Author
Akari Suzuki
Bio: Akari Suzuki is an academic researcher from University of Tokyo. The author has contributed to research in topics: Genome-wide association study & Genetic association. The author has an hindex of 5, co-authored 6 publications receiving 1848 citations.
Papers
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Broad Institute1, Harvard University2, 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, National Health Service32, University of Manchester33, 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
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Oklahoma Medical Research Foundation1, Howard Hughes Medical Institute2, Peking University3, Hanyang University4, Tokyo Medical and Dental University5, Shanghai Jiao Tong University6, Kyungpook National University Hospital7, Ajou University8, Dong-A University Hospital9, Yonsei University10, The Catholic University of America11, Chungnam National University12, University of Tsukuba13, University of Tokyo14, Chonnam National University15, Virginia Commonwealth University16, Cincinnati Children's Hospital Medical Center17, University of Malaya18
TL;DR: Ten new SLE susceptibility loci are identified and the new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.
Abstract: Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta = 3.75 × 10(-117), odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression in cis or in trans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.
194 citations
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TL;DR: It is shown that PAD4 regulates the proliferation of multipotent progenitors in the bone marrow by controlling c-myc expression and lymphoid enhancer-binding factor 1 and histone deacetylase 1 at the upstream region of the c- myc gene.
Abstract: Peptidylarginine deiminase 4 (PAD4) functions as a transcriptional coregulator by catalyzing the conversion of histone H3 arginine residues to citrulline residues. Although the high level of PAD4 expression in bone marrow cells suggests its involvement in haematopoiesis, its precise contribution remains unclear. Here we show that PAD4, which is highly expressed in lineage(-) Sca-1(+) c-Kit(+) (LSK) cells of mouse bone marrow compared with other progenitor cells, controls c-myc expression by catalyzing the citrullination of histone H3 on its promoter. Furthermore, PAD4 is associated with lymphoid enhancer-binding factor 1 and histone deacetylase 1 at the upstream region of the c-myc gene. Supporting these findings, LSK cells, especially multipotent progenitors, in PAD4-deficient mice show increased proliferation in a cell-autonomous fashion compared with those in wild-type mice. Together, our results strongly suggest that PAD4 regulates the proliferation of multipotent progenitors in the bone marrow by controlling c-myc expression.
52 citations
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TL;DR: The genetic architecture of RA as determined through GWASs and meta-analyses is described and the potential use of genetic data in clinical practice in RA treatment is examined, which represents a challenge in medical genetics in the post-GWAS era.
47 citations
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TL;DR: The genetic heterogeneity observed in the PADI4 and PTPN22 genes suggests that ethnic variation should be considered in patients of Asian populations.
Abstract: Genome-wide association studies (GWAS) have uncovered numerous susceptibility genes for rheumatoid arthritis (RA) in patients of European, Asian and other ethnic ancestries. Although previous transethnic GWAS meta-analyses enabled the identification of several novel loci, the genetic heterogeneity observed in the PADI4 and PTPN22 genes suggests that ethnic variation should be considered. In addition, the effects of genetic polymorphisms on gene expression profiles are important when assessing the association of genetic information with disease pathogenesis and will influence the development of personalized medicine. Gene expression is controlled by epigenetic modifications, which in turn can be affected by environmental stimuli. Altogether, genetic and epigenetic information of Asian populations will contribute considerably to future rheumatology research.
45 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
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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
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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
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Wellcome Trust Sanger Institute1, University Medical Center Groningen2, Harvard University3, The Chinese University of Hong Kong4, Wellcome Trust Centre for Human Genetics5, Yonsei University6, Icahn School of Medicine at Mount Sinai7, University of Delhi8, University of Liverpool9, Central Manchester University Hospitals NHS Foundation Trust10, St Mary's Hospital11, Asan Medical Center12
TL;DR: The first trans-ancestry association study of IBD is reported, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent, implicate 38 loci in IBD risk for the first time.
Abstract: Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.
1,826 citations
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1,756 citations