A Genome-Wide Meta-Analysis Yields 46 New Loci Associating with Biomarkers of Iron Homeostasis

Steven Bell, Andreas S. Rigas, Magnus K. Magnusson, Egil Ferkingstad, Elias Allara, Gyda Bjornsdottir, Anna Ramond, Erik Sørensen, Gisli H. Halldorsson, Dirk S. Paul, Kristoffer Sølvsten Burgdorf, Hanne P. Eggertsson, Joanna M. M. Howson, Lise W. Thørner, Snaedis Kristmundsdottir, William J. Astle, Christian Erikstrup, Jon K. Sigurdsson, Dragana Vukovic, Khoa M. DinhVinicius Tragante, Praveen Surendran, Ole Birger Pedersen, Brynja Vidarsson, Tao Jiang, Helene M. Paarup, Pall T. Onundarson, Parsa Akbari, Kaspar René Nielsen, Sigrun H. Lund, Kristinn Juliusson, Magnus I. Magnusson, Michael L. Frigge, Asmundur Oddsson, Isleifur Olafsson, Stephen Kaptoge, Henrik Hjalgrim, Gudmundur Runarsson, Angela M. Wood, Ingileif Jonsdottir, Thomas Folkmann Hansen, Olof Sigurdardottir, Hreinn Stefansson, David Rye, Steffen Andersen, Karina Banasik, Søren Brunak, Kristoffer Burgdorf, Christian Erikstrup, Gregor Borut Ernst Jemec, Poul Jennum, Pär I. Johanssond, Mette Nyegaard, Mikkel Petersen, Thomas Werge, James E. Peters, David Westergaard, Hilma Holm, Nicole Soranzo, Gudmar Thorleifsson, Willem H. Ouwehand, Unnur Thorsteinsdottir, David J. Roberts, Patrick Sulem, Adam S. Butterworth, Daniel F. Gudbjartsson, John Danesh, Søren Brunak, Emanuele Di Angelantonio, Henrik Ullum, Kari Stefansson*

*Corresponding author for this work

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Abstract

Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.
Original languageEnglish
Article number156
JournalCommunications Biology
Volume4
Issue number1
Number of pages14
ISSN2399-3642
DOIs
Publication statusPublished - Dec 2021

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