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.  Dinh; Vinicius  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

doi:10.1038/s42003-020-01575-z

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

Department of Finance

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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 language	English
Article number	156
Journal	Communications Biology
Volume	4
Issue number	1
Number of pages	14
ISSN	2399-3642
DOIs	https://doi.org/10.1038/s42003-020-01575-z
Publication status	Published - Dec 2021

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Bell, S., Rigas, A. S., Magnusson, M. K., Ferkingstad, E., Allara, E., Bjornsdottir, G., Ramond, A., Sørensen, E., Halldorsson, G. H., Paul, D. S., Burgdorf, K. S., Eggertsson, H. P., Howson, J. M. M., Thørner, L. W., Kristmundsdottir, S., Astle, W. J., Erikstrup, C., Sigurdsson, J. K., Vukovic, D., ... Stefansson, K. (2021). A Genome-Wide Meta-Analysis Yields 46 New Loci Associating with Biomarkers of Iron Homeostasis. Communications Biology, 4(1), [156]. https://doi.org/10.1038/s42003-020-01575-z

Bell, Steven ; Rigas, Andreas S. ; Magnusson, Magnus K. ; Ferkingstad, Egil ; Allara, Elias ; Bjornsdottir, Gyda ; Ramond, Anna ; Sørensen, Erik ; Halldorsson, Gisli H. ; Paul, Dirk S. ; Burgdorf, Kristoffer Sølvsten ; Eggertsson, Hanne P. ; Howson, Joanna M. M. ; Thørner, Lise W. ; Kristmundsdottir, Snaedis ; Astle, William J. ; Erikstrup, Christian ; Sigurdsson, Jon K. ; Vukovic, Dragana ; Dinh, Khoa M. ; Tragante, Vinicius ; Surendran, Praveen ; Pedersen, Ole Birger ; Vidarsson, Brynja ; Jiang, Tao ; Paarup, Helene M. ; Onundarson, Pall T. ; Akbari, Parsa ; Nielsen, Kaspar René ; Lund, Sigrun H. ; Juliusson, Kristinn ; Magnusson, Magnus I. ; Frigge, Michael L. ; Oddsson, Asmundur ; Olafsson, Isleifur ; Kaptoge, Stephen ; Hjalgrim, Henrik ; Runarsson, Gudmundur ; Wood, Angela M. ; Jonsdottir, Ingileif ; Folkmann Hansen, Thomas ; Sigurdardottir, Olof ; Stefansson, Hreinn ; Rye, David ; Andersen, Steffen ; Banasik, Karina ; Brunak, Søren ; Burgdorf, Kristoffer ; Erikstrup, Christian ; Jemec, Gregor Borut Ernst ; Jennum, Poul ; Johanssond, Pär I. ; Nyegaard, Mette ; Petersen, Mikkel ; Werge, Thomas ; Peters, James E. ; Westergaard, David ; Holm, Hilma ; Soranzo, Nicole ; Thorleifsson, Gudmar ; Ouwehand, Willem H. ; Thorsteinsdottir, Unnur ; Roberts, David J. ; Sulem, Patrick ; Butterworth, Adam S. ; Gudbjartsson, Daniel F. ; Danesh, John ; Brunak, Søren ; Angelantonio, Emanuele Di ; Ullum, Henrik ; Stefansson, Kari . / A Genome-Wide Meta-Analysis Yields 46 New Loci Associating with Biomarkers of Iron Homeostasis. In: Communications Biology. 2021 ; Vol. 4, No. 1.

