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The impact of cell type and context-dependent regulatory variants on human immune traits

BACKGROUND: The vast majority of trait-associated variants identified using genome-wide association studies (GWAS) are noncoding, and therefore assumed to impact gene regulation. However, the majority of trait-associated loci are unexplained by regulatory quantitative trait loci (QTLs). RESULTS: We...

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Autores principales: Mu, Zepeng, Wei, Wei, Fair, Benjamin, Miao, Jinlin, Zhu, Ping, Li, Yang I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082814/
https://www.ncbi.nlm.nih.gov/pubmed/33926512
http://dx.doi.org/10.1186/s13059-021-02334-x
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author Mu, Zepeng
Wei, Wei
Fair, Benjamin
Miao, Jinlin
Zhu, Ping
Li, Yang I.
author_facet Mu, Zepeng
Wei, Wei
Fair, Benjamin
Miao, Jinlin
Zhu, Ping
Li, Yang I.
author_sort Mu, Zepeng
collection PubMed
description BACKGROUND: The vast majority of trait-associated variants identified using genome-wide association studies (GWAS) are noncoding, and therefore assumed to impact gene regulation. However, the majority of trait-associated loci are unexplained by regulatory quantitative trait loci (QTLs). RESULTS: We perform a comprehensive characterization of the putative mechanisms by which GWAS loci impact human immune traits. By harmonizing four major immune QTL studies, we identify 26,271 expression QTLs (eQTLs) and 23,121 splicing QTLs (sQTLs) spanning 18 immune cell types. Our colocalization analyses between QTLs and trait-associated loci from 72 GWAS reveals that genetic effects on RNA expression and splicing in immune cells colocalize with 40.4% of GWAS loci for immune-related traits, in many cases increasing the fraction of colocalized loci by two fold compared to previous studies. Notably, we find that the largest contributors of this increase are splicing QTLs, which colocalize on average with 14% of all GWAS loci that do not colocalize with eQTLs. By contrast, we find that cell type-specific eQTLs, and eQTLs with small effect sizes contribute very few new colocalizations. To investigate the 60% of GWAS loci that remain unexplained, we collect H3K27ac CUT&Tag data from rheumatoid arthritis and healthy controls, and find large-scale differences between immune cells from the different disease contexts, including at regions overlapping unexplained GWAS loci. CONCLUSION: Altogether, our work supports RNA splicing as an important mediator of genetic effects on immune traits, and suggests that we must expand our study of regulatory processes in disease contexts to improve functional interpretation of as yet unexplained GWAS loci. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at (10.1186/s13059-021-02334-x).
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spelling pubmed-80828142021-04-29 The impact of cell type and context-dependent regulatory variants on human immune traits Mu, Zepeng Wei, Wei Fair, Benjamin Miao, Jinlin Zhu, Ping Li, Yang I. Genome Biol Research BACKGROUND: The vast majority of trait-associated variants identified using genome-wide association studies (GWAS) are noncoding, and therefore assumed to impact gene regulation. However, the majority of trait-associated loci are unexplained by regulatory quantitative trait loci (QTLs). RESULTS: We perform a comprehensive characterization of the putative mechanisms by which GWAS loci impact human immune traits. By harmonizing four major immune QTL studies, we identify 26,271 expression QTLs (eQTLs) and 23,121 splicing QTLs (sQTLs) spanning 18 immune cell types. Our colocalization analyses between QTLs and trait-associated loci from 72 GWAS reveals that genetic effects on RNA expression and splicing in immune cells colocalize with 40.4% of GWAS loci for immune-related traits, in many cases increasing the fraction of colocalized loci by two fold compared to previous studies. Notably, we find that the largest contributors of this increase are splicing QTLs, which colocalize on average with 14% of all GWAS loci that do not colocalize with eQTLs. By contrast, we find that cell type-specific eQTLs, and eQTLs with small effect sizes contribute very few new colocalizations. To investigate the 60% of GWAS loci that remain unexplained, we collect H3K27ac CUT&Tag data from rheumatoid arthritis and healthy controls, and find large-scale differences between immune cells from the different disease contexts, including at regions overlapping unexplained GWAS loci. CONCLUSION: Altogether, our work supports RNA splicing as an important mediator of genetic effects on immune traits, and suggests that we must expand our study of regulatory processes in disease contexts to improve functional interpretation of as yet unexplained GWAS loci. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at (10.1186/s13059-021-02334-x). BioMed Central 2021-04-29 /pmc/articles/PMC8082814/ /pubmed/33926512 http://dx.doi.org/10.1186/s13059-021-02334-x Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Mu, Zepeng
Wei, Wei
Fair, Benjamin
Miao, Jinlin
Zhu, Ping
Li, Yang I.
The impact of cell type and context-dependent regulatory variants on human immune traits
title The impact of cell type and context-dependent regulatory variants on human immune traits
title_full The impact of cell type and context-dependent regulatory variants on human immune traits
title_fullStr The impact of cell type and context-dependent regulatory variants on human immune traits
title_full_unstemmed The impact of cell type and context-dependent regulatory variants on human immune traits
title_short The impact of cell type and context-dependent regulatory variants on human immune traits
title_sort impact of cell type and context-dependent regulatory variants on human immune traits
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082814/
https://www.ncbi.nlm.nih.gov/pubmed/33926512
http://dx.doi.org/10.1186/s13059-021-02334-x
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