Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Beben Benyamin; Tonu Esko; Janina S. Ried; Aparna Radhakrishnan; Sita H. Vermeulen; Michela Traglia; Martin Gögele; Denise Anderson; Linda Broer; Clara Podmore; Jian'An Luan; Zoltan Kutalik; Serena Sanna; Peter Van Der Meer; Toshiko Tanaka; Fudi Wang; Harm Jan Westra; Lude Franke; Evelin Mihailov; Lili Milani; Jonas Häldin; Juliane Winkelmann; Thomas Meitinger; Joachim Thiery; Annette Peters; Melanie Waldenberger; Augusto Rendon; Jennifer Jolley; Jennifer Sambrook; Lambertus A. Kiemeney; Fred C. Sweep; Cinzia F. Sala; Christine Schwienbacher; Irene Pichler; Jennie Hui; Ayse Demirkan; Aaron Isaacs; Najaf Amin; Maristella Steri; Gérard Waeber; Niek Verweij; Joseph E. Powell; Dale R. Nyholt; Andrew C. Heath; Pamela A.F. Madden; Peter M. Visscher; Margaret J. Wright; Grant W. Montgomery; Nicholas G. Martin; Dena Hernandez; Stefania Bandinelli; Pim Van Der Harst; Manuela Uda; Peter Vollenweider; Robert A. Scott; Claudia Langenberg; Nicholas J. Wareham; Cornelia Van Duijn; John Beilby; Peter P. Pramstaller; Andrew A. Hicks; Willem H. Ouwehand; Konrad Oexle; Christian Gieger; Andres Metspalu; Clara Camaschella; Daniela Toniolo; Dorine W. Swinkels; John B. Whitfield

doi:10.1038/ncomms5926

Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Beben Benyamin
, Tonu Esko
, Janina S. Ried
, Aparna Radhakrishnan
, Sita H. Vermeulen
, Michela Traglia
, Martin Gögele
, Denise Anderson
, Linda Broer
, Clara Podmore
, Jian'An Luan
, Zoltan Kutalik
, Serena Sanna
, Peter Van Der Meer
, Toshiko Tanaka
, Fudi Wang
, Harm Jan Westra
, Lude Franke
, Evelin Mihailov
, Lili Milani

Jonas Häldin, Juliane Winkelmann, Thomas Meitinger, Joachim Thiery, Annette Peters, Melanie Waldenberger, Augusto Rendon, Jennifer Jolley, Jennifer Sambrook, Lambertus A. Kiemeney, Fred C. Sweep, Cinzia F. Sala, Christine Schwienbacher, Irene Pichler, Jennie Hui, Ayse Demirkan, Aaron Isaacs, Najaf Amin, Maristella Steri, Gérard Waeber, Niek Verweij, Joseph E. Powell, Dale R. Nyholt, Andrew C. Heath, Pamela A.F. Madden, Peter M. Visscher, Margaret J. Wright, Grant W. Montgomery, Nicholas G. Martin, Dena Hernandez, Stefania Bandinelli, Pim Van Der Harst, Manuela Uda, Peter Vollenweider, Robert A. Scott, Claudia Langenberg, Nicholas J. Wareham, Cornelia Van Duijn, John Beilby, Peter P. Pramstaller, Andrew A. Hicks, Willem H. Ouwehand, Konrad Oexle, Christian Gieger, Andres Metspalu, Clara Camaschella, Daniela Toniolo, Dorine W. Swinkels, John B. Whitfield

