense sampling of bird diversity increases power of comparative genomics
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 587:7833
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Tidskriftsartikel (refereegranskat)abstract
- Whole-genome sequencing projects are increasingly populating the tree of life and characterizing biodiversity(1-4). Sparse taxon sampling has previously been proposed to confound phylogenetic inference(5), and captures only a fraction of the genomic diversity. Here we report a substantial step towards the dense representation of avian phylogenetic and molecular diversity, by analysing 363 genomes from 92.4% of bird families-including 267 newly sequenced genomes produced for phase II of the Bird 10,000 Genomes (B10K) Project. We use this comparative genome dataset in combination with a pipeline that leverages a reference-free whole-genome alignment to identify orthologous regions in greater numbers than has previously been possible and to recognize genomic novelties in particular bird lineages. The densely sampled alignment provides a single-base-pair map of selection, has more than doubled the fraction of bases that are confidently predicted to be under conservation and reveals extensive patterns of weak selection in predominantly non-coding DNA. Our results demonstrate that increasing the diversity of genomes used in comparative studies can reveal more shared and lineage-specific variation, and improve the investigation of genomic characteristics. We anticipate that this genomic resource will offer new perspectives on evolutionary processes in cross-species comparative analyses and assist in efforts to conserve species. A dataset of the genomes of 363 species from the Bird 10,000 Genomes Project shows increased power to detect shared and lineage-specific variation, demonstrating the importance of phylogenetically diverse taxon sampling in whole-genome sequencing.
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| 4. |
- Cuni-Sanchez, Aida, et al.
(författare)
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High aboveground carbon stock of African tropical montane forests
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 596:7873, s. 536-542
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Tidskriftsartikel (refereegranskat)abstract
- Tropical forests store 40–50per cent of terrestrial vegetation carbon. However, spatial variations in aboveground live tree biomass carbon (AGC) stocks remain poorly understood, in particular in tropical montane forests. Owing to climatic and soil changes with increasing elevation, AGC stocks are lower in tropical montane forests compared with lowland forests. Here we assemble and analyse a dataset of structurally intact old-growth forests (AfriMont) spanning 44 montane sites in 12 African countries. We find that montane sites in the AfriMont plot network have a mean AGC stock of 149.4megagrams of carbon per hectare (95% confidence interval 137.1–164.2), which is comparable to lowland forests in the African Tropical Rainforest Observation Network4 and about 70per cent and 32per cent higher than averages from plot networks in montane and lowland forests in the Neotropics, respectively. Notably, our results are two-thirds higher than the Intergovernmental Panel on Climate Change default values for these forests in Africa8. We find that the low stem density and high abundance of large trees of African lowland forests is mirrored in the montane forests sampled. This carbon store is endangered: we estimate that 0.8 million hectares of old-growth African montane forest have been lost since 2000. We provide country-specific montane forest AGC stock estimates modelled from our plot network to helpto guide forest conservation and reforestation interventions. Our findings highlight the need for conserving these biodiverse and carbon-rich ecosystems.
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| 5. |
- Downey, Harriet, et al.
(författare)
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Training future generations to deliver evidence-based conservation and ecosystem management
- 2021
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Ingår i: Ecological Solutions and Evidence. - : Wiley. - 2688-8319. ; 2:1
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Forskningsöversikt (refereegranskat)abstract
- 1. To be effective, the next generation of conservation practitioners and managers need to be critical thinkers with a deep understanding of how to make evidence-based decisions and of the value of evidence synthesis.2. If, as educators, we do not make these priorities a core part of what we teach, we are failing to prepare our students to make an effective contribution to conservation practice.3. To help overcome this problem we have created open access online teaching materials in multiple languages that are stored in Applied Ecology Resources. So far, 117 educators from 23 countries have acknowledged the importance of this and are already teaching or about to teach skills in appraising or using evidence in conservation decision-making. This includes 145 undergraduate, postgraduate or professional development courses.4. We call for wider teaching of the tools and skills that facilitate evidence-based conservation and also suggest that providing online teaching materials in multiple languages could be beneficial for improving global understanding of other subject areas.
