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Genomic approaches for understanding the genetics of complex disease

There are thousands of known associations between genetic variants and complex human phenotypes, and the rate of novel discoveries is rapidly increasing. Translating those associations into knowledge of disease mechanisms remains a fundamental challenge because the associated variants are overwhelmi...

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Detalles Bibliográficos
Autores principales: Lowe, William L., Reddy, Timothy E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579328/
https://www.ncbi.nlm.nih.gov/pubmed/26430153
http://dx.doi.org/10.1101/gr.190603.115
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author Lowe, William L.
Reddy, Timothy E.
author_facet Lowe, William L.
Reddy, Timothy E.
author_sort Lowe, William L.
collection PubMed
description There are thousands of known associations between genetic variants and complex human phenotypes, and the rate of novel discoveries is rapidly increasing. Translating those associations into knowledge of disease mechanisms remains a fundamental challenge because the associated variants are overwhelmingly in noncoding regions of the genome where we have few guiding principles to predict their function. Intersecting the compendium of identified genetic associations with maps of regulatory activity across the human genome has revealed that phenotype-associated variants are highly enriched in candidate regulatory elements. Allele-specific analyses of gene regulation can further prioritize variants that likely have a functional effect on disease mechanisms; and emerging high-throughput assays to quantify the activity of candidate regulatory elements are a promising next step in that direction. Together, these technologies have created the ability to systematically and empirically test hypotheses about the function of noncoding variants and haplotypes at the scale needed for comprehensive and systematic follow-up of genetic association studies. Major coordinated efforts to quantify regulatory mechanisms across genetically diverse populations in increasingly realistic cell models would be highly beneficial to realize that potential.
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spelling pubmed-45793282015-10-01 Genomic approaches for understanding the genetics of complex disease Lowe, William L. Reddy, Timothy E. Genome Res Perspective There are thousands of known associations between genetic variants and complex human phenotypes, and the rate of novel discoveries is rapidly increasing. Translating those associations into knowledge of disease mechanisms remains a fundamental challenge because the associated variants are overwhelmingly in noncoding regions of the genome where we have few guiding principles to predict their function. Intersecting the compendium of identified genetic associations with maps of regulatory activity across the human genome has revealed that phenotype-associated variants are highly enriched in candidate regulatory elements. Allele-specific analyses of gene regulation can further prioritize variants that likely have a functional effect on disease mechanisms; and emerging high-throughput assays to quantify the activity of candidate regulatory elements are a promising next step in that direction. Together, these technologies have created the ability to systematically and empirically test hypotheses about the function of noncoding variants and haplotypes at the scale needed for comprehensive and systematic follow-up of genetic association studies. Major coordinated efforts to quantify regulatory mechanisms across genetically diverse populations in increasingly realistic cell models would be highly beneficial to realize that potential. Cold Spring Harbor Laboratory Press 2015-10 /pmc/articles/PMC4579328/ /pubmed/26430153 http://dx.doi.org/10.1101/gr.190603.115 Text en © 2015 Lowe and Reddy; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Perspective
Lowe, William L.
Reddy, Timothy E.
Genomic approaches for understanding the genetics of complex disease
title Genomic approaches for understanding the genetics of complex disease
title_full Genomic approaches for understanding the genetics of complex disease
title_fullStr Genomic approaches for understanding the genetics of complex disease
title_full_unstemmed Genomic approaches for understanding the genetics of complex disease
title_short Genomic approaches for understanding the genetics of complex disease
title_sort genomic approaches for understanding the genetics of complex disease
topic Perspective
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579328/
https://www.ncbi.nlm.nih.gov/pubmed/26430153
http://dx.doi.org/10.1101/gr.190603.115
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