University of Queensland
Queensland Institute of Medical Research
University of Tartu
The Broad Institute of MIT and Harvard
Helmholtz Zentrum München German Research Center for Environmental Health
University of Cambridge
Amalia Children's Hospital
IRCCS San Raffaele Scientific Institute
Institute for Maternal and Child Health-IRCCS ''burlo Garofolo''- Trieste
Institute for Biomedicine (affiliated to the University of Lübeck)
University of Western Australia
Erasmus University Medical Center
University of Cambridge School of Clinical Medicine
Centre Hospitalier Universitaire Vaudois (CHUV)
Swiss Institute of Bioinformatics
Consiglio Nazionale Delle Ricerche (CNR)
University Medical Center Groningen
National Institute on Aging
Zhejiang University
University of Tartu
Stanford University School of Medicine
Technical University of Munich
Munich Cluster for Systems Neurology (SyNergy)
University Hospital Leipzig
University of Leipzig
Cambridge Biomedical Campus
Cambridge Biomedical Campus
PathWest Laboratory Medicine of WA
University of Western Australia
Leiden University Medical Centre
Center of Medical Systems Biology
University of Lausanne
Washington University in St. Louis
Azienda Sanitaria Firenze (ASF)
ICIN-Netherlands Heart Institute
Netherlands Consortium for Healthy Aging Sponsored by Netherlands Genomics Initiative
General Central Hospital
University Vita-Salute San Raffaele

Research output: Contribution to journal › Article › peer-review

239 Scopus citations

Abstract

Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10^-8) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease.

Original language	English
Article number	4926
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5926
State	Published - 2014

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10.1038/ncomms5926

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Benyamin, B., Esko, T., Ried, J. S., Radhakrishnan, A., Vermeulen, S. H., Traglia, M., Gögele, M., Anderson, D., Broer, L., Podmore, C., Luan, JA., Kutalik, Z., Sanna, S., Van Der Meer, P., Tanaka, T., Wang, F., Westra, H. J., Franke, L., Mihailov, E., ... Whitfield, J. B. (2014). Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis. Nature Communications, 5, Article 4926. https://doi.org/10.1038/ncomms5926

@article{c17e563aced5409d9ceef99273c860d7,

title = "Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis",

abstract = "Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 {\texttimes} 10-8) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease.",

author = "Beben Benyamin and Tonu Esko and Ried, \{Janina S.\} and Aparna Radhakrishnan and Vermeulen, \{Sita H.\} and Michela Traglia and Martin G{\"o}gele and Denise Anderson and Linda Broer and Clara Podmore and Jian'An Luan and Zoltan Kutalik and Serena Sanna and \{Van Der Meer\}, Peter and Toshiko Tanaka and Fudi Wang and Westra, \{Harm Jan\} and Lude Franke and Evelin Mihailov and Lili Milani and Jonas H{\"a}ldin and Juliane Winkelmann and Thomas Meitinger and Joachim Thiery and Annette Peters and Melanie Waldenberger and Augusto Rendon and Jennifer Jolley and Jennifer Sambrook and Kiemeney, \{Lambertus A.\} and Sweep, \{Fred C.\} and Sala, \{Cinzia F.\} and Christine Schwienbacher and Irene Pichler and Jennie Hui and Ayse Demirkan and Aaron Isaacs and Najaf Amin and Maristella Steri and G{\'e}rard Waeber and Niek Verweij and Powell, \{Joseph E.\} and Nyholt, \{Dale R.\} and Heath, \{Andrew C.\} and Madden, \{Pamela A.F.\} and Visscher, \{Peter M.\} and Wright, \{Margaret J.\} and Montgomery, \{Grant W.\} and Martin, \{Nicholas G.\} and Dena Hernandez and Stefania Bandinelli and \{Van Der Harst\}, Pim and Manuela Uda and Peter Vollenweider and Scott, \{Robert A.\} and Claudia Langenberg and Wareham, \{Nicholas J.\} and \{Van Duijn\}, Cornelia and John Beilby and Pramstaller, \{Peter P.\} and Hicks, \{Andrew A.\} and Ouwehand, \{Willem H.\} and Konrad Oexle and Christian Gieger and Andres Metspalu and Clara Camaschella and Daniela Toniolo and Swinkels, \{Dorine W.\} and Whitfield, \{John B.\}",

