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      Oxidative stress gene expression, DNA methylation, and gut microbiota interaction trigger Crohn’s disease: a multi-omics Mendelian randomization study


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          Oxidative stress (OS) is a key pathophysiological mechanism in Crohn’s disease (CD). OS-related genes can be affected by environmental factors, intestinal inflammation, gut microbiota, and epigenetic changes. However, the role of OS as a potential CD etiological factor or triggering factor is unknown, as differentially expressed OS genes in CD can be either a cause or a subsequent change of intestinal inflammation. Herein, we used a multi-omics summary data-based Mendelian randomization (SMR) approach to identify putative causal effects and underlying mechanisms of OS genes in CD.


          OS-related genes were extracted from the GeneCards database. Intestinal transcriptome datasets were collected from the Gene Expression Omnibus (GEO) database and meta-analyzed to identify differentially expressed genes (DEGs) related to OS in CD. Integration analyses of the largest CD genome-wide association study (GWAS) summaries with expression quantitative trait loci (eQTLs) and DNA methylation QTLs (mQTLs) from the blood were performed using SMR methods to prioritize putative blood OS genes and their regulatory elements associated with CD risk. Up-to-date intestinal eQTLs and fecal microbial QTLs (mbQTLs) were integrated to uncover potential interactions between host OS gene expression and gut microbiota through SMR and colocalization analysis. Two additional Mendelian randomization (MR) methods were used as sensitivity analyses. Putative results were validated in an independent multi-omics cohort from the First Affiliated Hospital of Sun Yat-sen University (FAH-SYS).


          A meta-analysis from six datasets identified 438 OS-related DEGs enriched in intestinal enterocytes in CD from 817 OS-related genes. Five genes from blood tissue were prioritized as candidate CD-causal genes using three-step SMR methods: BAD, SHC1, STAT3, MUC1, and GPX3. Furthermore, SMR analysis also identified five putative intestinal genes, three of which were involved in gene–microbiota interactions through colocalization analysis: MUC1, CD40, and PRKAB1. Validation results showed that 88.79% of DEGs were replicated in the FAH-SYS cohort. Associations between pairs of MUC1Bacillus aciditolerans and PRKAB1Escherichia coli in the FAH-SYS cohort were consistent with eQTL–mbQTL colocalization.


          This multi-omics integration study highlighted that OS genes causal to CD are regulated by DNA methylation and host-microbiota interactions. This provides evidence for future targeted functional research aimed at developing suitable therapeutic interventions and disease prevention.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12916-023-02878-8.

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          The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019

          Abstract The GWAS Catalog delivers a high-quality curated collection of all published genome-wide association studies enabling investigations to identify causal variants, understand disease mechanisms, and establish targets for novel therapies. The scope of the Catalog has also expanded to targeted and exome arrays with 1000 new associations added for these technologies. As of September 2018, the Catalog contains 5687 GWAS comprising 71673 variant-trait associations from 3567 publications. New content includes 284 full P-value summary statistics datasets for genome-wide and new targeted array studies, representing 6 × 109 individual variant-trait statistics. In the last 12 months, the Catalog's user interface was accessed by ∼90000 unique users who viewed >1 million pages. We have improved data access with the release of a new RESTful API to support high-throughput programmatic access, an improved web interface and a new summary statistics database. Summary statistics provision is supported by a new format proposed as a community standard for summary statistics data representation. This format was derived from our experience in standardizing heterogeneous submissions, mapping formats and in harmonizing content. Availability: https://www.ebi.ac.uk/gwas/.
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            The GTEx Consortium atlas of genetic regulatory effects across human tissues

            The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the version 8 data, examining 15,201 RNA-sequencing samples from 49 tissues of 838 postmortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue specificity of genetic effects and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.
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              Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases

              Inflammatory bowel diseases, which include Crohn’s disease and ulcerative colitis, affect several million individuals worldwide. Crohn’s disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study’s infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi’omics Database (http://ibdmdb.org), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases.

                Author and article information

                BMC Med
                BMC Med
                BMC Medicine
                BioMed Central (London )
                11 May 2023
                11 May 2023
                : 21
                : 179
                [1 ]GRID grid.412615.5, ISNI 0000 0004 1803 6239, Department of Gastroenterology, , The First Affiliated Hospital, Sun Yat-Sen University, ; Guangzhou, Guangdong China
                [2 ]GRID grid.417404.2, ISNI 0000 0004 1771 3058, Microbiome Medicine Center, Division of Laboratory Medicine, , Zhujiang Hospital, Southern Medical University, ; Guangzhou, Guangdong China
                [3 ]GRID grid.512472.7, Department of Computational Biology for Individualised Medicine, , Centre for Individualised Infection Medicine & TWINCORE, Joint Ventures Between the Helmholtz Centre for Infection Research and the Hannover Medical School, ; Hannover, Germany
                [4 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Changzhou Medical Center, , The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Nanjing Medical University, ; Changzhou, Jiangsu China
                [5 ]GRID grid.412676.0, ISNI 0000 0004 1799 0784, Department of Cardiology, , The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, ; Nanjing, Jiangsu China
                [6 ]GRID grid.412615.5, ISNI 0000 0004 1803 6239, Institute of Precision Medicine, , The First Affiliated Hospital, Sun Yat-Sen University, ; Guangzhou, Guangdong China
                [7 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, Department of Gastroenterology and Hepatology, , University of Groningen, University Medical Center Groningen, ; Groningen, The Netherlands
                [8 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, Zhongshan School of Medicine, , Center for Precision Medicine, Sun Yat-Sen University, ; Guangzhou, Guangdong China
                [9 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, Department of Gastroenterology, , Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-Sen University, ; Nanning, Guangxi China
                © The Author(s) 2023

                Open AccessThis 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/. The Creative Commons Public Domain Dedication waiver ( http://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.

                : 12 November 2022
                : 21 April 2023
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81870384
                Award ID: 82270579
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003453, Natural Science Foundation of Guangdong Province;
                Award ID: 2021A1515010572
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100007028, Leona M. and Harry B. Helmsley Charitable Trust;
                Award ID: 2019PG-CD018
                Award Recipient :
                Research Article
                Custom metadata
                © BioMed Central Ltd., part of Springer Nature 2023

                oxidative stress,crohn’s disease,integrative omics,mendelian randomization
                oxidative stress, crohn’s disease, integrative omics, mendelian randomization


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