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  • Lod Score  (2)
  • *Gene Expression Profiling  (1)
  • 1
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    Genetics of gene expression and its effect on disease (2008)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2008-03-18
    Description: Common human diseases result from the interplay of many genes and environmental factors. Therefore, a more integrative biology approach is needed to unravel the complexity and causes of such diseases. To elucidate the complexity of common human diseases such as obesity, we have analysed the expression of 23,720 transcripts in large population-based blood and adipose tissue cohorts comprehensively assessed for various phenotypes, including traits related to clinical obesity. In contrast to the blood expression profiles, we observed a marked correlation between gene expression in adipose tissue and obesity-related traits. Genome-wide linkage and association mapping revealed a highly significant genetic component to gene expression traits, including a strong genetic effect of proximal (cis) signals, with 50% of the cis signals overlapping between the two tissues profiled. Here we demonstrate an extensive transcriptional network constructed from the human adipose data that exhibits significant overlap with similar network modules constructed from mouse adipose data. A core network module in humans and mice was identified that is enriched for genes involved in the inflammatory and immune response and has been found to be causally associated to obesity-related traits.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Emilsson, Valur -- Thorleifsson, Gudmar -- Zhang, Bin -- Leonardson, Amy S -- Zink, Florian -- Zhu, Jun -- Carlson, Sonia -- Helgason, Agnar -- Walters, G Bragi -- Gunnarsdottir, Steinunn -- Mouy, Magali -- Steinthorsdottir, Valgerdur -- Eiriksdottir, Gudrun H -- Bjornsdottir, Gyda -- Reynisdottir, Inga -- Gudbjartsson, Daniel -- Helgadottir, Anna -- Jonasdottir, Aslaug -- Jonasdottir, Adalbjorg -- Styrkarsdottir, Unnur -- Gretarsdottir, Solveig -- Magnusson, Kristinn P -- Stefansson, Hreinn -- Fossdal, Ragnheidur -- Kristjansson, Kristleifur -- Gislason, Hjortur G -- Stefansson, Tryggvi -- Leifsson, Bjorn G -- Thorsteinsdottir, Unnur -- Lamb, John R -- Gulcher, Jeffrey R -- Reitman, Marc L -- Kong, Augustine -- Schadt, Eric E -- Stefansson, Kari -- England -- Nature. 2008 Mar 27;452(7186):423-8. doi: 10.1038/nature06758. Epub 2008 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉deCODE genetics, 101 Reykjavik, Iceland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18344981" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue/metabolism ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Animals ; Blood/metabolism ; Body Mass Index ; Cohort Studies ; European Continental Ancestry Group/genetics ; Female ; *Gene Expression Profiling ; Gene Expression Regulation/*genetics ; Genome, Human ; Humans ; Iceland ; Lod Score ; Male ; Mice ; Middle Aged ; Obesity/*genetics ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/genetics ; Sample Size ; Waist-Hip Ratio
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Variations in DNA elucidate molecular networks that cause disease (2008)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2008-03-18
    Description: Identifying variations in DNA that increase susceptibility to disease is one of the primary aims of genetic studies using a forward genetics approach. However, identification of disease-susceptibility genes by means of such studies provides limited functional information on how genes lead to disease. In fact, in most cases there is an absence of functional information altogether, preventing a definitive identification of the susceptibility gene or genes. Here we develop an alternative to the classic forward genetics approach for dissecting complex disease traits where, instead of identifying susceptibility genes directly affected by variations in DNA, we identify gene networks that are perturbed by susceptibility loci and that in turn lead to disease. Application of this method to liver and adipose gene expression data generated from a segregating mouse population results in the identification of a macrophage-enriched network supported as having a causal relationship with disease traits associated with metabolic syndrome. Three genes in this network, lipoprotein lipase (Lpl), lactamase beta (Lactb) and protein phosphatase 1-like (Ppm1l), are validated as previously unknown obesity genes, strengthening the association between this network and metabolic disease traits. Our analysis provides direct experimental support that complex traits such as obesity are emergent properties of molecular networks that are modulated by complex genetic loci and environmental factors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841398/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841398/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Yanqing -- Zhu, Jun -- Lum, Pek Yee -- Yang, Xia -- Pinto, Shirly -- MacNeil, Douglas J -- Zhang, Chunsheng -- Lamb, John -- Edwards, Stephen -- Sieberts, Solveig K -- Leonardson, Amy -- Castellini, Lawrence W -- Wang, Susanna -- Champy, Marie-France -- Zhang, Bin -- Emilsson, Valur -- Doss, Sudheer -- Ghazalpour, Anatole -- Horvath, Steve -- Drake, Thomas A -- Lusis, Aldons J -- Schadt, Eric E -- P01 HL028481/HL/NHLBI NIH HHS/ -- P01 HL028481-24/HL/NHLBI NIH HHS/ -- P01 HL028481-240010/HL/NHLBI NIH HHS/ -- P01 HL030568/HL/NHLBI NIH HHS/ -- P01 HL030568-250011/HL/NHLBI NIH HHS/ -- R01 DK071673/DK/NIDDK NIH HHS/ -- R01 DK071673-03/DK/NIDDK NIH HHS/ -- England -- Nature. 2008 Mar 27;452(7186):429-35. doi: 10.1038/nature06757. Epub 2008 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Rosetta Inpharmatics, LLC, Merck & Co., Inc., 401 Terry Avenue North, Seattle, Washington 98109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18344982" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue/metabolism ; Animals ; Apolipoprotein A-II/genetics ; Chromosomes, Mammalian/genetics ; Female ; Gene Regulatory Networks/*genetics ; Genetic Predisposition to Disease/*genetics ; Genetic Variation/*genetics ; Linkage Disequilibrium ; Lipoprotein Lipase/genetics ; Liver/metabolism ; Lod Score ; Macrophages/metabolism ; Male ; Membrane Proteins/genetics ; Metabolic Syndrome X/enzymology/*genetics/metabolism ; Mice ; Obesity/enzymology/*genetics/metabolism ; Phenotype ; Phosphoprotein Phosphatases/deficiency/genetics/metabolism ; Quantitative Trait Loci ; Reproducibility of Results ; Ribosomal Proteins/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
    Location Call Number Expected Availability
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    PAPER CURRENT
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