@article{299a23aefbae4bbeb431dff739668ee8,

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

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.",

author = "Steven Bell and Rigas, {Andreas S.} and Magnusson, {Magnus K.} and Egil Ferkingstad and Elias Allara and Gyda Bjornsdottir and Anna Ramond and Erik S{\o}rensen and Halldorsson, {Gisli H.} and Paul, {Dirk S.} and Burgdorf, {Kristoffer S{\o}lvsten} and Eggertsson, {Hanne P.} and Howson, {Joanna M. M.} and Th{\o}rner, {Lise W.} and Snaedis Kristmundsdottir and Astle, {William J.} and Christian Erikstrup and Sigurdsson, {Jon K.} and Dragana Vukovic and Dinh, {Khoa M.} and Vinicius Tragante and Praveen Surendran and Pedersen, {Ole Birger} and Brynja Vidarsson and Tao Jiang and Paarup, {Helene M.} and Onundarson, {Pall T.} and Parsa Akbari and Nielsen, {Kaspar Ren{\'e}} and Lund, {Sigrun H.} and Kristinn Juliusson and Magnusson, {Magnus I.} and Frigge, {Michael L.} and Asmundur Oddsson and Isleifur Olafsson and Stephen Kaptoge and Henrik Hjalgrim and Gudmundur Runarsson and Wood, {Angela M.} and Ingileif Jonsdottir and {Folkmann Hansen}, Thomas and Olof Sigurdardottir and Hreinn Stefansson and David Rye and Steffen Andersen and Karina Banasik and S{\o}ren Brunak and Kristoffer Burgdorf and Christian Erikstrup and Jemec, {Gregor Borut Ernst} and Poul Jennum and Johanssond, {P{\"a}r I.} and Mette Nyegaard and Mikkel Petersen and Thomas Werge and Peters, {James E.} and David Westergaard and Hilma Holm and Nicole Soranzo and Gudmar Thorleifsson and Ouwehand, {Willem H.} and Unnur Thorsteinsdottir and Roberts, {David J.} and Patrick Sulem and Butterworth, {Adam S.} and Gudbjartsson, {Daniel F.} and John Danesh and S{\o}ren Brunak and Angelantonio, {Emanuele Di} and Henrik Ullum and Kari Stefansson",

year = "2021",

month = dec,

doi = "10.1038/s42003-020-01575-z",

language = "English",

volume = "4",

journal = "Communications Biology",

issn = "2399-3642",

publisher = "Nature Publishing Group",

number = "1",

}

Bell, S, Rigas, AS, Magnusson, MK, Ferkingstad, E, Allara, E, Bjornsdottir, G, Ramond, A, Sørensen, E, Halldorsson, GH, Paul, DS, Burgdorf, KS, Eggertsson, HP, Howson, JMM, Thørner, LW, Kristmundsdottir, S, Astle, WJ, Erikstrup, C, Sigurdsson, JK, Vukovic, D, Dinh, KM, Tragante, V, Surendran, P, Pedersen, OB, Vidarsson, B, Jiang, T, Paarup, HM, Onundarson, PT, Akbari, P, Nielsen, KR, Lund, SH, Juliusson, K, Magnusson, MI, Frigge, ML, Oddsson, A, Olafsson, I, Kaptoge, S, Hjalgrim, H, Runarsson, G, Wood, AM, Jonsdottir, I, Folkmann Hansen, T, Sigurdardottir, O, Stefansson, H, Rye, D, Andersen, S, Banasik, K, Brunak, S, Burgdorf, K, Erikstrup, C, Jemec, GBE, Jennum, P, Johanssond, PI, Nyegaard, M, Petersen, M, Werge, T, Peters, JE, Westergaard, D, Holm, H, Soranzo, N, Thorleifsson, G, Ouwehand, WH, Thorsteinsdottir, U, Roberts, DJ, Sulem, P, Butterworth, AS, Gudbjartsson, DF, Danesh, J, Brunak, S, Angelantonio, ED, Ullum, H & Stefansson, K 2021, 'A Genome-Wide Meta-Analysis Yields 46 New Loci Associating with Biomarkers of Iron Homeostasis', Communications Biology, vol. 4, no. 1, 156. https://doi.org/10.1038/s42003-020-01575-z

