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 Burgdorf; Hannes P. Eggertsson; Joanna M.M. Howson; Lise W. Thørner; Snaedis Kristmundsdottir; William J. Astle; Christian Erikstrup; Jon K. Sigurdsson; Dragana Vuckovic; Khoa M. Dinh; Vinicius Tragante; Praveen Surendran; Ole B. Pedersen; Brynjar Vidarsson; Tao Jiang; Helene M. Paarup; Pall T. Onundarson; Parsa Akbari; Kaspar R. 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 F. Hansen; Olof Sigurdardottir; Hreinn Stefánsson; David Rye; Kristoffer Burgdorf; Poul Jennum; Pär Johansson; Thomas Werge; David Westergaard; Henrik Ullum; DBDS Genomic Consortium

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 Burgdorf, Hannes P. Eggertsson, Joanna M.M. Howson, Lise W. Thørner, Snaedis Kristmundsdottir, William J. Astle, Christian Erikstrup, Jon K. Sigurdsson, Dragana Vuckovic, Khoa M. DinhVinicius Tragante, Praveen Surendran, Ole B. Pedersen, Brynjar Vidarsson, Tao Jiang, Helene M. Paarup, Pall T. Onundarson, Parsa Akbari, Kaspar R. 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 F. Hansen, Olof Sigurdardottir, Hreinn Stefánsson, David Rye, Kristoffer Burgdorf, Poul Jennum, Pär Johansson, Thomas Werge, David Westergaard, Henrik Ullum, DBDS Genomic Consortium

92 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Communications biology
Vol/bind	4
Udgave nummer	1
Sider (fra-til)	156
ISSN	2399-3642
DOI	https://doi.org/10.1038/s42003-020-01575-z
Status	Udgivet - 3 feb. 2021

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10.1038/s42003-020-01575-z

Citationsformater

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., Eggertsson, H. P., Howson, J. M. M., Thørner, L. W., Kristmundsdottir, S., Astle, W. J., Erikstrup, C., Sigurdsson, J. K., Vuckovic, D., ... DBDS Genomic Consortium (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, S, Rigas, AS, Magnusson, MK, Ferkingstad, E, Allara, E, Bjornsdottir, G, Ramond, A, Sørensen, E, Halldorsson, GH, Paul, DS, Burgdorf, K, Eggertsson, HP, Howson, JMM, Thørner, LW, Kristmundsdottir, S, Astle, WJ, Erikstrup, C, Sigurdsson, JK, Vuckovic, 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, Hansen, TF, Sigurdardottir, O, Stefánsson, H, Rye, D, Burgdorf, K, Jennum, P , Johansson, P , Werge, T, Westergaard, D, Ullum, H & DBDS Genomic Consortium 2021, 'A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis', Communications biology, bind 4, nr. 1, s. 156. https://doi.org/10.1038/s42003-020-01575-z

@article{1130cd7ebc384732b4703ef35226ef84,

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.",

keywords = "Anemia, Iron-Deficiency/blood, Biomarkers/blood, Denmark, Ferritins/blood, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Genotype, Homeostasis, Humans, Iceland, Iron Overload/blood, Iron/blood, Phenotype, Risk Assessment, Risk Factors, Transferrin/metabolism, United Kingdom",

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 Kristoffer Burgdorf and Eggertsson, {Hannes 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 Vuckovic and Dinh, {Khoa M.} and Vinicius Tragante and Praveen Surendran and Pedersen, {Ole B.} and Brynjar Vidarsson and Tao Jiang and Paarup, {Helene M.} and Onundarson, {Pall T.} and Parsa Akbari and Nielsen, {Kaspar R.} 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 Hansen, {Thomas F.} and Olof Sigurdardottir and Hreinn Stef{\'a}nsson and David Rye and Kristoffer Burgdorf and Poul Jennum and P{\"a}r Johansson and Thomas Werge and David Westergaard and Henrik Ullum and {DBDS Genomic Consortium}",

note = "Funding Information: We thank all the study subjects for their valuable participation, the staff from all studies, and the participating physicians. Participants in the INTERVAL randomized controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (www.nhsbt.nhs.uk), which has supported fieldwork and other elements of the trial. DNA extraction and genotyping were co-funded by the National Institute for Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk/) and the NIHR Cambridge Biomedical Research Centre (BRC) [*]. The academic coordinating centre for INTERVAL was supported by core funding from NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK Medical Research Council (MR/L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/ 18/13/33946) and the NIHR Cambridge BRC [*]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. A complete list of the investigators and contributors to the INTERVAL trial is provided in reference87. The academic coordinating centre would like to thank blood donor centre staff and blood donors for participating in the INTERVAL trial. Professor John Danesh holds a British Heart Foundation Professorship and a National Institute for Health Research Senior Investigator Award. Steven Bell and Dragana Vuckovic were funded by the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). Stephen Kaptoge is funded by a BHF Program Grant (RG/18/13/33946). Will Astle, Joanna Howson, and Tao Jiang are funded by the NIHR Cambridge BRC. Angela M. Wood and Elias Allara are supported by the EC-Innovative Medicines Initiative (BigData@Heart). Praveen Surendran is supported by a Rutherford Fund Fellowship from the Medical Research Council grant MR/S003746/1. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. The Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594). The Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 115881 (RHAPSODY) (Karina Banasik and S{\o}ren Brunak). The Danish Administrative Regions; The Danish Administrative Regions{\textquoteright} Bio-and Genome Bank; The authors thank all the blood banks in Denmark for both collecting and contributing data to this study. Danish Blood Donor Research Fund. Aarhus University, Copenhagen University Hospital Research Fund. Funding Information: The authors declare the following competing interests: Henrik Ullum received an unrestricted research grant from Novartis. Cristian Erikstrup received an unrestricted research grant from Abbott. S{\o}ren Brunak reports grants from Innovation Fund Denmark, grants from Novo Nordisk Foundation during the conduct of the study; and personal fees from Intomics A/S and Proscion A/S, outside the submitted work. John Danesh sits on the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010); the Steering Committee of UK Biobank (since 2011); the MRC International Advisory Group (ING) member, London (since 2013); the MRC High Throughput Science {\textquoteleft}Omics Panel Member, London (since 2013); the Scientific Advisory Committee for Sanofi (since 2013); the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis; and the Astra Zeneca Genomics Advisory Board (2018). Adam S. Butterworth has received grants outside of this work from AstraZeneca, Biogen, BioMarin, Bioverativ, Merck, and Novartis and personal fees from Novartis. For the authors who are affiliated with deCODE genetics/Amgen, we declare competing financial interests as employees. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = feb,

