| 1. |
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| 2. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 3. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 4. |
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| 5. |
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| 6. |
- 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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| 7. |
- 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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| 8. |
- Taddei, C, et al.
(författare)
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Repositioning of the global epicentre of non-optimal cholesterol
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 582:7810, s. 73-
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Tidskriftsartikel (refereegranskat)abstract
- High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol—which is a marker of cardiovascular risk—changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million–4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.
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| 9. |
- Bousquet, J, et al.
(författare)
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Nrf2-interacting nutrients and COVID-19: time for research to develop adaptation strategies
- 2020
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Ingår i: Clinical and translational allergy. - : Wiley. - 2045-7022. ; 10:1, s. 58-
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Tidskriftsartikel (refereegranskat)abstract
- There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPARγ:Peroxisome proliferator-activated receptor, NFκB: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2α:Elongation initiation factor 2α). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT1R axis (AT1R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity.
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| 10. |
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| 11. |
- Stroth, U., et al.
(författare)
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Progress from ASDEX Upgrade experiments in preparing the physics basis of ITER operation and DEMO scenario development
- 2022
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 62:4
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Tidskriftsartikel (refereegranskat)abstract
- An overview of recent results obtained at the tokamak ASDEX Upgrade (AUG) is given. A work flow for predictive profile modelling of AUG discharges was established which is able to reproduce experimental H-mode plasma profiles based on engineering parameters only. In the plasma center, theoretical predictions on plasma current redistribution by a dynamo effect were confirmed experimentally. For core transport, the stabilizing effect of fast ion distributions on turbulent transport is shown to be important to explain the core isotope effect and improves the description of hollow low-Z impurity profiles. The L-H power threshold of hydrogen plasmas is not affected by small helium admixtures and it increases continuously from the deuterium to the hydrogen level when the hydrogen concentration is raised from 0 to 100%. One focus of recent campaigns was the search for a fusion relevant integrated plasma scenario without large edge localised modes (ELMs). Results from six different ELM-free confinement regimes are compared with respect to reactor relevance: ELM suppression by magnetic perturbation coils could be attributed to toroidally asymmetric turbulent fluctuations in the vicinity of the separatrix. Stable improved confinement mode plasma phases with a detached inner divertor were obtained using a feedback control of the plasma β. The enhanced D α H-mode regime was extended to higher heating power by feedback controlled radiative cooling with argon. The quasi-coherent exhaust regime was developed into an integrated scenario at high heating power and energy confinement, with a detached divertor and without large ELMs. Small ELMs close to the separatrix lead to peeling-ballooning stability and quasi continuous power exhaust. Helium beam density fluctuation measurements confirm that transport close to the separatrix is important to achieve the different ELM-free regimes. Based on separatrix plasma parameters and interchange-drift-Alfvén turbulence, an analytic model was derived that reproduces the experimentally found important operational boundaries of the density limit and between L- and H-mode confinement. Feedback control for the X-point radiator (XPR) position was established as an important element for divertor detachment control. Stable and detached ELM-free phases with H-mode confinement quality were obtained when the XPR was moved 10 cm above the X-point. Investigations of the plasma in the future flexible snow-flake divertor of AUG by means of first SOLPS-ITER simulations with drifts activated predict beneficial detachment properties and the activation of an additional strike point by the drifts.
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| 12. |
- Munk, P., et al.
(författare)
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Genomic analysis of sewage from 101 countries reveals global landscape of antimicrobial resistance
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Antimicrobial resistance (AMR) is a major threat to global health. Understanding the emergence, evolution, and transmission of individual antibiotic resistance genes (ARGs) is essential to develop sustainable strategies combatting this threat. Here, we use metagenomic sequencing to analyse ARGs in 757 sewage samples from 243 cities in 101 countries, collected from 2016 to 2019. We find regional patterns in resistomes, and these differ between subsets corresponding to drug classes and are partly driven by taxonomic variation. The genetic environments of 49 common ARGs are highly diverse, with most common ARGs carried by multiple distinct genomic contexts globally and sometimes on plasmids. Analysis of flanking sequence revealed ARG-specific patterns of dispersal limitation and global transmission. Our data furthermore suggest certain geographies are more prone to transmission events and should receive additional attention.
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| 13. |
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| 14. |
- Ackley, K., et al.
