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- Jungclaus, Johann H., et al.
(författare)
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The PMIP4 contribution to CMIP6 - Part 3 : The last millennium, scientific objective, and experimental design for the PMIP4 past1000 simulations
- 2017
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Ingår i: Geoscientific Model Development. - : Copernicus GmbH. - 1991-959X .- 1991-9603. ; 10:11, s. 4005-4033
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Tidskriftsartikel (refereegranskat)abstract
- The pre-industrial millennium is among the periods selected by the Paleoclimate Model Intercomparison Project (PMIP) for experiments contributing to the sixth phase of the Coupled Model Intercomparison Project (CMIP6) and the fourth phase of the PMIP (PMIP4). The past1000 transient simulations serve to investigate the response to (mainly) natural forcing under background conditions not too different from today, and to discriminate between forced and internally generated variability on interannual to centennial timescales. This paper describes the motivation and the experimental set-ups for the PMIP4-CMIP6 past1000 simulations, and discusses the forcing agents orbital, solar, volcanic, and land use/land cover changes, and variations in greenhouse gas concentrations. The past1000 simulations covering the pre-industrial millennium from 850 Common Era (CE) to 1849 CE have to be complemented by historical simulations (1850 to 2014 CE) following the CMIP6 protocol. The external forcings for the past1000 experiments have been adapted to provide a seamless transition across these time periods. Protocols for the past1000 simulations have been divided into three tiers. A default forcing data set has been defined for the Tier 1 (the CMIP6 past1000) experiment. However, the PMIP community has maintained the flexibility to conduct coordinated sensitivity experiments to explore uncertainty in forcing reconstructions as well as parameter uncertainty in dedicated Tier 2 simulations. Additional experiments (Tier 3) are defined to foster collaborative model experiments focusing on the early instrumental period and to extend the temporal range and the scope of the simulations. This paper outlines current and future research foci and common analyses for collaborative work between the PMIP and the observational communities (reconstructions, instrumental data).
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- 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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- Chattopadhyay, Subhayan, et al.
(författare)
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Enrichment of B cell receptor signaling and epidermal growth factor receptor pathways in monoclonal gammopathy of undetermined significance : a genome-wide genetic interaction study
- 2018
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Ingår i: Molecular Medicine. - : Springer Science and Business Media LLC. - 1528-3658 .- 1076-1551. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recent identification of 10 germline variants predisposing to monoclonal gammopathy of undetermined significance (MGUS) explicates genetic dependency of this asymptomatic precursor condition with multiple myeloma (MM). Yet much of genetic burden as well as functional links remain unexplained. We propose a workflow to expand the search for susceptibility loci with genome-wide interaction and for subsequent identification of genetic clusters and pathways.METHODS: Polygenic interaction analysis on 243 cases/1285 controls identified 14 paired risk loci belonging to unique chromosomal bands which were then replicated in two independent sets (case only study, 82 individuals; case/control study 236 cases/ 2484 controls). Further investigation on gene-set enrichment, regulatory pathway and genetic network was carried out with stand-alone in silico tools separately for both interaction and genome-wide association study-detected risk loci.RESULTS: Intronic-PREX1 (20q13.13), a reported locus predisposing to MM was confirmed to have contribution to excess MGUS risk in interaction with SETBP1, a well-established candidate predisposing to myeloid malignancies. Pathway enrichment showed B cell receptor signaling pathway (P < 5.3 × 10- 3) downstream to allograft rejection pathway (P < 5.6 × 10- 4) and autoimmune thyroid disease pathway (P < 9.3 × 10- 4) as well as epidermal growth factor receptor regulation pathway (P < 2.4 × 10- 2) to be differentially regulated. Oncogene ALK and CDH2 were also identified to be moderately interacting with rs10251201 and rs16966921, two previously reported risk loci for MGUS.CONCLUSIONS: We described novel pathways and variants potentially causal for MGUS. The methodology thus proposed to facilitate our search streamlines risk locus-based interaction, genetic network and pathway enrichment analyses.
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