| |  Online-Ressource |
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| Verfasst von: | Thormälen, Aenne Solvejg [VerfasserIn]  |
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| | Schuberth, Christian [VerfasserIn] |
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| | Blattmann, Peter Nils [VerfasserIn] |
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| | Joggerst-Thomalla, Brigitte [VerfasserIn] |
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| | Theiß, Susanne [VerfasserIn] |
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| | Pepperkok, Rainer [VerfasserIn] |
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| | Runz, Heiko [VerfasserIn] |
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| Titel: | Systematic cell-based phenotyping of missense alleles empowers rare variant association studies |
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| Titelzusatz: | a case for LDLR and myocardial infarction |
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| Verf.angabe: | Aenne S. Thormaehlen, Christian Schuberth, Hong-Hee Won, Peter Blattmann, Brigitte Joggerst-Thomalla, Susanne Theiss, Rosanna Asselta, Stefano Duga, Pier Angelica Merlini, Diego Ardissino, Eric S. Lander, Stacey Gabriel, Daniel J. Rader, Gina M. Peloso, Rainer Pepperkok, Sekar Kathiresan, Heiko Runz |
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| E-Jahr: | 2015 |
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| Jahr: | February 3, 2015 |
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| Umfang: | 23 S. |
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| Teil: | volume:11 |
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| | year:2015 |
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| | number:2 |
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| | extent:23 |
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| Fussnoten: | Gesehen am 02.07.2020 |
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| Titel Quelle: | Enthalten in: Public Library of SciencePLoS Genetics |
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| Ort Quelle: | San Francisco, Calif. : Public Library of Science, 2005 |
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| Jahr Quelle: | 2015 |
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| Band/Heft Quelle: | 11(2015,2) Artikel-Nummer e1004855, 23 Seiten |
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| ISSN Quelle: | 1553-7404 |
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| Abstract: | A fundamental challenge to contemporary genetics is to distinguish rare missense alleles that disrupt protein functions from the majority of alleles neutral on protein activities. High-throughput experimental tools to securely discriminate between disruptive and non-disruptive missense alleles are currently missing. Here we establish a scalable cell-based strategy to profile the biological effects and likely disease relevance of rare missense variants in vitro. We apply this strategy to systematically characterize missense alleles in the low-density lipoprotein receptor (LDLR) gene identified through exome sequencing of 3,235 individuals and exome-chip profiling of 39,186 individuals. Our strategy reliably identifies disruptive missense alleles, and disruptive-allele carriers have higher plasma LDL-cholesterol (LDL-C). Importantly, considering experimental data refined the risk of rare LDLR allele carriers from 4.5- to 25.3-fold for high LDL-C, and from 2.1- to 20-fold for early-onset myocardial infarction. Our study generates proof-of-concept that systematic functional variant profiling may empower rare variant-association studies by orders of magnitude. |
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| DOI: | doi:10.1371/journal.pgen.1004855 |
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| URL: | Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.
Volltext ; Verlag: https://doi.org/10.1371/journal.pgen.1004855 |
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| | Volltext: https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004855 |
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| | DOI: https://doi.org/10.1371/journal.pgen.1004855 |
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| Datenträger: | Online-Ressource |
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| Sprache: | eng |
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| Sach-SW: | Alleles |
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| | Cholesterol |
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| | Gene disruption |
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| | Gene sequencing |
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| | Lipoprotein receptors |
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| | Mutation databases |
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| | Myocardial infarction |
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| | Small interfering RNAs |
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| K10plus-PPN: | 1703213548 |
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| Verknüpfungen: | → Zeitschrift |
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Systematic cell-based phenotyping of missense alleles empowers rare variant association studies / Thormälen, Aenne Solvejg [VerfasserIn]; February 3, 2015 (Online-Ressource)
