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- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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- 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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- 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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- Shah, S, et al.
(författare)
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Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 163-
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Tidskriftsartikel (refereegranskat)abstract
- Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
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- Bulut, N., et al.
(författare)
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Gas phase Elemental abundances in Molecular cloudS (GEMS): III. Unlocking the CS chemistry: The CS+O reaction
- 2021
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 646
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Tidskriftsartikel (refereegranskat)abstract
- Context. Carbon monosulphide (CS) is among the most abundant gas-phase S-bearing molecules in cold dark molecular clouds. It is easily observable with several transitions in the millimeter wavelength range, and has been widely used as a tracer of the gas density in the interstellar medium in our Galaxy and external galaxies. However, chemical models fail to account for the observed CS abundances when assuming the cosmic value for the elemental abundance of sulfur. Aims. The CS+O → CO + S reaction has been proposed as a relevant CS destruction mechanism at low temperatures, and could explain the discrepancy between models and observations. Its reaction rate has been experimentally measured at temperatures of 150-400 K, but the extrapolation to lower temperatures is doubtful. Our goal is to calculate the CS+O reaction rate at temperatures <150 K which are prevailing in the interstellar medium. Methods. We performed ab initio calculations to obtain the three lowest potential energy surfaces (PES) of the CS+O system. These PESs are used to study the reaction dynamics, using several methods (classical, quantum, and semiclassical) to eventually calculate the CS + O thermal reaction rates. In order to check the accuracy of our calculations, we compare the results of our theoretical calculations for T ~ 150-400 K with those obtained in the laboratory. Results. Our detailed theoretical study on the CS+O reaction, which is in agreement with the experimental data obtained at 150-400 K, demonstrates the reliability of our approach. After a careful analysis at lower temperatures, we find that the rate constant at 10 K is negligible, below 10-15 cm s-1, which is consistent with the extrapolation of experimental data using the Arrhenius expression. Conclusions. We use the updated chemical network to model the sulfur chemistry in Taurus Molecular Cloud 1 (TMC 1) based on molecular abundances determined from Gas phase Elemental abundances in Molecular CloudS (GEMS) project observations. In our model, we take into account the expected decrease of the cosmic ray ionization rate, ζH2, along the cloud. The abundance of CS is still overestimated when assuming the cosmic value for the sulfur abundance.
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- Rodríguez-Baras, M., et al.
(författare)
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Gas phase Elemental abundances in Molecular cloudS (GEMS): IV. Observational results and statistical trends
- 2021
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 648
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Tidskriftsartikel (refereegranskat)abstract
- Gas phase Elemental abundances in Molecular CloudS (GEMS) is an IRAM 30 m Large Program designed to provide estimates of the S, C, N, and O depletions and gas ionization degree, X(e-), in a selected set of star-forming filaments of Taurus, Perseus, and Orion. Our immediate goal is to build up a complete and large database of molecular abundances that can serve as an observational basis for estimating X(e-) and the C, O, N, and S depletions through chemical modeling. We observed and derived the abundances of 14 species (13CO, C18O, HCO+, H13CO+, HC18O+, HCN, H13CN, HNC, HCS+, CS, SO, 34SO, H2S, and OCS) in 244 positions, covering the AV ~3 to ~100 mag, n(H2) ~ a few 103 to 106 cm-3, and Tk ~10 to ~30 K ranges in these clouds, and avoiding protostars, HII regions, and bipolar outflows. A statistical analysis is carried out in order to identify general trends between different species and with physical parameters. Relations between molecules reveal strong linear correlations which define three different families of species: (1) 13CO and C18O isotopologs; (2) H13CO+, HC18O+, H13 CN, and HNC; and (3) the S-bearing molecules. The abundances of the CO isotopologs increase with the gas kinetic temperature until TK ~ 15 K. For higher temperatures, the abundance remains constant with a scatter of a factor of ~3. The abundances of H13 CO+, HC18 O+, H13 CN, and HNC are well correlated with each other, and all of them decrease with molecular hydrogen density, following the law ∝ n(H2)-0.8 ± 0.2. The abundances of S-bearing species also decrease with molecular hydrogen density at a rate of (S-bearing/H)gas ∝ n(H2)-0.6 ± 0.1. The abundances of molecules belonging to groups 2 and 3 do not present any clear trend with gas temperature. At scales of molecular clouds, the C18O abundance is the quantity that better correlates with the cloud mass. We discuss the utility of the 13CO/C18O, HCO+/H13CO+, and H13 CO+/H13CN abundance ratios as chemical diagnostics of star formation in external galaxies.
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- Zhou, S. R., et al.
(författare)
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Converging evidence from exome sequencing and common variants implicates target genes for osteoporosis
- 2023
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Ingår i: Nature Genetics. - 1061-4036. ; 55:8, s. 1277-87
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we leveraged the combined evidence of rare coding variants and common alleles to identify therapeutic targets for osteoporosis. We undertook a large-scale multiancestry exome-wide association study for estimated bone mineral density, which showed that the burden of rare coding alleles in 19 genes was associated with estimated bone mineral density (P<3.6x10(-7)). These genes were highly enriched for a set of known causal genes for osteoporosis (65-fold; P=2.5x10(-5)). Exome-wide significant genes had 96-fold increased odds of being the top ranked effector gene at a given GWAS locus (P=1.8x10(-10)). By integrating proteomics Mendelian randomization evidence, we prioritized CD109 (cluster of differentiation 109) as a gene for which heterozygous loss of function is associated with higher bone density. CRISPR-Cas9 editing of CD109 in SaOS-2 osteoblast-like cell lines showed that partial CD109 knockdown led to increased mineralization. This study demonstrates that the convergence of common and rare variants, proteomics and CRISPR can highlight new bone biology to guide therapeutic development. Analysis of exome sequencing data identifies a burden of rare coding variants in 19 genes associated with bone mineral density. Integrated analyses show convergence of common- and rare-variant signals and highlight likely effector genes influencing osteoporosis risk.
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