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Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features

Genome-wide association studies have associated thousands of genetic variants with complex traits and diseases, but pinpointing the causal variant(s) among those in tight linkage disequilibrium with each associated variant remains a major challenge. Here, we use seven experimental assays to characte...

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Autores principales: Ray, John P., de Boer, Carl G., Fulco, Charles P., Lareau, Caleb A., Kanai, Masahiro, Ulirsch, Jacob C., Tewhey, Ryan, Ludwig, Leif S., Reilly, Steven K., Bergman, Drew T., Engreitz, Jesse M., Issner, Robbyn, Finucane, Hilary K., Lander, Eric S., Regev, Aviv, Hacohen, Nir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060350/
https://www.ncbi.nlm.nih.gov/pubmed/32144282
http://dx.doi.org/10.1038/s41467-020-15022-4
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author Ray, John P.
de Boer, Carl G.
Fulco, Charles P.
Lareau, Caleb A.
Kanai, Masahiro
Ulirsch, Jacob C.
Tewhey, Ryan
Ludwig, Leif S.
Reilly, Steven K.
Bergman, Drew T.
Engreitz, Jesse M.
Issner, Robbyn
Finucane, Hilary K.
Lander, Eric S.
Regev, Aviv
Hacohen, Nir
author_facet Ray, John P.
de Boer, Carl G.
Fulco, Charles P.
Lareau, Caleb A.
Kanai, Masahiro
Ulirsch, Jacob C.
Tewhey, Ryan
Ludwig, Leif S.
Reilly, Steven K.
Bergman, Drew T.
Engreitz, Jesse M.
Issner, Robbyn
Finucane, Hilary K.
Lander, Eric S.
Regev, Aviv
Hacohen, Nir
author_sort Ray, John P.
collection PubMed
description Genome-wide association studies have associated thousands of genetic variants with complex traits and diseases, but pinpointing the causal variant(s) among those in tight linkage disequilibrium with each associated variant remains a major challenge. Here, we use seven experimental assays to characterize all common variants at the multiple disease-associated TNFAIP3 locus in five disease-relevant immune cell lines, based on a set of features related to regulatory potential. Trait/disease-associated variants are enriched among SNPs prioritized based on either: (1) residing within CRISPRi-sensitive regulatory regions, or (2) localizing in a chromatin accessible region while displaying allele-specific reporter activity. Of the 15 trait/disease-associated haplotypes at TNFAIP3, 9 have at least one variant meeting one or both of these criteria, 5 of which are further supported by genetic fine-mapping. Our work provides a comprehensive strategy to characterize genetic variation at important disease-associated loci, and aids in the effort to identify trait causal genetic variants.
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spelling pubmed-70603502020-03-18 Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features Ray, John P. de Boer, Carl G. Fulco, Charles P. Lareau, Caleb A. Kanai, Masahiro Ulirsch, Jacob C. Tewhey, Ryan Ludwig, Leif S. Reilly, Steven K. Bergman, Drew T. Engreitz, Jesse M. Issner, Robbyn Finucane, Hilary K. Lander, Eric S. Regev, Aviv Hacohen, Nir Nat Commun Article Genome-wide association studies have associated thousands of genetic variants with complex traits and diseases, but pinpointing the causal variant(s) among those in tight linkage disequilibrium with each associated variant remains a major challenge. Here, we use seven experimental assays to characterize all common variants at the multiple disease-associated TNFAIP3 locus in five disease-relevant immune cell lines, based on a set of features related to regulatory potential. Trait/disease-associated variants are enriched among SNPs prioritized based on either: (1) residing within CRISPRi-sensitive regulatory regions, or (2) localizing in a chromatin accessible region while displaying allele-specific reporter activity. Of the 15 trait/disease-associated haplotypes at TNFAIP3, 9 have at least one variant meeting one or both of these criteria, 5 of which are further supported by genetic fine-mapping. Our work provides a comprehensive strategy to characterize genetic variation at important disease-associated loci, and aids in the effort to identify trait causal genetic variants. Nature Publishing Group UK 2020-03-06 /pmc/articles/PMC7060350/ /pubmed/32144282 http://dx.doi.org/10.1038/s41467-020-15022-4 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Ray, John P.
de Boer, Carl G.
Fulco, Charles P.
Lareau, Caleb A.
Kanai, Masahiro
Ulirsch, Jacob C.
Tewhey, Ryan
Ludwig, Leif S.
Reilly, Steven K.
Bergman, Drew T.
Engreitz, Jesse M.
Issner, Robbyn
Finucane, Hilary K.
Lander, Eric S.
Regev, Aviv
Hacohen, Nir
Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features
title Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features
title_full Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features
title_fullStr Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features
title_full_unstemmed Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features
title_short Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features
title_sort prioritizing disease and trait causal variants at the tnfaip3 locus using functional and genomic features
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060350/
https://www.ncbi.nlm.nih.gov/pubmed/32144282
http://dx.doi.org/10.1038/s41467-020-15022-4
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