Dokumentenart: | Artikel | ||||
---|---|---|---|---|---|
Titel eines Journals oder einer Zeitschrift: | PLOS Computational Biology | ||||
Verlag: | PUBLIC LIBRARY SCIENCE | ||||
Ort der Veröffentlichung: | SAN FRANCISCO | ||||
Band: | 14 | ||||
Nummer des Zeitschriftenheftes oder des Kapitels: | 3 | ||||
Seitenbereich: | e1005934 | ||||
Datum: | 2018 | ||||
Institutionen: | Medizin > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) | ||||
Identifikationsnummer: |
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Stichwörter / Keywords: | INFLAMMATORY-BOWEL-DISEASE; WIDE ASSOCIATION; CROHNS-DISEASE; METAANALYSIS; CHOLESTEROL; EXPRESSION; METFORMIN; HERITABILITY; ENHANCERS; VARIANTS; | ||||
Dewey-Dezimal-Klassifikation: | Nicht ausgewählt | ||||
Status: | Veröffentlicht | ||||
Begutachtet: | Ja, diese Version wurde begutachtet | ||||
An der Universität Regensburg entstanden: | Ja | ||||
Dokumenten-ID: | 47413 |
Zusammenfassung
Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci ...
Zusammenfassung
Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly-coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn's disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely to respond differently to pharmacological therapy. Together, these findings enable a deeper biological understanding of the causal basis of complex traits.
Metadaten zuletzt geändert: 28 Jul 2021 17:22