| 1. |
- Kanoni, Stavroula, et al.
(author)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Journal article (peer-reviewed)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 2. |
- Dam, Veerle, et al.
(author)
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Genetically Determined Reproductive Aging and Coronary Heart Disease : A Bidirectional 2-sample Mendelian Randomization
- 2022
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In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 107:7, s. E2952-E2961
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Journal article (peer-reviewed)abstract
- Background: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause. Objectives: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men. Design: Two-sample MR, using both cohort data as well as summary statistics, with 4 methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression. Participants: Data from EPIC-CVD and summary statistics from UK Biobank and publicly available genome-wide association studies were pooled for the different analyses. Main Outcome Measures: CHD, CHD risk factors, and ANM. Results: Across different methods of MR, no association was found between genetically determined reproductive aging and CHD risk in women (relative risk estimateIVW = 0.99; 95% confidence interval (CI), 0.97-1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging. Conclusion: Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men.
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| 3. |
- Ward, James P.J., et al.
(author)
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Stable silicon isotopes uncover a mineralogical control on the benthic silicon cycle in the Arctic Barents Sea
- 2022
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In: Geochimica et Cosmochimica Acta. - : Elsevier BV. - 0016-7037. ; 329, s. 206-230
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Journal article (peer-reviewed)abstract
- Biogeochemical cycling of silicon (Si) in the Barents Sea is under considerable pressure from physical and chemical changes, including dramatic warming and sea ice retreat, together with a decline in dissolved silicic acid (DSi) concentrations of Atlantic inflow waters since 1990. Associated changes in the community composition of phytoplankton blooms will alter the material comprising the depositional flux, which will subsequently influence recycling processes at and within the seafloor. In this study we assess the predominant controls on the early diagenetic cycling of Si, a key nutrient in marine ecosystems, by combining stable isotopic analysis (δ30Si) of pore water DSi and of operationally defined reactive pools of the solid phase. We show that low biogenic silica (BSi) contents (0.26–0.52 wt% or 92–185 μmol g dry wt−1) drive correspondingly low asymptotic concentrations of pore water DSi of ∼100 μM, relative to biosiliceous sediments (>20 wt% BSi) wherein DSi can reach ∼900 μM. While Barents Sea surface sediments appear almost devoid of BSi, we present evidence for the rapid recycling of bloom derived BSi that generates striking transient peaks in sediment pore water [DSi] of up to 300 μM, which is a feature that is subject to future shifts in phytoplankton community compositions. Using a simple isotopic mass balance calculation we show that at two of three stations the pore water DSi pool at 0.5 cm below the seafloor (+0.96 to +1.36 ‰) is sourced from the mixing of core top waters (+1.46 to +1.69 ‰) with the dissolution of BSi (+0.82 to +1.50 ‰), supplemented with a lithogenic Si source (LSi) (−0.89 ±0.16‰). Further, our sediment pore water δ30Si profiles uncover a coupling of the Si cycle with the redox cycling of metal oxides associated with isotopically light Si (−2.88 ±0.17‰). We suggest that a high LSi:BSi ratio and apparent metal oxide influence could lead to a degree of stability in the annual background benthic flux of DSi, despite current pressures on pelagic phytoplankton communities. Coupled with supporting isotopic evidence for the precipitation of authigenic clays in Barents Sea sediment cores, our observations have implications for the regional Si budget.
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