(författare)
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Observational constraints on the optical and near-infrared emission from the neutron star-black hole binary merger candidate S190814bv
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 643
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Tidskriftsartikel (refereegranskat)abstract
- Context. Gravitational wave (GW) astronomy has rapidly reached maturity, becoming a fundamental observing window for modern astrophysics. The coalescences of a few tens of black hole (BH) binaries have been detected, while the number of events possibly including a neutron star (NS) is still limited to a few. On 2019 August 14, the LIGO and Virgo interferometers detected a high-significance event labelled S190814bv. A preliminary analysis of the GW data suggests that the event was likely due to the merger of a compact binary system formed by a BH and a NS.Aims. In this paper, we present our extensive search campaign aimed at uncovering the potential optical and near infrared electromagnetic counterpart of S190814bv. We found no convincing electromagnetic counterpart in our data. We therefore use our non-detection to place limits on the properties of the putative outflows that could have been produced by the binary during and after the merger.Methods. Thanks to the three-detector observation of S190814bv, and given the characteristics of the signal, the LIGO and Virgo Collaborations delivered a relatively narrow localisation in low latency - a 50% (90%) credible area of 5 deg(2) (23 deg(2)) - despite the relatively large distance of 26752 Mpc. ElectromagNetic counterparts of GRAvitational wave sources at the VEry Large Telescope collaboration members carried out an intensive multi-epoch, multi-instrument observational campaign to identify the possible optical and near infrared counterpart of the event. In addition, the ATLAS, GOTO, GRAWITA-VST, Pan-STARRS, and VINROUGE projects also carried out a search on this event. In this paper, we describe the combined observational campaign of these groups.Results. Our observations allow us to place limits on the presence of any counterpart and discuss the implications for the kilonova (KN), which was possibly generated by this NS-BH merger, and for the strategy of future searches. The typical depth of our wide-field observations, which cover most of the projected sky localisation probability (up to 99.8%, depending on the night and filter considered), is r similar to 22 (resp. K similar to 21) in the optical (resp. near infrared). We reach deeper limits in a subset of our galaxy-targeted observations, which cover a total similar to 50% of the galaxy-mass-weighted localisation probability. Altogether, our observations allow us to exclude a KN with large ejecta mass M greater than or similar to 0.1 M-circle dot to a high (> 90%) confidence, and we can exclude much smaller masses in a sub-sample of our observations. This disfavours the tidal disruption of the neutron star during the merger.Conclusions. Despite the sensitive instruments involved in the campaign, given the distance of S190814bv, we could not reach sufficiently deep limits to constrain a KN comparable in luminosity to AT 2017gfo on a large fraction of the localisation probability. This suggests that future (likely common) events at a few hundred megaparsecs will be detected only by large facilities with both a high sensitivity and large field of view. Galaxy-targeted observations can reach the needed depth over a relevant portion of the localisation probability with a smaller investment of resources, but the number of galaxies to be targeted in order to get a fairly complete coverage is large, even in the case of a localisation as good as that of this event.
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| 15. |
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| 16. |
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| 17. |
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| 18. |
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| 19. |
- Bosson, J. K., et al.
(författare)
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Psychometric Properties and Correlates of Precarious Manhood Beliefs in 62 Nations
- 2021
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Ingår i: Journal of Cross-Cultural Psychology. - : SAGE Publications. - 0022-0221 .- 1552-5422. ; 52:3
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Tidskriftsartikel (refereegranskat)abstract
- Precarious manhood beliefs portray manhood, relative to womanhood, as a social status that is hard to earn, easy to lose, and proven via public action. Here, we present cross-cultural data on a brief measure of precarious manhood beliefs (the Precarious Manhood Beliefs scale [PMB]) that covaries meaningfully with other cross-culturally validated gender ideologies and with country-level indices of gender equality and human development. Using data from university samples in 62 countries across 13 world regions (N = 33,417), we demonstrate: (1) the psychometric isomorphism of the PMB (i.e., its comparability in meaning and statistical properties across the individual and country levels); (2) the PMB's distinctness from, and associations with, ambivalent sexism and ambivalence toward men; and (3) associations of the PMB with nation-level gender equality and human development. Findings are discussed in terms of their statistical and theoretical implications for understanding widely-held beliefs about the precariousness of the male gender role.
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| 20. |
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| 21. |
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| 22. |
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| 23. |
- 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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| 24. |
- Eijsbouts, C., et al.
(författare)
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Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders
- 2021
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53:11, s. 1543-1552
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Tidskriftsartikel (refereegranskat)abstract
- Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS. © 2021, The Author(s).
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| 25. |
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| 26. |
- Kurki, MI, et al.
(författare)
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FinnGen provides genetic insights from a well-phenotyped isolated population
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 613:7944, s. 508-
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Tidskriftsartikel (refereegranskat)abstract
- Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
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| 27. |
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| 28. |
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| 29. |
- 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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| 30. |
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| 31. |
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| 32. |
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| 33. |
- Dareng, EO, et al.
(författare)
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Polygenic risk modeling for prediction of epithelial ovarian cancer risk
- 2022
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Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 30:3, s. 349-362
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
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| 34. |
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| 35. |
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| 36. |
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| 37. |
- Barnes, DR, et al.
