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      Expression Quantitative Trait Loci (eQTL) Mapping in Korean Patients With Crohn’s Disease and Identification of Potential Causal Genes Through Integration With Disease Associations

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          Abstract

          Background

          Expression quantitative trait loci (eQTL) datasets have extensively been used to help interpret genome-wide association study signals. Most eQTL analyses have been conducted with populations of European ancestry.

          Objective

          To determine the most functionally relevant genes at the Crohn’s disease (CD) loci identified in genome-wide association studies (GWAS) involving Asian populations and to find novel disease-associated genes, we conducted an eQTL analysis.

          Methods

          eQTL analysis was performed using whole-blood RNA-sequencing of 101 Korean patients with CD. FastQTL was used for a pair-wise genome analysis of ∼ 6.5 M SNPs and ∼ 22 K transcripts.

          Results

          We identified 135,164 cis-eQTL and 3,816 eGenes with a false discovery rate less than 0.05. A significant proportion of the genes identified in our study overlapped with those identified in previous studies. The significantly enriched pathways of these 3,816 eGenes included neutrophil degranulation and small molecule biosynthetic process. Integrated analysis of CD GWAS with Korean eQTL revealed two putative target genes, TNFSF15 and GPR35, at two previously reported loci, whereas TNFSF15 only with the whole blood data from the Genotype-Tissue Expression (GTEx) project, highlighting the utility of building a population-specific data set, even of modest size. The risk alleles of these genes were found to be associated with lower expression levels of TNFSF15 and GPR35, respectively. Our eQTL browser can be accessed at “ http://asan.crohneqtl.com/”.

          Conclusion

          This resource would be useful for studies that need to employ genome-wide association analyses involving Asian populations.

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          Most cited references13

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          Gene Ontology: tool for the unification of biology

          Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
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            Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

            Genetic association studies have identified 215 risk loci for inflammatory bowel disease 1–8, which have revealed fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals, and meta-analyzed with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new loci, three of which contain integrin genes that encode proteins in pathways identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4, ITGB8) and at previously implicated loci (ITGAL, ICAM1). In all four cases, the expression increasing allele also increases disease risk. We also identified likely causal missense variants in the primary immune deficiency gene PLCG2 and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new common variant associations continue to identify genes relevant to therapeutic target identification and prioritization.
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              GM-CSF: An immune modulatory cytokine that can suppress autoimmunity.

              GM-CSF was originally identified as a colony stimulating factor (CSF) because of its ability to induce granulocyte and macrophage populations from precursor cells. Multiple studies have demonstrated that GM-CSF is also an immune-modulatory cytokine, capable of affecting not only the phenotype of myeloid lineage cells, but also T-cell activation through various myeloid intermediaries. This property has been implicated in the sustenance of several autoimmune diseases like arthritis and multiple sclerosis. In contrast, several studies using animal models have shown that GM-CSF is also capable of suppressing many autoimmune diseases such as Crohn's disease, Type-1 diabetes, Myasthenia gravis and experimental autoimmune thyroiditis. Knockout mouse studies have suggested that the role of GM-CSF in maintaining granulocyte and macrophage populations in the physiological steady state is largely redundant. Instead, its immune-modulatory role plays a significant role in the development or resolution of autoimmune diseases. This is mediated either through the differentiation of precursor cells into specialized non-steady state granulocytes, macrophages and dendritic cells, or through the modulation of the phenotype of mature myeloid cells. Thus, outside of myelopoiesis, GM-CSF has a profound role in regulating the immune response and maintaining immunological tolerance.
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                Author and article information

                Contributors
                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                14 May 2020
                2020
                : 11
                : 486
                Affiliations
                [1] 1Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine , Seoul, South Korea
                [2] 2Human Genetics, Genome Institute of Singapore , Singapore, Singapore
                [3] 3Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, South Korea
                [4] 4Department of Medicine, Seoul National University College of Medicine , Seoul, South Korea
                Author notes

                Edited by: Ahmed Rebai, Centre of Biotechnology of Sfax, Tunisia

                Reviewed by: Kais Ghedira, Institut Pasteur de Tunis, Tunisia; Fakher Frikha, Faculty of Science of Sfax, Tunisia

                *Correspondence: Kyuyoung Song, kysong@ 123456amc.seoul.kr

                These authors have contributed equally to this work

                This article was submitted to Genomic Medicine, a section of the journal Frontiers in Genetics

                Article
                10.3389/fgene.2020.00486
                7240107
                32477412
                031e9f62-8963-4790-8757-f60b964f8667
                Copyright © 2020 Jung, Liu, Baek, Moon, Ye, Lee, Park, Yang, Han, Liu and Song.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 15 January 2020
                : 20 April 2020
                Page count
                Figures: 2, Tables: 2, Equations: 0, References: 33, Pages: 11, Words: 0
                Funding
                Funded by: National Research Foundation of Korea 10.13039/501100003725
                Award ID: 2017R1A2A1A05001119
                Categories
                Genetics
                Original Research

                Genetics
                crohn’s disease,gene expression,eqtl,asian,blood
                Genetics
                crohn’s disease, gene expression, eqtl, asian, blood

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