A comprehensive integrated post-GWAS analysis of Type 1 diabetes reveals enhancer-based immune dysregulation.

Type 1 diabetes (T1D) is an organ-specific autoimmune disease, whereby immune cell-mediated killing leads to loss of the insulin-producing β cells in the pancreas. Genome-wide association studies (GWAS) have identified over 200 genetic variants associated with risk for T1D. The majority of the GWAS...

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Autores principales:	Seung-Soo Kim, Adam D Hudgins, Jiping Yang, Yizhou Zhu, Zhidong Tu, Michael G Rosenfeld, Teresa P DiLorenzo, Yousin Suh
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ef6473d563c743d89291adf7966b5f00
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spelling	oai:doaj.org-article:ef6473d563c743d89291adf7966b5f002021-12-02T20:17:28ZA comprehensive integrated post-GWAS analysis of Type 1 diabetes reveals enhancer-based immune dysregulation.1932-620310.1371/journal.pone.0257265https://doaj.org/article/ef6473d563c743d89291adf7966b5f002021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0257265https://doaj.org/toc/1932-6203Type 1 diabetes (T1D) is an organ-specific autoimmune disease, whereby immune cell-mediated killing leads to loss of the insulin-producing β cells in the pancreas. Genome-wide association studies (GWAS) have identified over 200 genetic variants associated with risk for T1D. The majority of the GWAS risk variants reside in the non-coding regions of the genome, suggesting that gene regulatory changes substantially contribute to T1D. However, identification of causal regulatory variants associated with T1D risk and their affected genes is challenging due to incomplete knowledge of non-coding regulatory elements and the cellular states and processes in which they function. Here, we performed a comprehensive integrated post-GWAS analysis of T1D to identify functional regulatory variants in enhancers and their cognate target genes. Starting with 1,817 candidate T1D SNPs defined from the GWAS catalog and LDlink databases, we conducted functional annotation analysis using genomic data from various public databases. These include 1) Roadmap Epigenomics, ENCODE, and RegulomeDB for epigenome data; 2) GTEx for tissue-specific gene expression and expression quantitative trait loci data; and 3) lncRNASNP2 for long non-coding RNA data. Our results indicated a prevalent enhancer-based immune dysregulation in T1D pathogenesis. We identified 26 high-probability causal enhancer SNPs associated with T1D, and 64 predicted target genes. The majority of the target genes play major roles in antigen presentation and immune response and are regulated through complex transcriptional regulatory circuits, including those in HLA (6p21) and non-HLA (16p11.2) loci. These candidate causal enhancer SNPs are supported by strong evidence and warrant functional follow-up studies.Seung-Soo KimAdam D HudginsJiping YangYizhou ZhuZhidong TuMichael G RosenfeldTeresa P DiLorenzoYousin SuhPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 9, p e0257265 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Seung-Soo Kim Adam D Hudgins Jiping Yang Yizhou Zhu Zhidong Tu Michael G Rosenfeld Teresa P DiLorenzo Yousin Suh A comprehensive integrated post-GWAS analysis of Type 1 diabetes reveals enhancer-based immune dysregulation.
description	Type 1 diabetes (T1D) is an organ-specific autoimmune disease, whereby immune cell-mediated killing leads to loss of the insulin-producing β cells in the pancreas. Genome-wide association studies (GWAS) have identified over 200 genetic variants associated with risk for T1D. The majority of the GWAS risk variants reside in the non-coding regions of the genome, suggesting that gene regulatory changes substantially contribute to T1D. However, identification of causal regulatory variants associated with T1D risk and their affected genes is challenging due to incomplete knowledge of non-coding regulatory elements and the cellular states and processes in which they function. Here, we performed a comprehensive integrated post-GWAS analysis of T1D to identify functional regulatory variants in enhancers and their cognate target genes. Starting with 1,817 candidate T1D SNPs defined from the GWAS catalog and LDlink databases, we conducted functional annotation analysis using genomic data from various public databases. These include 1) Roadmap Epigenomics, ENCODE, and RegulomeDB for epigenome data; 2) GTEx for tissue-specific gene expression and expression quantitative trait loci data; and 3) lncRNASNP2 for long non-coding RNA data. Our results indicated a prevalent enhancer-based immune dysregulation in T1D pathogenesis. We identified 26 high-probability causal enhancer SNPs associated with T1D, and 64 predicted target genes. The majority of the target genes play major roles in antigen presentation and immune response and are regulated through complex transcriptional regulatory circuits, including those in HLA (6p21) and non-HLA (16p11.2) loci. These candidate causal enhancer SNPs are supported by strong evidence and warrant functional follow-up studies.
format	article
author	Seung-Soo Kim Adam D Hudgins Jiping Yang Yizhou Zhu Zhidong Tu Michael G Rosenfeld Teresa P DiLorenzo Yousin Suh
author_facet	Seung-Soo Kim Adam D Hudgins Jiping Yang Yizhou Zhu Zhidong Tu Michael G Rosenfeld Teresa P DiLorenzo Yousin Suh
author_sort	Seung-Soo Kim
title	A comprehensive integrated post-GWAS analysis of Type 1 diabetes reveals enhancer-based immune dysregulation.
title_short	A comprehensive integrated post-GWAS analysis of Type 1 diabetes reveals enhancer-based immune dysregulation.
title_full	A comprehensive integrated post-GWAS analysis of Type 1 diabetes reveals enhancer-based immune dysregulation.
title_fullStr	A comprehensive integrated post-GWAS analysis of Type 1 diabetes reveals enhancer-based immune dysregulation.
title_full_unstemmed	A comprehensive integrated post-GWAS analysis of Type 1 diabetes reveals enhancer-based immune dysregulation.
title_sort	comprehensive integrated post-gwas analysis of type 1 diabetes reveals enhancer-based immune dysregulation.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/ef6473d563c743d89291adf7966b5f00
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A comprehensive integrated post-GWAS analysis of Type 1 diabetes reveals enhancer-based immune dysregulation.

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