Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2018-11

AUTHORS

Anubha Mahajan, Daniel Taliun, Matthias Thurner, Neil R. Robertson, Jason M. Torres, N. William Rayner, Anthony J. Payne, Valgerdur Steinthorsdottir, Robert A. Scott, Niels Grarup, James P. Cook, Ellen M. Schmidt, Matthias Wuttke, Chloé Sarnowski, Reedik Mägi, Jana Nano, Christian Gieger, Stella Trompet, Cécile Lecoeur, Michael H. Preuss, Bram Peter Prins, Xiuqing Guo, Lawrence F. Bielak, Jennifer E. Below, Donald W. Bowden, John Campbell Chambers, Young Jin Kim, Maggie C. Y. Ng, Lauren E. Petty, Xueling Sim, Weihua Zhang, Amanda J. Bennett, Jette Bork-Jensen, Chad M. Brummett, Mickaël Canouil, Kai-Uwe Ec kardt, Krista Fischer, Sharon L. R. Kardia, Florian Kronenberg, Kristi Läll, Ching-Ti Liu, Adam E. Locke, Jian’an Luan, Ioanna Ntalla, Vibe Nylander, Sebastian Schönherr, Claudia Schurmann, Loïc Yengo, Erwin P. Bottinger, Ivan Brandslund, Cramer Christensen, George Dedoussis, Jose C. Florez, Ian Ford, Oscar H. Franco, Timothy M. Frayling, Vilmantas Giedraitis, Sophie Hackinger, Andrew T. Hattersley, Christian Herder, M. Arfan Ikram, Martin Ingelsson, Marit E. Jørgensen, Torben Jørgensen, Jennifer Kriebel, Johanna Kuusisto, Symen Ligthart, Cecilia M. Lindgren, Allan Linneberg, Valeriya Lyssenko, Vasiliki Mamakou, Thomas Meitinger, Karen L. Mohlke, Andrew D. Morris, Girish Nadkarni, James S. Pankow, Annette Peters, Naveed Sattar, Alena Stančáková, Konstantin Strauch, Kent D. Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Jaakko Tuomilehto, Daniel R. Witte, Josée Dupuis, Patricia A. Peyser, Eleftheria Zeggini, Ruth J. F. Loos, Philippe Froguel, Erik Ingelsson, Lars Lind, Leif Groop, Markku Laakso, Francis S. Collins, J. Wouter Jukema, Colin N. A. Palmer, Harald Grallert, Andres Metspalu, Abbas Dehghan, Anna Köttgen, Goncalo R. Abecasis, James B. Meigs, Jerome I. Rotter, Jonathan Marchini, Oluf Pedersen, Torben Hansen, Claudia Langenberg, Nicholas J. Wareham, Kari Stefansson, Anna L. Gloyn, Andrew P. Morris, Michael Boehnke, Mark I. McCarthy

ABSTRACT

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence). More... »

PAGES

1505-1513

Journal

TITLE

Nature Genetics

ISSUE

11

VOLUME

50

Author Affiliations

  • University of Oxford
  • University of Michigan–Ann Arbor
  • Wellcome Centre for Human Genetics
  • Wellcome Sanger Institute
  • Institute of Metabolic Science
  • University of Copenhagen
  • University of Liverpool
  • University of Freiburg
  • Boston University
  • University of Tartu
  • Erasmus University Medical Center
  • German Center for Diabetes Research
  • Leiden University Medical Center
  • Lille 1 University
  • Icahn School of Medicine at Mount Sinai
  • Harbor–UCLA Medical Center
  • Vanderbilt University Medical Center
  • Wake Forest University
  • Imperial College London
  • Korea National Institute of Health
  • National University of Singapore
  • Ealing Hospital
  • Innsbruck Medical University
  • Washington University in St. Louis
  • Queen Mary University of London
  • Vejle Sygehus
  • Harokopio University
  • Broad Institute
  • University of Glasgow
  • University of Exeter
  • Uppsala University
  • German Diabetes Center - Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf
  • Danish National Institute of Public Health
  • Aalborg University
  • University of Bergen
  • National and Kapodistrian University of Athens
  • German Centre for Cardiovascular Research
  • University of North Carolina at Chapel Hill
  • University of Edinburgh
  • University of Minnesota
  • Ludwig Maximilian University of Munich
  • University of Iceland
  • King Abdulaziz University
  • Danish Diabetes Academy
  • National Heart Lung and Blood Institute
  • University of Helsinki
  • National Human Genome Research Institute
  • Massachusetts General Hospital
  • University of Southern Denmark
  • NIHR Oxford Musculoskeletal Biomedical Research Unit
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41588-018-0241-6

    DOI

    http://dx.doi.org/10.1038/s41588-018-0241-6

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1107353303

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30297969


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