| 1. |
- Bar, N., et al.
(author)
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A reference map of potential determinants for the human serum metabolome
- 2020
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In: Nature. - : Nature Research. - 0028-0836 .- 1476-4687. ; 588:7836, s. 135-140
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Journal article (peer-reviewed)abstract
- The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
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| 2. |
- Wilman, H. R., et al.
(author)
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Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration
- 2019
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In: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 71:3, s. 594-602
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Journal article (peer-reviewed)abstract
- Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10−8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Lay summary: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.
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| 3. |
- van Weeren, R. J., et al.
(author)
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LOFAR Facet Calibration
- 2016
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In: Astrophysical Journal, Supplement Series. - : American Astronomical Society. - 1538-4365 .- 0067-0049. ; 223:1
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Journal article (peer-reviewed)abstract
- LOFAR, the Low-Frequency Array, is a powerful new radio telescope operating between 10 and 240 MHz. LOFAR allows detailed sensitive high-resolution studies of the low-frequency radio sky. At the same time LOFAR also provides excellent short baseline coverage to map diffuse extended emission. However, producing highquality deep images is challenging due to the presence of direction-dependent calibration errors, caused by imperfect knowledge of the station beam shapes and the ionosphere. Furthermore, the large data volume and presence of station clock errors present additional difficulties. In this paper we present a new calibration scheme, which we name facet calibration, to obtain deep high-resolution LOFAR High Band Antenna images using the Dutch part of the array. This scheme solves and corrects the direction-dependent errors in a number of facets that cover the observed field of view. Facet calibration provides close to thermal noise limited images for a typical 8 hr observing run at similar to 5. resolution, meeting the specifications of the LOFAR Tier-1 northern survey.
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| 4. |
- van Weeren, R. J., et al.
(author)
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LOFAR, VLA, AND CHANDRA OBSERVATIONS OF THE TOOTHBRUSH GALAXY CLUSTER
- 2016
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In: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 818:2
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Journal article (peer-reviewed)abstract
- We present deep LOFAR observations between 120 and 181 MHz of the "Toothbrush" (RX J0603.3+ 4214), a cluster that contains one of the brightest radio relic sources known. Our LOFAR observations exploit a new and novel calibration scheme to probe 10 times deeper than any previous study in this relatively unexplored part of the spectrum. The LOFAR observations, when combined with VLA, GMRT, and Chandra X-ray data, provide new information about the nature of cluster merger shocks and their role in re-accelerating relativistic particles. We derive a spectral index of alpha = -0.8 +/- 0.1 at the northern edge of the main radio relic, steepening toward the south to alpha approximate to-2. The spectral index of the radio halo is remarkably uniform (alpha = -1.16, with an intrinsic scatter of
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| 5. |
- Huyghe, Jeroen R., et al.
(author)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Journal article (peer-reviewed)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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| 6. |
- Hu, Zhensong, et al.
(author)
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AMUSE-Antlia. I. Nuclear X-Ray Properties of Early-type Galaxies in a Dynamically Young Galaxy Cluster
- 2023
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In: Astrophysical Journal. - 1538-4357 .- 0004-637X. ; 956:2
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Journal article (peer-reviewed)abstract
- To understand the formation and growth of supermassive black holes (SMBHs) and their coevolution with host galaxies, it is essential to know the impact of environment on the activity of active galactic nuclei (AGNs). We present new Chandra X-ray observations of nuclear emission from member galaxies in the Antlia cluster, the nearest non-cool core and the nearest merging galaxy cluster, residing at D = 35.2 Mpc. Its inner region, centered on two dominant galaxies NGC 3268 and NGC 3258, has been mapped with three deep Chandra ACIS-I pointings. Nuclear X-ray sources are detected in 7/84 (8.3%) early-type galaxies (ETG) and 2/8 (25%) late-type galaxies with a median detection limit of 8 × 1038 erg s−1. All nuclear X-ray sources but one have a corresponding radio continuum source detected by MeerKAT at the L band. Nuclear X-ray sources detected in early-type galaxies are considered the genuine X-ray counterpart of low-luminosity AGN. When restricted to a detection limit of log ( L X / erg s − 1 ) ≥ 38.9 and a stellar mass of 10 ≤ log ( M ⋆ / M ⊙ ) < 11.6 , six of 11 ETGs are found to contain an X-ray AGN in Antlia, exceeding the AGN occupation fraction of 7/39 (18.0%) and 2/12 (16.7%) in the more relaxed, cool core clusters, Virgo and Fornax, respectively, and rivaling that of the AMUSE-Field ETG of 27/49 (55.1%). Furthermore, more than half of the X-ray AGN in Antlia is hosted by its younger subcluster, centered on NGC 3258. We believe that this is because SMBH activity is enhanced in a dynamically young cluster compared to relatively relaxed clusters.
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| 7. |
- Ostrander, E. A., et al.
(author)
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Dog10K : An international sequencing effort to advance studies of canine domestication, phenotypes and health
- 2019
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In: National Science Review. - : Oxford University Press (OUP). - 2095-5138 .- 2053-714X. ; 6:4, s. 810-824
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Journal article (peer-reviewed)abstract
- Dogs are the most phenotypically diverse mammalian species, and they possess more known heritable disorders than any other non-human mammal. Efforts to catalog and characterize genetic variation across well-chosen populations of canines are necessary to advance our understanding of their evolutionary history and genetic architecture. To date, no organized effort has been undertaken to sequence the world's canid populations. The Dog10K Consortium (http://www.dog10kgenomes.org) is an international collaboration of researchers from across the globe who will generate 20× whole genomes from 10 000 canids in 5 years. This effort will capture the genetic diversity that underlies the phenotypic and geographical variability of modern canids worldwide. Breeds, village dogs, niche populations and extended pedigrees are currently being sequenced, and de novo assemblies of multiple canids are being constructed. This unprecedented dataset will address the genetic underpinnings of domestication, breed formation, aging, behavior and morphological variation. More generally, this effort will advance our understanding of human and canine health.
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| 8. |
- Daly, L., et al.
(author)
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Boom boom pow : Shock-facilitated aqueous alteration and evidence for two shock events in the Martian nakhlite meteorites
- 2019
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In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 5:9
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Journal article (peer-reviewed)abstract
- Nakhlite meteorites are similar to 1.4 to 1.3 Ga old igneous rocks, aqueously altered on Mars similar to 630 Ma ago. We test the theory that water-rock interaction was impact driven. Electron backscatter diffraction demonstrates that the meteorites Miller Range 03346 and Lafayette were heterogeneously deformed, leading to localized regions of brecciation, plastic deformation, and mechanical twinning of augite. Numerical modeling shows that the pattern of deformation is consistent with shock-generated compressive and tensile stresses. Mesostasis within shocked areas was aqueously altered to phyllosilicates, carbonates, and oxides, suggesting a genetic link between the two processes. We propose that an impact similar to 630 Ma ago simultaneously deformed the nakhlite parent rocks and generated liquid water by melting of permafrost. Ensuing water-rock interaction focused on shocked mesostasis with a high density of reactive sites. The nakhlite source location must have two spatially correlated craters, one similar to 630 Ma old and another, ejecting the meteorites, similar to 11 Ma ago.
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