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| 6. |
- Evangelou, Evangelos, et al.
(författare)
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Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22
- 2011
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 70:2, s. 349-355
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in older people. It is characterised by changes in joint structure, including degeneration of the articular cartilage, and its aetiology is multifactorial with a strong postulated genetic component. Methods A meta-analysis was performed of four genome-wide association (GWA) studies of 2371 cases of knee OA and 35 909 controls in Caucasian populations. Replication of the top hits was attempted with data from 10 additional replication datasets. Results With a cumulative sample size of 6709 cases and 44 439 controls, one genome-wide significant locus was identified on chromosome 7q22 for knee OA (rs4730250, p = 9.2 x 10(-9)), thereby confirming its role as a susceptibility locus for OA. Conclusion The associated signal is located within a large (500 kb) linkage disequilibrium block that contains six genes: PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, beta), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like) and BCAP29 (B cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment.
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| 7. |
- Hart, James L., et al.
(författare)
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Electron-beam-induced ferroelectric domain behavior in the transmission electron microscope : Toward deterministic domain patterning
- 2016
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Ingår i: Physical Review B. - 2469-9950 .- 2469-9969. ; 94:17
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Tidskriftsartikel (refereegranskat)abstract
- We report on transmission electron microscope beam-induced ferroelectric domain nucleation and motion. While previous observations of this phenomenon have been reported, a consistent theory explaining induced domain response is lacking, and little control over domain behavior has been demonstrated. We identify positive sample charging, a result of Auger and secondary electron emission, as the underlying mechanism driving domain behavior. By converging the electron beam to a focused probe, we demonstrate controlled nucleation of nanoscale domains. Molecular dynamics simulations performed are consistent with experimental results, confirming positive sample charging and reproducing the result of controlled domain nucleation. Furthermore, we discuss the effects of sample geometry and electron irradiation conditions on induced domain response. These findings elucidate past reports of electron beam-induced domain behavior in the transmission electron microscope and provide a path towards more predictive, deterministic domain patterning through electron irradiation.
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| 8. |
- Khalili, Hamed, et al.
(författare)
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Adherence to a Mediterranean diet is associated with a lower risk of later-onset Crohn's disease : results from two large prospective cohort studies.
- 2020
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Ingår i: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 69:9, s. 1637-1644
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine the relationship between Mediterranean diet and risk of later-onset Crohn's disease (CD) or ulcerative colitis (UC).DESIGN: We conducted a prospective cohort study of 83 147 participants (age range: 45-79 years) enrolled in the Cohort of Swedish Men and Swedish Mammography Cohort. A validated food frequency questionnaire was used to calculate an adherence score to a modified Mediterranean diet (mMED) at baseline in 1997. Incident diagnoses of CD and UC were ascertained from the Swedish Patient Register. We used Cox proportional hazards modelling to calculate HRs and 95% CI.RESULTS: Through December of 2017, we confirmed 164 incident cases of CD and 395 incident cases of UC with an average follow-up of 17 years. Higher mMED score was associated with a lower risk of CD (Ptrend=0.03) but not UC (Ptrend=0.61). Compared with participants in the lowest category of mMED score (0-2), there was a statistically significant lower risk of CD (HR=0.42, 95% CI 0.22 to 0.80) but not UC (HR=1.08, 95% CI 0.74 to 1.58). These associations were not modified by age, sex, education level, body mass index or smoking (all Pinteraction >0.30). The prevalence of poor adherence to a Mediterranean diet (mMED score=0-2) was 27% in our cohorts, conferring a population attributable risk of 12% for later-onset CD.CONCLUSION: In two prospective studies, greater adherence to a Mediterranean diet was associated with a significantly lower risk of later-onset CD.
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| 9. |
- Khalili, Hamed, et al.