(författare)
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Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores
- 2022
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 114:1, s. 109-122
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundRecent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.Methods483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)–negative (PRSER-), or ER-positive (PRSER+) breast cancer risk.ResultsPRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.ConclusionsPopulation-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.
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| 38. |
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| 39. |
- Coignard, J, et al.
(författare)
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A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 1078-
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
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| 40. |
- Osborn, H. P., et al.
(författare)
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Two warm Neptunes transiting HIP 9618 revealed by TESS and Cheops
- 2023
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Ingår i: Monthly Notices of the Royal Astronomical Society. - 0035-8711 .- 1365-2966. ; 523:2, s. 3069-3089
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Tidskriftsartikel (refereegranskat)abstract
- HIP 9618 (HD 12572, TOI-1471, TIC 306263608) is a bright (G = 9.0 mag) solar analogue. TESS photometry revealed the star to have two candidate planets with radii of 3.9 ± 0.044 R (HIP 9618 b) and 3.343 ± 0.039 R (HIP 9618 c). While the 20.77291 d period of HIP 9618 b was measured unambiguously, HIP 9618 c showed only two transits separated by a 680-d gap in the time series, leaving many possibilities for the period. To solve this issue, CHEOPS performed targeted photometry of period aliases to attempt to recover the true period of planet c, and successfully determined the true period to be 52.56349 d. High-resolution spectroscopy with HARPS-N, SOPHIE, and CAFE revealed a mass of 10.0 ± 3.1M for HIP 9618 b, which, according to our interior structure models, corresponds to a 6.8 ± 1.4 per cent gas fraction. HIP 9618 c appears to have a lower mass than HIP 9618 b, with a 3-sigma upper limit of <18M. Follow-up and archival RV measurements also reveal a clear long-term trend which, when combined with imaging and astrometric information, reveal a low-mass companion (0.08+−000512M☉) orbiting at 26.0+−111900 au. This detection makes HIP 9618 one of only five bright (K < 8 mag) transiting multiplanet systems known to host a planet with P > 50 d, opening the door for the atmospheric characterization of warm (Teq < 750 K) sub-Neptunes.
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| 41. |
- Hoyer, S., et al.
(författare)
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TOI-220b: a warm sub-Neptune discovered by TESS
- 2021
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 505:3, s. 3361-3379
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, we report the discovery of TOI-220b, a new sub-Neptune detected by the Transiting Exoplanet Survey Satellite (TESS) and confirmed by radial velocity follow-up observations with the HARPS spectrograph. Based on the combined analysis of TESS transit photometry and high precision radial velocity measurements, we estimate a planetary mass of 13.8 +/- 1.0M(circle plus) and radius of 3.03 +/- 0.15R(circle plus), implying a bulk density of 2.73 +/- 0.47. TOI-220b orbits a relative bright (V=10.4) and old (10.1 +/- 1.4Gyr) K dwarf star with a period of similar to 10.69d. Thus, TOI-220b is a new warm sub-Neptune with very precise mass and radius determinations. A Bayesian analysis of the TOI-220b internal structure indicates that due to the strong irradiation it receives, the low density of this planet could be explained with a steam atmosphere in radiative-convective equilibrium and a supercritical water layer on top of a differentiated interior made of a silicate mantle and a small iron core.
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| 42. |
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| 43. |
- Hawthorn, F., et al.
(författare)
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TOI-836: A super-Earth and mini-Neptune transiting a nearby K-dwarf
- 2023
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 520:3, s. 3649-3668
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Tidskriftsartikel (refereegranskat)abstract
- We present the discovery of two exoplanets transiting TOI-836 (TIC 440887364) using data from TESS Sector 11 and Sector 38. TOI-836 is a bright (T = 8.5 mag), high proper motion (∼200 mas yr−1), low metallicity ([Fe/H]≈−0.28) K-dwarf with a mass of 0.68 ± 0.05 M and a radius of 0.67 ± 0.01 R. We obtain photometric follow-up observations with a variety of facilities, and we use these data sets to determine that the inner planet, TOI-836 b, is a 1.70 ± 0.07 R super-Earth in a 3.82-d orbit, placing it directly within the so-called ‘radius valley’. The outer planet, TOI-836 c, is a 2.59 ± 0.09 R mini-Neptune in an 8.60-d orbit. Radial velocity measurements reveal that TOI-836 b has a mass of 4.5 ± 0.9 M, while TOI-836 c has a mass of 9.6 ± 2.6 M. Photometric observations show Transit Timing Variations (TTVs) on the order of 20 min for TOI-836 c, although there are no detectable TTVs for TOI-836 b. The TTVs of planet TOI-836 c may be caused by an undetected exterior planet.
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| 44. |
- Saevarsdottir, S., et al.
