Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-04

AUTHORS

Anubha Mahajan, Jennifer Wessel, Sara M Willems, Wei Zhao, Neil R Robertson, Audrey Y Chu, Wei Gan, Hidetoshi Kitajima, Daniel Taliun, N William Rayner, Xiuqing Guo, Yingchang Lu, Man Li, Richard A Jensen, Yao Hu, Shaofeng Huo, Kurt K Lohman, Weihua Zhang, James P Cook, Bram Peter Prins, Jason Flannick, Niels Grarup, Vassily Vladimirovich Trubetskoy, Jasmina Kravic, Young Jin Kim, Denis V Rybin, Hanieh Yaghootkar, Martina Müller-Nurasyid, Karina Meidtner, Ruifang Li-Gao, Tibor V Varga, Jonathan Marten, Jin Li, Albert Vernon Smith, Ping An, Symen Ligthart, Stefan Gustafsson, Giovanni Malerba, Ayse Demirkan, Juan Fernandez Tajes, Valgerdur Steinthorsdottir, Matthias Wuttke, Cécile Lecoeur, Michael Preuss, Lawrence F Bielak, Marielisa Graff, Heather M Highland, Anne E Justice, Dajiang J Liu, Eirini Marouli, Gina Marie Peloso, Helen R Warren, , , , Saima Afaq, Shoaib Afzal, Emma Ahlqvist, Peter Almgren, Najaf Amin, Lia B Bang, Alain G Bertoni, Cristina Bombieri, Jette Bork-Jensen, Ivan Brandslund, Jennifer A Brody, Noël P Burtt, Mickaël Canouil, Yii-Der I da Chen, Yoon Shin Cho, Cramer Christensen, Sophie V Eastwood, Kai-Uwe Eckardt, Krista Fischer, Giovanni Gambaro, Vilmantas Giedraitis, Megan L Grove, Hugoline G de Haan, Sophie Hackinger, Yang Hai, Sohee Han, Anne Tybjærg-Hansen, Marie-France Hivert, Bo Isomaa, Susanne Jäger, Marit E Jørgensen, Torben Jørgensen, Annemari Käräjämäki, Bong-Jo Kim, Sung Soo Kim, Heikki A Koistinen, Peter Kovacs, Jennifer Kriebel, Florian Kronenberg, Kristi Läll, Leslie A Lange, Jung-Jin Lee, Benjamin Lehne, Huaixing Li, Keng-Hung Lin, Allan Linneberg, Ching-Ti Liu, Jun Liu, Marie Loh, Reedik Mägi, Vasiliki Mamakou, Roberta McKean-Cowdin, Girish Nadkarni, Matt Neville, Sune F Nielsen, Ioanna Ntalla, Patricia A Peyser, Wolfgang Rathmann, Kenneth Rice, Stephen S Rich, Line Rode, Olov Rolandsson, Sebastian Schönherr, Elizabeth Selvin, Kerrin S Small, Alena Stančáková, Praveen Surendran, Kent D Taylor, Tanya M Teslovich, Barbara Thorand, Gudmar Thorleifsson, Adrienne Tin, Anke Tönjes, Anette Varbo, Daniel R Witte, Andrew R Wood, Pranav Yajnik, Jie Yao, Loïc Yengo, Robin Young, Philippe Amouyel, Heiner Boeing, Eric Boerwinkle, Erwin P Bottinger, Rajiv Chowdhury, Francis S Collins, George Dedoussis, Abbas Dehghan, Panos Deloukas, Marco M Ferrario, Jean Ferrières, Jose C Florez, Philippe Frossard, Vilmundur Gudnason, Tamara B Harris, Susan R Heckbert, Joanna M M Howson, Martin Ingelsson, Sekar Kathiresan, Frank Kee, Johanna Kuusisto, Claudia Langenberg, Lenore J Launer, Cecilia M Lindgren, Satu Männistö, Thomas Meitinger, Olle Melander, Karen L Mohlke, Marie Moitry, Andrew D Morris, Alison D Murray, Renée de Mutsert, Marju Orho-Melander, Katharine R Owen, Markus Perola, Annette Peters, Michael A Province, Asif Rasheed, Paul M Ridker, Fernando Rivadineira, Frits R Rosendaal, Anders H Rosengren, Veikko Salomaa, Wayne H -H Sheu, Rob Sladek, Blair H Smith, Konstantin Strauch, André G Uitterlinden, Rohit Varma, Cristen J Willer, Matthias Blüher, Adam S Butterworth, John Campbell Chambers, Daniel I Chasman, John Danesh, Cornelia van Duijn, Josée Dupuis, Oscar H Franco, Paul W Franks, Philippe Froguel, Harald Grallert, Leif Groop, Bok-Ghee Han, Torben Hansen, Andrew T Hattersley, Caroline Hayward, Erik Ingelsson, Sharon LR Kardia, Fredrik Karpe, Jaspal Singh Kooner, Anna Köttgen, Kari Kuulasmaa, Markku Laakso, Xu Lin, Lars Lind, Yongmei Liu, Ruth J F Loos, Jonathan Marchini, Andres Metspalu, Dennis Mook-Kanamori, Børge G Nordestgaard, Colin N A Palmer, James S Pankow, Oluf Pedersen, Bruce M Psaty, Rainer Rauramaa, Naveed Sattar, Matthias B Schulze, Nicole Soranzo, Timothy D Spector, Kari Stefansson, Michael Stumvoll, Unnur Thorsteinsdottir, Tiinamaija Tuomi, Jaakko Tuomilehto, Nicholas J Wareham, James G Wilson, Eleftheria Zeggini, Robert A Scott, Inês Barroso, Timothy M Frayling, Mark O Goodarzi, James B Meigs, Michael Boehnke, Danish Saleheen, Andrew P Morris, Jerome I Rotter, Mark I McCarthy