(författare)
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No Association Between Consumption of Sweetened Beverages and Later Risk of Crohn's Disease or Ulcerative Colitis
- 2019
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Ingår i: Clinical Gastroenterology and Hepatology. - : Elsevier. - 1542-3565 .- 1542-7714. ; 17:1, s. 123-129
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Consumption of sweetened beverages has been associated with inflammation, based on measurements of C-reactive protein and tumor necrosis factor, as well as immune-mediated disorders including rheumatoid arthritis. We investigated associations with Crohn's disease (CD) or ulcerative colitis (UC).METHODS: We conducted a prospective cohort study of 83,042 participants (44-83 years old) enrolled in the Cohort of Swedish Men or the Swedish Mammography Study. Dietary and lifestyle data were collected using a validated food frequency questionnaire at baseline in 1997. Diagnoses of CD and UC were ascertained from the Swedish Patient Register. We used Cox proportional hazards modeling to calculate hazard ratios (HR) and 95% CIs.RESULTS: Through December of 2014, we confirmed 143 incident cases of CD (incidence; rate = 11 cases/100,000 person-years) and 349 incident cases of UC (incidence rate = 28 cases/100,000 person-years) over 1,264,345 person-years of follow up. Consumption of sweetened beverages was not associated with increased risk of CD (Ptrend = 0.34) or UC (Ptrend = 0.40). Compared to participants who reported no consumption of sweetened beverages, the multivariable-adjusted HRs for 1 or more servings per day were 1.02 for CD (95% CI, 0.60-1.73) and 1.14 for UC (95% CI, 0.83-1.57). The association between consumption of sugar-sweetened beverages and risk of CD or UC were not modified by age, sex (cohort), body mass index, or smoking (all Pinteraction ≥ 0.12).CONCLUSION: In analyses of data from 2 large prospective cohort studies from Sweden, we observed no evidence for associations between consumption of sweetened beverages and later risk of CD or UC.
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| 10. |
- Khalili, Hamed, et al.
(författare)
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No Association Between Consumption of Sweetened Beverages and Risk of Later-Onset Crohn's Disease or Ulcerative Colitis.
- 2019
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Ingår i: Clinical Gastroenterology and Hepatology. - : Elsevier BV. - 1542-3565 .- 1542-7714. ; 17:1, s. 123-129
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Consumption of sweetened beverages has been associated with inflammation based on measurements of C-reactive protein and tumor necrosis factor, as well as immune-mediated disorders including rheumatoid arthritis. We investigated associations with Crohn's disease (CD) or ulcerative colitis (UC).METHODS: We conducted a prospective cohort study of 83,042 participants (age, 44-83 y) enrolled in the Cohort of Swedish Men or the Swedish Mammography Study. Dietary and lifestyle data were collected using a validated food frequency questionnaire at baseline in 1997. Diagnoses of CD and UC were ascertained from the Swedish Patient Register. We used Cox proportional hazards modeling to calculate hazard ratios and 95% CIs.RESULTS: Through December of 2014, we confirmed 143 incident cases of CD (incidence rate, 11 cases/100,000 person-years) and 349 incident cases of UC (incidence rate, 28 cases/100,000 person-years) over 1,264,345 person-years of follow-up evaluation. Consumption of sweetened beverages was not associated with increased risk of CD (Ptrend = .34) or UC (Ptrend = .40). Compared with participants who reported no consumption of sweetened beverages, the multivariable-adjusted hazard ratios for 1 or more servings per day were 1.02 for CD (95% CI, 0.60-1.73) and 1.14 for UC (95% CI, 0.83-1.57). The association between consumption of sugar-sweetened beverages and risk of CD or UC were not modified by age, sex (cohort), body mass index, or smoking (all Pinteraction ≥ .12).CONCLUSIONS: In analyses of data from 2 large prospective cohort studies from Sweden, we observed no evidence for associations between consumption of sweetened beverages and later risk of CD or UC.
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