(författare)
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Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
- 2022
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:8
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
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| 45. |
- Bluhm, P., et al.
(författare)
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Precise mass and radius of a transiting super-Earth planet orbiting the M dwarf TOI-1235: a planet in the radius gap?
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 639
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Tidskriftsartikel (refereegranskat)abstract
- We report the confirmation of a transiting planet around the bright weakly active M0.5 V star TOI-1235 (TYC 4384-1735-1, V ≈ 11.5 mag), whose transit signal was detected in the photometric time series of sectors 14, 20, and 21 of the TESS space mission. We confirm the planetary nature of the transit signal, which has a period of 3.44 d, by using precise RV measurements with the CARMENES, HARPS-N, and iSHELL spectrographs, supplemented by high-resolution imaging and ground-based photometry. A comparison of the properties derived for TOI-1235 b with theoretical models reveals that the planet has a rocky composition, with a bulk density slightly higher than that of Earth. In particular, we measure a mass of Mp = 5.9 ± 0.6 M⊕ and a radius of Rp = 1.69 ± 0.08 R⊕, which together result in a density of ρp = 6.7- 1.1+ 1.3 g cm-3. When compared with other well-characterized exoplanetary systems, the particular combination of planetary radius and mass places our discovery in the radius gap, which is a transition region between rocky planets and planets with significant atmospheric envelopes. A few examples of planets occupying the radius gap are known to date. While the exact location of the radius gap for M dwarfs is still a matter of debate, our results constrain it to be located at around 1.7 R⊕ or larger at the insolation levels received by TOI-1235 b (~60 S⊕). This makes it an extremely interesting object for further studies of planet formation and atmospheric evolution.
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| 46. |
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| 47. |
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| 48. |
- Surendran, Praveen, et al.
(författare)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 49. |
- Bédard, A., et al.
(författare)
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Treatment of allergic rhinitis during and outside the pollen season using mobile technology : A MASK study
- 2020
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Ingår i: Clinical and Translational Allergy. - : Wiley. - 2045-7022. ; 10:1
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Forskningsöversikt (refereegranskat)abstract
- BackgroundThe analysis of mobile health (mHealth) data has generated innovative insights into improving allergic rhinitis control, but additive information is needed. A cross-sectional real-world observational study was undertaken in 17 European countries during and outside the estimated pollen season. The aim was to collect novel information including the phenotypic characteristics of the users.MethodsThe Allergy Diary–MASK-air–mobile phone app, freely available via Google Play and App, was used to collect the data of daily visual analogue scales (VASs) for overall allergic symptoms and medication use. Fluticasone Furoate (FF), Mometasone Furoate (MF), Azelastine Fluticasone Proprionate combination (MPAzeFlu) and eight oral H1-antihistamines were studied. Phenotypic characteristics were recorded at entry. The ARIA severity score was derived from entry data. This was an a priori planned analysis.Results9037 users filled in 70,286 days of VAS in 2016, 2017 and 2018. The ARIA severity score was lower outside than during the pollen season. Severity was similar for all treatment groups during the pollen season, and lower in the MPAzeFlu group outside the pollen season. Days with MPAzeFlu had lower VAS levels and a higher frequency of monotherapy than the other treatments during the season. Outside the season, days with MPAzeFlu also had a higher frequency of monotherapy. The number of reported days was significantly higher with MPAzeFlu during and outside the season than with MF, FF or oral H1-antihistamines.ConclusionsThis study shows that the overall efficacy of treatments is similar during and outside the pollen season and indicates that medications are similarly effective during the year.
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| 50. |
- Klimek, L, et al.
(författare)
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Anwendung von Biologika bei allergischen und Typ-2-entzündlichen Erkrankungen in der aktuellen Covid-19-Pandemiea, b, c: Positionspapier des Ärzteverbands Deutscher Allergologen (AeDA)A, der Deutschen Gesellschaft für Allergologie und klinische Immunologie (DGAKI)B, der Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA)C, der Österreichischen Gesellschaft für Allergologie und Immunologie (ÖGAI)D, der Luxemburgischen Gesellschaft für Allergologie und Immunologie (LGAI)E, der Österreichischen Gesellschaft für Pneumologie (ÖGP)F in Kooperation mit der deutschen, österreichischen, und schweizerischen ARIA-GruppeG und der Europäischen Akademie für Allergologie und Klinische Immunologie (EAACI)H
- 2020
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Ingår i: Allergo Journal : interdisziplinare Zeitschrift fur Allergologie und Umweltmedizin : Organ der Deutschen Gesellschaft fur Allergie- und Immunitatsforschung. - : Springer Science and Business Media LLC. - 0941-8849. ; 29:4, s. 14-27
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Tidskriftsartikel (refereegranskat)
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