Author
Stephan Brand
Other affiliations: Kantonsspital St. Gallen, Hochschule Hannover
Bio: Stephan Brand is an academic researcher from Ludwig Maximilian University of Munich. The author has contributed to research in topics: Inflammatory bowel disease & Crohn's disease. The author has an hindex of 57, co-authored 161 publications receiving 18149 citations. Previous affiliations of Stephan Brand include Kantonsspital St. Gallen & Hochschule Hannover.
Papers published on a yearly basis
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Wellcome Trust Sanger Institute1, Broad Institute2, University of Groningen3, University of Pittsburgh4, Cedars-Sinai Medical Center5, Yale University6, University of Cambridge7, University of Chicago8, Harvard University9, Katholieke Universiteit Leuven10, University of Liège11, King's College London12, Université de Montréal13, New Jersey Institute of Technology14, Cleveland Clinic15, Peninsula College of Medicine and Dentistry16, Université libre de Bruxelles17, Aarhus University18, University of Adelaide19, University of Kiel20, Flinders University21, McGill University22, Ludwig Maximilian University of Munich23, Charité24, Icahn School of Medicine at Mount Sinai25, University of Bonn26, Karolinska Institutet27, Torbay Hospital28, University of Auckland29, Christchurch Hospital30, Imperial College London31, Queen's University32, University of Oslo33, Lithuanian University of Health Sciences34, Emory University35, Casa Sollievo della Sofferenza36, Ghent University37, University of Western Australia38, University of Edinburgh39, Queensland Health40, Newcastle University41, University of Dundee42, University of Manchester43, University of Amsterdam44, University of Maribor45, Royal Hospital for Sick Children46, Guy's and St Thomas' NHS Foundation Trust47, QIMR Berghofer Medical Research Institute48, Norfolk and Norwich University Hospital49, Leiden University50, Technische Universität München51, University of Toronto52, University of Pennsylvania53, Johns Hopkins University54, University of Queensland55
TL;DR: A meta-analysis of Crohn’s disease and ulcerative colitis genome-wide association scans is undertaken, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls.
Abstract: Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
4,094 citations
University of Kiel1, Cedars-Sinai Medical Center2, Wellcome Trust Sanger Institute3, University of Pennsylvania4, QIMR Berghofer Medical Research Institute5, Peninsula College of Medicine and Dentistry6, University of Edinburgh7, University of Cambridge8, University of Otago9, University of Washington10, University of Groningen11, University of Liège12, Harvard University13, Casa Sollievo della Sofferenza14, King's College London15, University of Chicago16, Yale University17, Johns Hopkins University18, Ludwig Maximilian University of Munich19, Charité20, McGill University21, Lille University of Science and Technology22, Cincinnati Children's Hospital Medical Center23, Ghent University24, Torbay Hospital25, Mater Health Services26, Université libre de Bruxelles27, RWTH Aachen University28, University of Utah29, Örebro University30, Leiden University31, University of Paris32, Technion – Israel Institute of Technology33, University of Western Australia34, Tel Aviv University35, University of Dundee36, University of Manchester37, University of Pittsburgh38, Royal Hospital for Sick Children39, Katholieke Universiteit Leuven40, Guy's and St Thomas' NHS Foundation Trust41, University of Bern42, University of Toronto43, University of Amsterdam44, Karolinska Institutet45, University of Zurich46, Université de Montréal47, Emory University48, Newcastle University49
TL;DR: A meta-analysis of six Crohn's disease genome-wide association studies and a series of in silico analyses highlighted particular genes within these loci implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP.
Abstract: We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
2,482 citations
TL;DR: A myeloid-derived mucosal DC in mice is identified, which populates the entire lamina propria of the small intestine, and CX3CR1-dependent processes, which control host interactions of specialized DCs with commensal and pathogenic bacteria, may regulate immunological tolerance and inflammation.
Abstract: Dendritic cells (DCs) and macrophages are critical to innate and adaptive immunity to the intestinal bacterial microbiota. Here, we identify a myeloid-derived mucosal DC in mice, which populates the entire lamina propria of the small intestine. Lamina propria DCs were found to depend on the chemokine receptor CX3CR1 to form transepithelial dendrites, which enable the cells to directly sample luminal antigens. CX3CR1 was also found to control the clearance of entero-invasive pathogens by DCs. Thus, CX3CR1-dependent processes, which control host interactions of specialized DCs with commensal and pathogenic bacteria, may regulate immunological tolerance and inflammation.
