Seventy-five genetic loci influencing the human red blood cell

Pim Van Der Harst, Weihua Zhang, Irene Mateo Leach, Augusto Rendon, Niek Verweij, Joban Sehmi, Dirk S. Paul, Ulrich Elling, Hooman Allayee, Xinzhong Li, Aparna Radhakrishnan, Sian Tsung Tan, Katrin Voss, Christian X. Weichenberger, Cornelis A. Albers, Abtehale Al-Hussani, Folkert W. Asselbergs, Marina Ciullo, Fabrice Danjou, Christian Dina & 175 others Tõnu Esko, David M. Evans, Lude Franke, Martin Gögele, Jaana Hartiala, Micha Hersch, Hilma Holm, Jouke Jan Hottenga, Stavroula Kanoni, Marcus E. Kleber, Vasiliki Lagou, Claudia Langenberg, Lorna M. Lopez, Leo Pekka Lyytikäinen, Olle Melander, Federico Murgia, Ilja M. Nolte, Paul F. O'Reilly, Sandosh Padmanabhan, Afshin Parsa, Nicola Pirastu, Eleonora Porcu, Laura Portas, Inga Prokopenko, Janina S. Ried, So Youn Shin, Clara S. Tang, Alexander Teumer, Michela Traglia, Sheila Ulivi, Harm Jan Westra, Jian Yang, Jing Hua Zhao, Franco Anni, Abdel Abdellaoui, Antony Attwood, Beverley Balkau, Stefania Bandinelli, François Bastardot, Beben Benyamin, Bernhard O. Boehm, William O. Cookson, Debashish Das, Paul I.W. De Bakker, Rudolf A. De Boer, Eco J.C. De Geus, Marleen H. De Moor, Maria Dimitriou, Francisco S. Domingues, Angela Döring, Gunnar Engström, Gudmundur Ingi Eyjolfsson, Luigi Ferrucci, Krista Fischer, Renzo Galanello, Stephen F. Garner, Bernd Genser, Quince D. Gibson, Giorgia Girotto, Daniel Fannar Gudbjartsson, Sarah E. Harris, Anna Liisa Hartikainen, Claire E. Hastie, Bo Hedblad, Thomas Illig, Jennifer Jolley, Mika Kähönen, Ido P. Kema, John P. Kemp, Liming Liang, Heather Lloyd-Jones, Ruth J.F. Loos, Stuart Meacham, Sarah E. Medland, Christa Meisinger, Yasin Memari, Evelin Mihailov, Kathy Miller, Miriam F. Moffatt, Matthias Nauck, Maria Novatchkova, Teresa Nutile, Isleifur Olafsson, Pall T. Onundarson, Debora Parracciani, Brenda W. Penninx, Lucia Perseu, Antonio Piga, Giorgio Pistis, Anneli Pouta, Ursula Puc, Olli Raitakari, Susan M. Ring, Antonietta Robino, Daniela Ruggiero, Aimo Ruokonen, Aude Saint-Pierre, Cinzia Sala, Andres Salumets, Jennifer Sambrook, Hein Schepers, Carsten Oliver Schmidt, Herman H.W. Silljé, Rob Sladek, Johannes H. Smit, John M. Starr, Jonathan Stephens, Patrick Sulem, Toshiko Tanaka, Unnur Thorsteinsdottir, Vinicius Tragante, Wiek H. Van Gilst, L. Joost Van Pelt, Dirk J. Van Veldhuisen, Uwe Völker, John B. Whitfield, Gonneke Willemsen, Bernhard R. Winkelmann, Gerald Wirnsberger, Ale Algra, Francesco Cucca, Adamo Pio D'Adamo, John Danesh, Ian J. Deary, Anna F. Dominiczak, Paul Elliott, Paolo Fortina, Philippe Froguel, Paolo Gasparini, Andreas Greinacher, Stanley L. Hazen, Marjo Riitta Jarvelin, Kay Tee Khaw, Terho Lehtimäki, Winfried Maerz, Nicholas G. Martin, Andres Metspalu, Braxton D. Mitchell, Grant W. Montgomery, Carmel Moore, Gerjan Navis, Mario Pirastu, Peter P. Pramstaller, Ramiro Ramirez-Solis, Eric Schadt, James Scott, Alan R. Shuldiner, George Davey Smith, J. Gustav Smith, Harold Snieder, Rossella Sorice, Tim D. Spector, Kari Stefansson, Michael Stumvoll, W. H. Wilson Tang, Daniela Toniolo, Anke Tönjes, Peter M. Visscher, Peter Vollenweider, Nicholas J. Wareham, Bruce H.R. Wolffenbuttel, Dorret I. Boomsma, Jacques S. Beckmann, George V. Dedoussis, Panos Deloukas, Manuel A. Ferreira, Serena Sanna, Manuela Uda, Andrew A. Hicks, Josef Martin Penninger, Christian Gieger, Jaspal S. Kooner, Willem H. Ouwehand, Nicole Soranzo, John C. Chambers

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Abstract

Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10 -8, which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.

LanguageEnglish
Pages369-375
Number of pages7
JournalNature
Volume492
Issue number7429
DOIs
Publication statusPublished - 20 Dec 2012

ASJC Scopus subject areas

  • General

Cite this

Van Der Harst, P., Zhang, W., Mateo Leach, I., Rendon, A., Verweij, N., Sehmi, J., ... Chambers, J. C. (2012). Seventy-five genetic loci influencing the human red blood cell. Nature, 492(7429), 369-375. https://doi.org/10.1038/nature11677