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Approaches for establishing the function of regulatory genetic variants involved in disease

The diversity of regulatory genetic variants and their mechanisms of action reflect the complexity and context-specificity of gene regulation. Regulatory variants are important in human disease and defining such variants and establishing mechanism is crucial to the interpretation of disease-associat...

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Autor principal: Knight, Julian Charles
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254439/
https://www.ncbi.nlm.nih.gov/pubmed/25473428
http://dx.doi.org/10.1186/s13073-014-0092-4
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author Knight, Julian Charles
author_facet Knight, Julian Charles
author_sort Knight, Julian Charles
collection PubMed
description The diversity of regulatory genetic variants and their mechanisms of action reflect the complexity and context-specificity of gene regulation. Regulatory variants are important in human disease and defining such variants and establishing mechanism is crucial to the interpretation of disease-association studies. This review describes approaches for identifying and functionally characterizing regulatory variants, illustrated using examples from common diseases. Insights from recent advances in resolving the functional epigenomic regulatory landscape in which variants act are highlighted, showing how this has enabled functional annotation of variants and the generation of hypotheses about mechanism of action. The utility of quantitative trait mapping at the transcript, protein and metabolite level to define association of specific genes with particular variants and further inform disease associations are reviewed. Establishing mechanism of action is an essential step in resolving functional regulatory variants, and this review describes how this is being facilitated by new methods for analyzing allele-specific expression, mapping chromatin interactions and advances in genome editing. Finally, integrative approaches are discussed together with examples highlighting how defining the mechanism of action of regulatory variants and identifying specific modulated genes can maximize the translational utility of genome-wide association studies to understand the pathogenesis of diseases and discover new drug targets or opportunities to repurpose existing drugs to treat them.
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spelling pubmed-42544392014-12-04 Approaches for establishing the function of regulatory genetic variants involved in disease Knight, Julian Charles Genome Med Review The diversity of regulatory genetic variants and their mechanisms of action reflect the complexity and context-specificity of gene regulation. Regulatory variants are important in human disease and defining such variants and establishing mechanism is crucial to the interpretation of disease-association studies. This review describes approaches for identifying and functionally characterizing regulatory variants, illustrated using examples from common diseases. Insights from recent advances in resolving the functional epigenomic regulatory landscape in which variants act are highlighted, showing how this has enabled functional annotation of variants and the generation of hypotheses about mechanism of action. The utility of quantitative trait mapping at the transcript, protein and metabolite level to define association of specific genes with particular variants and further inform disease associations are reviewed. Establishing mechanism of action is an essential step in resolving functional regulatory variants, and this review describes how this is being facilitated by new methods for analyzing allele-specific expression, mapping chromatin interactions and advances in genome editing. Finally, integrative approaches are discussed together with examples highlighting how defining the mechanism of action of regulatory variants and identifying specific modulated genes can maximize the translational utility of genome-wide association studies to understand the pathogenesis of diseases and discover new drug targets or opportunities to repurpose existing drugs to treat them. BioMed Central 2014-10-31 /pmc/articles/PMC4254439/ /pubmed/25473428 http://dx.doi.org/10.1186/s13073-014-0092-4 Text en © Knight; licensee BioMed Central Ltd. 2014 The licensee has exclusive rights to distribute this article, in any medium, for 12 months following its publication. After this time, the article is available under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Review
Knight, Julian Charles
Approaches for establishing the function of regulatory genetic variants involved in disease
title Approaches for establishing the function of regulatory genetic variants involved in disease
title_full Approaches for establishing the function of regulatory genetic variants involved in disease
title_fullStr Approaches for establishing the function of regulatory genetic variants involved in disease
title_full_unstemmed Approaches for establishing the function of regulatory genetic variants involved in disease
title_short Approaches for establishing the function of regulatory genetic variants involved in disease
title_sort approaches for establishing the function of regulatory genetic variants involved in disease
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254439/
https://www.ncbi.nlm.nih.gov/pubmed/25473428
http://dx.doi.org/10.1186/s13073-014-0092-4
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