| 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. |
- Namkoong, H, et al.
(författare)
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DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
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| 5. |
- 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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| 6. |
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| 7. |
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| 8. |
- 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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| 9. |
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| 10. |
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| 11. |
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| 12. |
- Carninci, P, et al.
(författare)
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The transcriptional landscape of the mammalian genome
- 2005
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 309:5740, s. 1559-1563
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Tidskriftsartikel (refereegranskat)abstract
- This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5′ and 3′ boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
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| 13. |
- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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| 14. |
- Polme, S., et al.
(författare)
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FungalTraits: a user-friendly traits database of fungi and fungus-like stramenopiles
- 2020
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Ingår i: Fungal Diversity. - : Springer Science and Business Media LLC. - 1560-2745 .- 1878-9129. ; 105:1, s. 1-16
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Tidskriftsartikel (refereegranskat)abstract
- The cryptic lifestyle of most fungi necessitates molecular identification of the guild in environmental studies. Over the past decades, rapid development and affordability of molecular tools have tremendously improved insights of the fungal diversity in all ecosystems and habitats. Yet, in spite of the progress of molecular methods, knowledge about functional properties of the fungal taxa is vague and interpretation of environmental studies in an ecologically meaningful manner remains challenging. In order to facilitate functional assignments and ecological interpretation of environmental studies we introduce a user friendly traits and character database FungalTraits operating at genus and species hypothesis levels. Combining the information from previous efforts such as FUNGuild and Fun(Fun) together with involvement of expert knowledge, we reannotated 10,210 and 151 fungal and Stramenopila genera, respectively. This resulted in a stand-alone spreadsheet dataset covering 17 lifestyle related traits of fungal and Stramenopila genera, designed for rapid functional assignments of environmental studies. In order to assign the trait states to fungal species hypotheses, the scientific community of experts manually categorised and assigned available trait information to 697,413 fungal ITS sequences. On the basis of those sequences we were able to summarise trait and host information into 92,623 fungal species hypotheses at 1% dissimilarity threshold.
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| 15. |
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| 16. |
- Asano, H., et al.
(författare)
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Spectroscopic study of the Λ(1405) resonance via the d (K-, n) reaction at J-PARC
- 2019
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Ingår i: 13th International Conference on Hypernuclear and Strange Particle Physics, HYP 2018. - : AIP Publishing. - 9780735418721 ; 2130
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Konferensbidrag (refereegranskat)abstract
- The structure of the Λ(1405) hyperon is an important and long-standing issue related to the K̄-nucleus interaction. The J-PARC E31 experiment has been performed to investigate the Λ(1405) spectrum shape. Because it is hard to form the Λ(1405) directly by a K̄N scattering in free space, E31 uses the d(K-, n) reaction with an incident kaon momentum of 1 GeV/c. We will identify three final states - ς-π+, ς+π-, ς0π0-so that the isospin structure of hyperon resonance states produced can be decomposed. The first physics run of the E31 experiment was performed in 2016. To enhance the statistics of the data set, we have performed the second physics run in the beginning of 2018. During the second run of E31, around 3.9×1010 kaons impacted on the deuteron target.
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| 17. |
- Imanishi, T., et al.
(författare)
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Integrative annotation of 21,037 human genes validated by full-length cDNA clones
- 2004
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Ingår i: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 2:6, s. 856-875
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Tidskriftsartikel (refereegranskat)abstract
- The human genome sequence defines our inherent biological potential; the realization of the biology encoded therein requires knowledge of the function of each gene. Currently, our knowledge in this area is still limited. Several lines of investigation have been used to elucidate the structure and function of the genes in the human genome. Even so, gene prediction remains a difficult task, as the varieties of transcripts of a gene may vary to a great extent. We thus performed an exhaustive integrative characterization of 41,118 full-length cDNAs that capture the gene transcripts as complete functional cassettes, providing an unequivocal report of structural and functional diversity at the gene level. Our international collaboration has validated 21,037 human gene candidates by analysis of high-quality full-length cDNA clones through curation using unified criteria. This led to the identification of 5,155 new gene candidates. It also manifested the most reliable way to control the quality of the cDNA clones. We have developed a human gene database, called the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/). It provides the following: integrative annotation of human genes, description of gene structures, details of novel alternative splicing isoforms, non-protein-coding RNAs, functional domains, subcellular localizations, metabolic pathways, predictions of protein three-dimensional structure, mapping of known single nucleotide polymorphisms (SNPs), identification of polymorphic microsatellite repeats within human genes, and comparative results with mouse full-length cDNAs. The H-InvDB analysis has shown that up to 4% of the human genome sequence (National Center for Biotechnology Information build 34 assembly) may contain misassembled or missing regions. We found that 6.5% of the human gene candidates (1,377 loci) did not have a good protein-coding open reading frame, of which 296 loci are strong candidates for non-protein-coding RNA genes. In addition, among 72,027 uniquely mapped SNPs and insertions/deletions localized within human genes, 13,215 nonsynonymous SNPs, 315 nonsense SNPs, and 452 indels occurred in coding regions. Together with 25 polymorphic microsatellite repeats present in coding regions, they may alter protein structure, causing phenotypic effects or resulting in disease. The H-InvDB platform represents a substantial contribution to resources needed for the exploration of human biology and pathology.
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| 18. |
- 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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| 19. |
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| 20. |
- Winkler, TW, et al.
(författare)
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Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals
- 2022
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 580-
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
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| 21. |
- Yamaga, Takumi, et al.