A Genome-Wide Meta-Analysis Yields 46 New Loci Associating with Biomarkers of Iron Homeostasis. / Bell, Steven ; Rigas, Andreas S. ; Magnusson, Magnus K. ; Ferkingstad, Egil ; Allara, Elias ; Bjornsdottir, Gyda ; Ramond, Anna ; Sørensen, Erik; Halldorsson, Gisli H. ; Paul, Dirk S. ; Burgdorf, Kristoffer Sølvsten; Eggertsson, Hanne P. ; Howson, Joanna M. M. ; Thørner, Lise W. ; Kristmundsdottir, Snaedis ; Astle, William J. ; Erikstrup, Christian; Sigurdsson, Jon K. ; Vukovic, Dragana; Dinh, Khoa M. ; Tragante, Vinicius ; Surendran, Praveen ; Pedersen, Ole Birger; Vidarsson, Brynja ; Jiang, Tao; Paarup, Helene M.; Onundarson, Pall T. ; Akbari, Parsa ; Nielsen, Kaspar René; Lund, Sigrun H. ; Juliusson, Kristinn ; Magnusson, Magnus I. ; Frigge, Michael L. ; Oddsson, Asmundur ; Olafsson, Isleifur ; Kaptoge, Stephen ; Hjalgrim, Henrik; Runarsson, Gudmundur ; Wood, Angela M. ; Jonsdottir, Ingileif ; Folkmann Hansen, Thomas; Sigurdardottir, Olof ; Stefansson, Hreinn ; Rye, David ; Andersen, Steffen; Banasik, Karina; Brunak, Søren; Burgdorf, Kristoffer ; Erikstrup, Christian; Jemec, Gregor Borut Ernst; Jennum, Poul; Johanssond, Pär I.; Nyegaard, Mette; Petersen, Mikkel; Werge, Thomas; Peters, James E. ; Westergaard, David; Holm, Hilma ; Soranzo, Nicole ; Thorleifsson, Gudmar ; Ouwehand, Willem H. ; Thorsteinsdottir, Unnur ; Roberts, David J. ; Sulem, Patrick; Butterworth, Adam S. ; Gudbjartsson, Daniel F. ; Danesh, John ; Brunak, Søren; Angelantonio, Emanuele Di ; Ullum, Henrik; Stefansson, Kari .

In: Communications Biology, Vol. 4, No. 1, 156, 12.2021.

Research output: Contribution to journal › Journal article › Research › peer-review

TY - JOUR

T1 - A Genome-Wide Meta-Analysis Yields 46 New Loci Associating with Biomarkers of Iron Homeostasis

AU - Bell, Steven

AU - Rigas, Andreas S.

AU - Magnusson, Magnus K.

AU - Ferkingstad, Egil

AU - Allara, Elias

AU - Bjornsdottir, Gyda

AU - Ramond, Anna

AU - Sørensen, Erik

AU - Halldorsson, Gisli H.

AU - Paul, Dirk S.

AU - Burgdorf, Kristoffer Sølvsten

AU - Eggertsson, Hanne P.

AU - Howson, Joanna M. M.

AU - Thørner, Lise W.

AU - Kristmundsdottir, Snaedis

AU - Astle, William J.

AU - Erikstrup, Christian

AU - Sigurdsson, Jon K.

AU - Vukovic, Dragana

AU - Dinh, Khoa M.

AU - Tragante, Vinicius

AU - Surendran, Praveen

AU - Pedersen, Ole Birger

AU - Vidarsson, Brynja

AU - Jiang, Tao

AU - Paarup, Helene M.

AU - Onundarson, Pall T.

AU - Akbari, Parsa

AU - Nielsen, Kaspar René

AU - Lund, Sigrun H.

AU - Juliusson, Kristinn

AU - Magnusson, Magnus I.

AU - Frigge, Michael L.

AU - Oddsson, Asmundur

AU - Olafsson, Isleifur

AU - Kaptoge, Stephen

AU - Hjalgrim, Henrik

AU - Runarsson, Gudmundur

AU - Wood, Angela M.

AU - Jonsdottir, Ingileif

AU - Folkmann Hansen, Thomas

AU - Sigurdardottir, Olof

AU - Stefansson, Hreinn

AU - Rye, David

AU - Andersen, Steffen

AU - Banasik, Karina

AU - Brunak, Søren

AU - Burgdorf, Kristoffer

AU - Erikstrup, Christian

AU - Jemec, Gregor Borut Ernst

AU - Jennum, Poul

AU - Johanssond, Pär I.

AU - Nyegaard, Mette

AU - Petersen, Mikkel

AU - Werge, Thomas

AU - Peters, James E.

AU - Westergaard, David

AU - Holm, Hilma

AU - Soranzo, Nicole

AU - Thorleifsson, Gudmar

AU - Ouwehand, Willem H.

AU - Thorsteinsdottir, Unnur

AU - Roberts, David J.

AU - Sulem, Patrick

AU - Butterworth, Adam S.

AU - Gudbjartsson, Daniel F.

AU - Danesh, John

AU - Brunak, Søren

AU - Angelantonio, Emanuele Di

AU - Ullum, Henrik

AU - Stefansson, Kari

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

U2 - 10.1038/s42003-020-01575-z

DO - 10.1038/s42003-020-01575-z

M3 - Journal article

VL - 4

JO - Communications Biology

JF - Communications Biology

SN - 2399-3642

IS - 1

M1 - 156

ER -