year = "2014",

doi = "10.1038/ncomms5926",

language = "English",

volume = "5",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Benyamin, B, Esko, T, Ried, JS, Radhakrishnan, A, Vermeulen, SH, Traglia, M, Gögele, M, Anderson, D, Broer, L, Podmore, C, Luan, JA, Kutalik, Z, Sanna, S, Van Der Meer, P, Tanaka, T, Wang, F, Westra, HJ, Franke, L, Mihailov, E, Milani, L, Häldin, J, Winkelmann, J , Meitinger, T, Thiery, J, Peters, A, Waldenberger, M, Rendon, A, Jolley, J, Sambrook, J, Kiemeney, LA, Sweep, FC, Sala, CF, Schwienbacher, C, Pichler, I, Hui, J, Demirkan, A, Isaacs, A, Amin, N, Steri, M, Waeber, G, Verweij, N, Powell, JE, Nyholt, DR, Heath, AC, Madden, PAF, Visscher, PM, Wright, MJ, Montgomery, GW, Martin, NG, Hernandez, D, Bandinelli, S, Van Der Harst, P, Uda, M, Vollenweider, P, Scott, RA, Langenberg, C, Wareham, NJ, Van Duijn, C, Beilby, J, Pramstaller, PP, Hicks, AA, Ouwehand, WH, Oexle, K, Gieger, C, Metspalu, A, Camaschella, C, Toniolo, D, Swinkels, DW & Whitfield, JB 2014, 'Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis', Nature Communications, vol. 5, 4926. https://doi.org/10.1038/ncomms5926

TY - JOUR

T1 - Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

AU - Benyamin, Beben

AU - Esko, Tonu

AU - Ried, Janina S.

AU - Radhakrishnan, Aparna

AU - Vermeulen, Sita H.

AU - Traglia, Michela

AU - Gögele, Martin

AU - Anderson, Denise

AU - Broer, Linda

AU - Podmore, Clara

AU - Luan, Jian'An

AU - Kutalik, Zoltan

AU - Sanna, Serena

AU - Van Der Meer, Peter

AU - Tanaka, Toshiko

AU - Wang, Fudi

AU - Westra, Harm Jan

AU - Franke, Lude

AU - Mihailov, Evelin

AU - Milani, Lili

AU - Häldin, Jonas

AU - Winkelmann, Juliane

AU - Meitinger, Thomas

AU - Thiery, Joachim

AU - Peters, Annette

AU - Waldenberger, Melanie

AU - Rendon, Augusto

AU - Jolley, Jennifer

AU - Sambrook, Jennifer

AU - Kiemeney, Lambertus A.

AU - Sweep, Fred C.

AU - Sala, Cinzia F.

AU - Schwienbacher, Christine

AU - Pichler, Irene

AU - Hui, Jennie

AU - Demirkan, Ayse

AU - Isaacs, Aaron

AU - Amin, Najaf

AU - Steri, Maristella

AU - Waeber, Gérard

AU - Verweij, Niek

AU - Powell, Joseph E.

AU - Nyholt, Dale R.

AU - Heath, Andrew C.

AU - Madden, Pamela A.F.

AU - Visscher, Peter M.

AU - Wright, Margaret J.

AU - Montgomery, Grant W.

AU - Martin, Nicholas G.

AU - Hernandez, Dena

AU - Bandinelli, Stefania

AU - Van Der Harst, Pim

AU - Uda, Manuela

AU - Vollenweider, Peter

AU - Scott, Robert A.

AU - Langenberg, Claudia

AU - Wareham, Nicholas J.

AU - Van Duijn, Cornelia

AU - Beilby, John

AU - Pramstaller, Peter P.

AU - Hicks, Andrew A.

AU - Ouwehand, Willem H.

AU - Oexle, Konrad

AU - Gieger, Christian

AU - Metspalu, Andres

AU - Camaschella, Clara

AU - Toniolo, Daniela

AU - Swinkels, Dorine W.

AU - Whitfield, John B.

PY - 2014

Y1 - 2014

N2 - Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10-8) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease.

AB - Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10-8) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease.

UR - https://www.scopus.com/pages/publications/84923272209

U2 - 10.1038/ncomms5926

DO - 10.1038/ncomms5926

M3 - Article

C2 - 25352340

AN - SCOPUS:84923272209

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 4926

ER -

Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Abstract

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