Heike Vogel, Anne Kamitz, Nicole Hallahan, Sandra Lebek, Tanja Schallschmidt, Wenke Jonas, Markus Jähnert, Pascal Gottmann, Lisa Zellner, Timo Kanzleiter, Mareike Damen, Delsi Altenhofen, Ralph Burkhardt, Simone Renner, Maik Dahlhoff, Eckhard Wolf, Timo Dirk Müller, Matthias Blüher, Hans-Georg Joost, Alexandra Chadt, Hadi Al-Hasani, Annette Schürmann
- To explore the genetic determinants of obesity and Type 2 diabetes (T2D), the German Center for Diabetes Research (DZD) conducted crossbreedings of the obese and diabetes-prone New Zealand Obese mouse strain with four different lean strains (B6, DBA, C3H, 129P2) that vary in their susceptibility to develop T2D. Genome-wide linkage analyses localized more than 290 quantitative trait loci (QTL) for obesity, 190 QTL for diabetes-related traits and 100 QTL for plasma metabolites in the out-cross populations. A computational framework was developed that allowed to refine critical regions and to nominate a small number of candidate genes by integrating reciprocal haplotype mapping and transcriptome data. The efficiency of the complex procedure was demonstrated for one obesity QTL. The genomic interval of 35 Mb with 502 annotated candidate genes was narrowed down to six candidates. Accordingly, congenic mice retained the obesity phenotype owing to an interval that contains three of the six candidate genes. Among these the phospholipaseTo explore the genetic determinants of obesity and Type 2 diabetes (T2D), the German Center for Diabetes Research (DZD) conducted crossbreedings of the obese and diabetes-prone New Zealand Obese mouse strain with four different lean strains (B6, DBA, C3H, 129P2) that vary in their susceptibility to develop T2D. Genome-wide linkage analyses localized more than 290 quantitative trait loci (QTL) for obesity, 190 QTL for diabetes-related traits and 100 QTL for plasma metabolites in the out-cross populations. A computational framework was developed that allowed to refine critical regions and to nominate a small number of candidate genes by integrating reciprocal haplotype mapping and transcriptome data. The efficiency of the complex procedure was demonstrated for one obesity QTL. The genomic interval of 35 Mb with 502 annotated candidate genes was narrowed down to six candidates. Accordingly, congenic mice retained the obesity phenotype owing to an interval that contains three of the six candidate genes. Among these the phospholipase PLA2G4A exhibited an elevated expression in adipose tissue of obese human subjects and is therefore a critical regulator of the obesity locus. Together, our broad and complex approach demonstrates that combined- and comparative-cross analysis exhibits improved mapping resolution and represents a valid tool for the identification of disease genes.…
MetadatenAuthor details: | Heike VogelORCiDGND, Anne KamitzGND, Nicole HallahanGND, Sandra LebekGND, Tanja SchallschmidtGND, Wenke JonasORCiDGND, Markus JähnertORCiD, Pascal GottmannORCiDGND, Lisa Zellner, Timo KanzleiterGND, Mareike DamenGND, Delsi AltenhofenGND, Ralph BurkhardtORCiDGND, Simone RennerGND, Maik DahlhoffGND, Eckhard WolfORCiDGND, Timo Dirk MüllerGND, Matthias BlüherGND, Hans-Georg JoostORCiD, Alexandra ChadtORCiDGND, Hadi Al-HasaniGND, Annette SchürmannORCiDGND |
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DOI: | https://doi.org/10.1093/hmg/ddy217 |
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ISSN: | 0964-6906 |
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ISSN: | 1460-2083 |
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Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/29893858 |
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Title of parent work (English): | Human molecular genetics |
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Publisher: | Oxford Univ. Press |
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Place of publishing: | Oxford |
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Publication type: | Article |
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Language: | English |
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Date of first publication: | 2018/05/08 |
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Publication year: | 2018 |
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Release date: | 2021/10/07 |
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Volume: | 27 |
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Issue: | 17 |
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Number of pages: | 14 |
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First page: | 3099 |
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Last Page: | 3112 |
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Funding institution: | German Ministry of Education and ResearchFederal Ministry of Education & Research (BMBF); State of Brandenburg; State of North-Rhine-Westfalia [82DZD00302, 82DZD00202]; German Institute of Human Nutrtion |
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Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft |
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DDC classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Peer review: | Referiert |
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Publishing method: | Open Access / Hybrid Open-Access |
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