Author
Huji Xu
Other affiliations: QIMR Berghofer Medical Research Institute, Tsinghua University
Bio: Huji Xu is an academic researcher from Second Military Medical University. The author has contributed to research in topics: Medicine & Genome-wide association study. The author has an hindex of 30, co-authored 78 publications receiving 5419 citations. Previous affiliations of Huji Xu include QIMR Berghofer Medical Research Institute & Tsinghua University.
Papers published on a yearly basis
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Harvard University1, Broad Institute2, Monash University3, Kyoto University4, Genentech5, Vanderbilt University6, New York University7, NewYork–Presbyterian Hospital8, Second Military Medical University9, University of Queensland10, University of Toronto11, University of Groningen12, University of Tartu13, Beijing Jiaotong University14, Icahn School of Medicine at Mount Sinai15, Radboud University Nijmegen16, Medisch Spectrum Twente17, Leiden University18, University of Paris19, French Institute of Health and Medical Research20, University of Alabama at Birmingham21, University of Cambridge22, University of Amsterdam23, GlaxoSmithKline24, Hanyang University25, Spanish National Research Council26, Complutense University of Madrid27, Umeå University28, Boston University29, Council on Education for Public Health30, McGill University31, University of Manchester32, National Health Service33, University of Pittsburgh34, University of California, San Francisco35, Karolinska Institutet36, North Shore-LIJ Health System37, University of Chicago38, University of Tokyo39
TL;DR: A genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries provides empirical evidence that the genetics of RA can provide important information for drug discovery, and sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis.
Abstract: A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
1,910 citations
Medical Research Council1, University of Oxford2, National Institute for Health Research3, Structural Genomics Consortium4, University of Bristol5, University of Bath6, University of Queensland7, National Institutes of Health8, Cedars-Sinai Medical Center9, University of Toronto10, University of Alberta11, Memorial University of Newfoundland12, University of Leeds13, Norfolk and Norwich University Hospital14, Repatriation General Hospital15, University of Porto16, Sapienza University of Rome17, QIMR Berghofer Medical Research Institute18, Second Military Medical University19, Telethon Institute for Child Health Research20, Wellcome Trust Sanger Institute21, University of London22, Trinity College, Dublin23, Cardiff University24, Wellcome Trust25, Wellcome Trust Centre for Human Genetics26, St George's, University of London27, King's College London28, Churchill Hospital29, University of Leicester30, University of Cambridge31, Moorfields Eye Hospital32, University College London33, University of Texas Health Science Center at Houston34, Princess Alexandra Hospital35
TL;DR: In this paper, the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all their datasets (p < 5x 10(-6) overall, with support in each of the three datasets studied).
Abstract: Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 x 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.
798 citations
University of Queensland1, Nuffield Orthopaedic Centre2, Hanyang University3, Cedars-Sinai Medical Center4, National Institutes of Health5, University of Paris6, University of Oslo7, King Abdulaziz University8, Danube University Krems9, National Institute for Health and Welfare10, Second Military Medical University11, Ghent University12, National Autonomous University of Mexico13, University of Otago14, University of Toronto15, Royal Brisbane and Women's Hospital16, Autonomous University of Madrid17, Central University, India18, Wellcome Trust Sanger Institute19, University of Oxford20, Norfolk and Norwich University Hospital21, University of Cambridge22, University Health Network23, Memorial University of Newfoundland24, University of Alberta25, Nova Southeastern University26, Norwegian University of Science and Technology27, Universidad de La Sabana28, Spanish National Research Council29, Université Paris-Saclay30, Medical Research Council31
TL;DR: In this paper, the authors used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls.
Abstract: Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis-associated haplotypes at 11 loci. Two ankylosing spondylitis-associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.
620 citations
01 Jan 2011
TL;DR: This paper reported the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P -8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9.
Abstract: Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P -8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P -6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.
255 citations
TL;DR: Data suggest that this may be hastened by exposure to malaria antigens in low dose, leading to augmented cellular immunity and rapid parasite clearance.
Abstract: The immune response to the malaria parasite is complex and poorly understood. Although antibodies and T cells can control parasite growth in model systems, natural immunity to malaria in regions of high endemicity takes several years to develop. Variation and polymorphism of antibody target antigens are known to impede immune responses, but these factors alone cannot account for the slow acquisition of immunity. In human and animal model systems, cell-mediated responses can control parasite growth effectively, but such responses are regulated by parasite load via direct effects on dendritic cells and possibly on T and B cells as well. Furthermore, high parasite load is associated with pathology, and cell-mediated responses may also harm the host. Inflammatory cytokines have been implicated in the pathogenesis of cerebral malaria, anemia, weight loss, and respiratory distress in malaria. Immunity without pathology requires rapid parasite clearance, effective regulation of the inflammatory antiparasite effects of cellular responses, and the eventual development of a repertoire of antibodies effective against multiple strains. Data suggest that this may be hastened by exposure to malaria antigens in low dose, leading to augmented cellular immunity and rapid parasite clearance.
202 citations
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TL;DR: The remarkable range of discoveriesGWASs has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics are reviewed.
Abstract: Application of the experimental design of genome-wide association studies (GWASs) is now 10 years old (young), and here we review the remarkable range of discoveries it has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics. We predict the likely discoveries in the next 10 years, when GWASs will be based on millions of samples with array data imputed to a large fully sequenced reference panel and on hundreds of thousands of samples with whole-genome sequencing data.
2,669 citations
TL;DR: The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs), which were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders.
Abstract: The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs). These studies were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders. We start by giving a number of quotes from scientists and journalists about perceived problems with GWASs. We will then briefly give the history of GWASs and focus on the discoveries made through this experimental design, what those discoveries tell us and do not tell us about the genetics and biology of complex traits, and what immediate utility has come out of these studies. Rather than giving an exhaustive review of all reported findings for all diseases and other complex traits, we focus on the results for auto-immune diseases and metabolic diseases. We return to the perceived failure or disappointment about GWASs in the concluding section.
2,361 citations
TL;DR: It is proposed that gene regulatory networks are sufficiently interconnected such that all genes expressed in disease-relevant cells are liable to affect the functions of core disease-related genes and that most heritability can be explained by effects on genes outside core pathways.
2,257 citations
Journal Article•
TL;DR: Definition: To what extent does the study allow us to draw conclusions about a causal effect between two or more constructs?
Abstract: Definition: To what extent does the study allow us to draw conclusions about a causal effect between two or more constructs? Issues: Selection, maturation, history, mortality, testing, regression towrd the mean, selection by maturation, treatment by mortality, treatment by testing, measured treatment variables Increase: Eliminate the threats, above all do experimental manipulations, random assignment, and counterbalancing.
2,006 citations
TL;DR: A new method is introduced, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers, which is computationally tractable at very large sample sizes and leverages genome-wide information.
Abstract: Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here we analyze a broad set of functional elements, including cell type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes and leverages genome-wide information. Our findings include a large enrichment of heritability in conserved regions across many traits, a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers and many cell type-specific enrichments, including significant enrichment of central nervous system cell types in the heritability of body mass index, age at menarche, educational attainment and smoking behavior.
1,939 citations