ABSTRACT

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition. More... »

PAGES

559-571

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  • Journal

    TITLE

    Nature Genetics

    ISSUE

    4

    VOLUME

    50

    Author Affiliations

  • Wellcome Centre for Human Genetics
  • Indiana University – Purdue University Indianapolis
  • Institute of Metabolic Science
  • University of Pennsylvania
  • University of Oxford
  • Brigham and Women's Hospital
  • University of Michigan–Ann Arbor
  • Wellcome Sanger Institute
  • Harbor–UCLA Medical Center
  • Icahn School of Medicine at Mount Sinai
  • University of Utah
  • University of Washington
  • Shanghai Institutes for Biological Sciences
  • Wake Forest Baptist Medical Center
  • Ealing Hospital
  • University of Liverpool
  • Massachusetts General Hospital
  • University of Copenhagen
  • Lund University
  • Korea National Institute of Health
  • Boston University
  • University of Exeter
  • German Centre for Cardiovascular Research
  • German Center for Diabetes Research
  • Leiden University Medical Center
  • University of Edinburgh
  • Stanford University
  • University of Iceland
  • Washington University in St. Louis
  • Erasmus University Medical Center
  • Uppsala University
  • University of Verona
  • deCODE Genetics (Iceland)
  • Lille 1 University
  • University of North Carolina System
  • The University of Texas Health Science Center at Houston
  • Penn State Milton S. Hershey Medical Center
  • Queen Mary University of London
  • Imperial College London
  • Vejle Sygehus
  • Broad Institute
  • Hallym University
  • University College London
  • Charité
  • University of Tartu
  • Catholic University of the Sacred Heart
  • Université de Sherbrooke
  • Folkhälsans Forskningscentrum
  • Danish National Institute of Public Health
  • Aalborg University
  • Vaasa Central Hospital
  • Helsinki University Central Hospital
  • Leipzig University
  • Innsbruck Medical University
  • University of Colorado Anschutz Medical Campus
  • Taichung Veterans General Hospital
  • Agency for Science, Technology and Research
  • National and Kapodistrian University of Athens
  • University of Southern California
  • NIHR Oxford Musculoskeletal Biomedical Research Unit
  • German Diabetes Center - Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf
  • University of Virginia
  • Umeå University
  • Johns Hopkins University
  • King's College London
  • University of Cambridge
  • Helmholtz Zentrum München
  • Danish Diabetes Academy
  • University of Glasgow
  • German Institute of Human Nutrition
  • Baylor College of Medicine
  • National Human Genome Research Institute
  • Harokopio University
  • King Abdulaziz University
  • University of Insubria
  • Hôpital Rangueil
  • Harvard University
  • Center for Non-Communicable Diseases
  • National Institutes of Health
  • Queen's University Belfast
  • National Institute for Health and Welfare
  • Technical University Munich
  • University of North Carolina at Chapel Hill
  • Hôpitaux Universitaires de Strasbourg
  • University of Aberdeen
  • University of Helsinki
  • National Yang Ming University
  • McGill University
  • Ludwig Maximilian University of Munich
  • University of Southern Denmark
  • University of Minnesota
  • Kuopion Liikuntalääketieteen Tutkimuslaitos
  • University Hospital Leipzig
  • University of Mississippi Medical Center
  • Cedars-Sinai Medical Center
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41588-018-0084-1

    DOI

    http://dx.doi.org/10.1038/s41588-018-0084-1

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1103192964

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29632382


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