day = "3",

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

language = "English",

volume = "4",

pages = "156",

journal = "Communications biology",

issn = "2399-3642",

publisher = "Nature Publishing Group",

number = "1",

}

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

AU - Eggertsson, Hannes 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 - Vuckovic, Dragana

AU - Dinh, Khoa M.

AU - Tragante, Vinicius

AU - Surendran, Praveen

AU - Pedersen, Ole B.

AU - Vidarsson, Brynjar

AU - Jiang, Tao

AU - Paarup, Helene M.

AU - Onundarson, Pall T.

AU - Akbari, Parsa

AU - Nielsen, Kaspar R.

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 - Hansen, Thomas F.

AU - Sigurdardottir, Olof

AU - Stefánsson, Hreinn

AU - Rye, David

AU - Burgdorf, Kristoffer

AU - Jennum, Poul

AU - Johansson, Pär

AU - Werge, Thomas

AU - Westergaard, David

AU - Ullum, Henrik

AU - DBDS Genomic Consortium

N1 - Funding Information: We thank all the study subjects for their valuable participation, the staff from all studies, and the participating physicians. Participants in the INTERVAL randomized controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (www.nhsbt.nhs.uk), which has supported fieldwork and other elements of the trial. DNA extraction and genotyping were co-funded by the National Institute for Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk/) and the NIHR Cambridge Biomedical Research Centre (BRC) [*]. The academic coordinating centre for INTERVAL was supported by core funding from NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK Medical Research Council (MR/L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/ 18/13/33946) and the NIHR Cambridge BRC [*]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. A complete list of the investigators and contributors to the INTERVAL trial is provided in reference87. The academic coordinating centre would like to thank blood donor centre staff and blood donors for participating in the INTERVAL trial. Professor John Danesh holds a British Heart Foundation Professorship and a National Institute for Health Research Senior Investigator Award. Steven Bell and Dragana Vuckovic were funded by the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). Stephen Kaptoge is funded by a BHF Program Grant (RG/18/13/33946). Will Astle, Joanna Howson, and Tao Jiang are funded by the NIHR Cambridge BRC. Angela M. Wood and Elias Allara are supported by the EC-Innovative Medicines Initiative (BigData@Heart). Praveen Surendran is supported by a Rutherford Fund Fellowship from the Medical Research Council grant MR/S003746/1. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. The Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594). The Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 115881 (RHAPSODY) (Karina Banasik and Søren Brunak). The Danish Administrative Regions; The Danish Administrative Regions’ Bio-and Genome Bank; The authors thank all the blood banks in Denmark for both collecting and contributing data to this study. Danish Blood Donor Research Fund. Aarhus University, Copenhagen University Hospital Research Fund. Funding Information: The authors declare the following competing interests: Henrik Ullum received an unrestricted research grant from Novartis. Cristian Erikstrup received an unrestricted research grant from Abbott. Søren Brunak reports grants from Innovation Fund Denmark, grants from Novo Nordisk Foundation during the conduct of the study; and personal fees from Intomics A/S and Proscion A/S, outside the submitted work. John Danesh sits on the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010); the Steering Committee of UK Biobank (since 2011); the MRC International Advisory Group (ING) member, London (since 2013); the MRC High Throughput Science ‘Omics Panel Member, London (since 2013); the Scientific Advisory Committee for Sanofi (since 2013); the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis; and the Astra Zeneca Genomics Advisory Board (2018). Adam S. Butterworth has received grants outside of this work from AstraZeneca, Biogen, BioMarin, Bioverativ, Merck, and Novartis and personal fees from Novartis. For the authors who are affiliated with deCODE genetics/Amgen, we declare competing financial interests as employees. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/2/3

Y1 - 2021/2/3

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.

KW - Anemia, Iron-Deficiency/blood

KW - Biomarkers/blood

KW - Denmark

KW - Ferritins/blood

KW - Genetic Loci

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Genotype

KW - Homeostasis

KW - Humans

KW - Iceland

KW - Iron Overload/blood

KW - Iron/blood

KW - Phenotype

KW - Risk Assessment

KW - Risk Factors

KW - Transferrin/metabolism

KW - United Kingdom

U2 - 10.1038/s42003-020-01575-z

DO - 10.1038/s42003-020-01575-z

M3 - Review

C2 - 33536631

AN - SCOPUS:85100560134

SN - 2399-3642

VL - 4

SP - 156

JO - Communications biology

JF - Communications biology

IS - 1

ER -

A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis

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