1,563 citations
Wellcome Trust Sanger Institute1, Université de Montréal2, University of Edinburgh3, University of Kiel4, Karolinska Institutet5, Cedars-Sinai Medical Center6, University of Cambridge7, University of Pennsylvania8, Casa Sollievo della Sofferenza9, University of Pittsburgh10, Université libre de Bruxelles11, University of Otago12, Johns Hopkins University13, Ludwig Maximilian University of Munich14, Charité15, Lille University of Science and Technology16, Cincinnati Children's Hospital Medical Center17, Ghent University18, Torbay Hospital19, University of Groningen20, Mater Health Services21, University of Liège22, University of Washington23, University of Utah24, QIMR Berghofer Medical Research Institute25, University of Paris26, University of Western Australia27, Tel Aviv University28, University of Dundee29, Harvard University30, University of Manchester31, Utrecht University32, University of Florence33, King's College London34, Yale University35, Royal Hospital for Sick Children36, Katholieke Universiteit Leuven37, Guy's and St Thomas' NHS Foundation Trust38, University of Barcelona39, University of Chicago40, University of Bern41, University of California, San Francisco42, Agency for Science, Technology and Research43, University of Toronto44, University of Oslo45, Leiden University46, University of Amsterdam47, Aarhus University48, National and Kapodistrian University of Athens49, Lithuanian University of Health Sciences50, Newcastle University51, Emory University52, Örebro University53, French Institute of Health and Medical Research54, Center for Applied Genomics55
TL;DR: A meta-analysis of six ulcerative colitis genome-wide association study datasets found many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1.
Abstract: Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.
1,291 citations
TL;DR: Both Th1 and Th17 cells are important mediators of inflammation in Crohn’s disease, although activities previously ascribed to IL12 may be mediated by IL23.
Abstract: Traditionally, Crohn’s disease has been associated with a Th1 cytokine profile, while Th2 cytokines are modulators of ulcerative colitis. This concept has been challenged by the description of tolerising regulatory T cells (Treg) and by proinflammatory Th17 cells, a novel T cell population characterised by the master transcription factor RORγt, the surface markers IL23R and CCR6, and by production of the proinflammatory cytokines IL17A, IL17F, IL21, IL22 and IL26, and the chemokine CCL20. Th17 cells differentiate under the influence of IL1β, IL6, IL21 and IL23. Recent studies indicate that TGFβ is essential not only for the development of murine Th17 cells but also for differentiation of human Th17 cells. TGFβ reciprocally regulates the differentiation of inflammatory Th17 cells and suppressive Treg subsets, with the concomitant presence of proinflammatory cytokines favouring Th17 cell differentiation. Several studies demonstrated an important role of Th17 cells in intestinal inflammation, particularly in Crohn’s disease. Genome-wide association studies indicate that IL23R and five additional genes involved in Th17 differentiation ( IL12B , JAK2 , STAT3 , CCR6 and TNFSF15 ) are associated with susceptibility to Crohn’s disease and partly also to ulcerative colitis. Taken together, both Th1 and Th17 cells are important mediators of inflammation in Crohn’s disease, although activities previously ascribed to IL12 may be mediated by IL23. Anti-IL12/IL23p40 antibody therapy, which targets both Th1 and Th17 cells, is effective in Crohn’s disease. However, the complex relationship between Th1 and Th17 cells has not been completely analysed. This will be of great importance to delineate the specific contributions of these cells to Crohn’s disease and other autoimmune diseases.
610 citations
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TL;DR: Associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses.
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
6,809 citations
Massachusetts Institute of Technology1, Broad Institute2, University of California, Los Angeles3, University of British Columbia4, Baylor College of Medicine5, Howard Hughes Medical Institute6, University of Washington7, Ludwig Institute for Cancer Research8, University of California, San Francisco9, University of Connecticut10, University of Zagreb11, University of Texas at Austin12, Washington University in St. Louis13, University of Queensland14, Harvard University15, Cold Spring Harbor Laboratory16, University of Southern California17, University of California, Santa Cruz18, Simon Fraser University19, Morgridge Institute for Research20, University of Texas at Dallas21, National Institutes of Health22
TL;DR: It is shown that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease.
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.
5,037 citations
TL;DR: It is shown that the orphan nuclear receptor RORgammat is the key transcription factor that orchestrates the differentiation of this effector cell lineage of proinflammatory T helper cells and its potential as a therapeutic target in inflammatory diseases is highlighted.
4,616 citations
TL;DR: The investigation of the differentiation, effector function, and regulation of Th17 cells has opened up a new framework for understanding T cell differentiation and now appreciate the importance of Th 17 cells in clearing pathogens during host defense reactions and in inducing tissue inflammation in autoimmune disease.
Abstract: CD4+ T cells, upon activation and expansion, develop into different T helper cell subsets with different cytokine profiles and distinct effector functions. Until recently, T cells were divided into Th1 or Th2 cells, depending on the cytokines they produce. A third subset of IL-17-producing effector T helper cells, called Th17 cells, has now been discovered and characterized. Here, we summarize the current information on the differentiation and effector functions of the Th17 lineage. Th17 cells produce IL-17, IL-17F, and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors. Th17 cells also secrete IL-21 to communicate with the cells of the immune system. The differentiation factors (TGF-β plus IL-6 or IL-21), the growth and stabilization factor (IL-23), and the transcription factors (STAT3, RORγt, and RORα) involved in the development of Th17 cells have just been identified. The participation of TGF-β in the differentiation of Th17 cells places ...
4,548 citations
TL;DR: The landscape of gene expression across tissues is described, thousands of tissue-specific and shared regulatory expression quantitative trait loci (eQTL) variants are cataloged, complex network relationships are described, and signals from genome-wide association studies explained by eQTLs are identified.
Abstract: Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysi...
4,418 citations