(författare)
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Study of the elementary (K -, n) reactions to search for the K NN bound state via the 3He (K -, n) reaction at J-PARC
- 2016
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Ingår i: XVIth International Conference on Hadron Spectroscopy, Hadron 2015. - : Author(s). - 9780735413894 ; 1735
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Konferensbidrag (refereegranskat)abstract
- We have searched for the simplest kaonic nuclear state, K̄NN, using the in-flight 3He (K-, n) reaction at the J-PARC hadron experimental facility. In the semi-inclusive neutron missing-mass spectrum at θnlab=0°, an excess of yield was observed just below the K- pp mass-threshold, which cannot be explained by any elementary reactions [PTEP 2015, 061D01]. To understand the missing-mass spectrum of 3He (K-, n) X, we investigated the elementary (K-, n) reactions using hydrogen and deuterium targets. The p (K-, n) X missing-mass spectrum was well described by the charge-exchange reaction. However, in the d (K-, n) X spectrum, we observed an excess of yield just below the K- p mass-threshold, which was similar to that in the 3He (K-, n) X spectrum.
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| 22. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 23. |
- Adolph, C., et al.
(författare)
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Azimuthal asymmetries of charged hadrons produced in high-energy muon scattering off longitudinally polarised deuterons
- 2018
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Ingår i: European Physical Journal C. - : SPRINGER. - 1434-6044 .- 1434-6052. ; 78:11
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Tidskriftsartikel (refereegranskat)abstract
- Single hadron azimuthal asymmetries of positive and negative hadrons produced in muon semi-inclusive deep inelastic scattering off longitudinally polarised deuterons are determined using the 2006 COMPASS data and also combined all deuteron COMPASS data. For each hadron charge, the dependence of the azimuthal asymmetry on the hadron azimuthal angle f is obtained by means of a fiveparameter fitting function that besides a f-independent term includes four modulations predicted by theory: sin f, sin 2f, sin 3f and cos f. The amplitudes of the five terms have been extracted, first, for the hadrons in the whole available kinematic region. In further fits, performed for hadrons from a restricted kinematic region, the f-dependence is determined as a function of one of three variables (Bjorken-x, fractional energy of virtual photon taken by the outgoing hadron and hadron transverse momentum), while disregarding the others. Except thef-independent term, all themodulation amplitudes are very small, and no clear kinematic dependence could be observed within experimental uncertainties.
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| 24. |
- Adolph, C., et al.
(författare)
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Final COMPASS results on the deuteron spin-dependent structure function g(1)(d) and the Bjorken sum rule
- 2017
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Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 769, s. 34-41
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Tidskriftsartikel (refereegranskat)abstract
- Final results are presented from the inclusive measurement of deep-inelastic polarised-muon scattering on longitudinally polarised deuterons using a 6LiD target. The data were taken at 160 GeV beam energy and the results are shown for the kinematic range 1 (GeV/c)2 < Q2 < 100 (GeV/c)2 in photon virtuality, 0.004 < x < 0.7 in the Bjorken scaling variable and W > 4GeV/c2 in the mass of the hadronic final state. The deuteron double-spin asymmetry A(1)(d) and the deuteron longitudinal-spin structure function g(1)(d) are presented in bins of x and Q2. Towards lowest accessible values of x, g(1)(d) decreases and becomes consistent with zero within uncertainties. The presented final g(1)(p) values together with the recently published final g(1)(p) values of COMPASS are used to again evaluate the Bjorken sum rule and perform the QCD fit to the g1 world data at next-to-leading order of the strong coupling constant. In both cases, changes in central values of the resulting numbers are well within statistical uncertainties. The flavour singlet axial charge a0, which is identified in the MS renormalisation scheme with the total contribution of quark helicities to the nucleon spin, is extracted at next-to-leading order accuracy from only the COMPASS deuteron data: a0(Q2 = 3 (GeV/c)2) = 0.32 +/- 0.02stat +/- 0.04syst +/- 0.05evol. Together with the recent results on the proton spin structure function g(1)(p), the results on g(1)(d) constitute the COMPASS legacy on the measurements of g1 through inclusive spin-dependent deep inelastic scattering.
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| 25. |
- Adolph, C., et al.
(författare)
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First measurement of the Sivers asymmetry for gluons using SIDIS data
- 2017
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Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 772, s. 854-864
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Tidskriftsartikel (refereegranskat)abstract
- The Sivers function describes the correlation between the transverse spin of a nucleon and the transverse motion of its partons. For quarks, it was studied in previous measurements of the azimuthal asymmetry of hadrons produced in semi-inclusive deep inelastic scattering of leptons off transversely polarised nucleon targets, and it was found to be non-zero. In this letter the evaluation of the Sivers asymmetry for gluons is presented. The contribution of the photon-gluon fusion subprocess is enhanced by requiring two high transverse-momentum hadrons. The analysis method is based on a Monte Carlo simulation that includes three hard processes: photon-gluon fusion, QCD Compton scattering and the leading-order virtual-photon absorption process. The Sivers asymmetries of the three processes are simultaneously extracted using the LEPTO event generator and a neural network approach. The method is applied to samples of events containing at least two hadrons with large transverse momentum from the COMPASS data taken with a 160 GeV/c muon beam scattered off transversely polarised deuterons and protons. With a significance of about two standard deviations, a negative value is obtained for the gluon Sivers asymmetry. The result of a similar analysis for a Collins-like asymmetry for gluons is consistent with zero. (C) 2017 The Author(s). Published by Elsevier B.V.
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