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 Hälldin; 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; InterAct Consortium; 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 Hälldin, 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, InterAct Consortium, John B Whitfield^*

^*Corresponding author for this work

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

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
Pages (from-to)	4926
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5926
Publication status	Published - 29 Oct 2014
Externally published	Yes

Keywords

Adult
Chromosomes, Human, Pair 7/genetics
Ferritins/metabolism
Gene Expression Regulation
Genetic Association Studies
Genetic Loci
Genetic Predisposition to Disease
Hemochromatosis/blood
Homeostasis/genetics
Humans
Iron/blood
Lipids/blood
Phenotype
Polymorphism, Single Nucleotide/genetics
Reproducibility of Results
Risk Factors
Transferrin/metabolism

Access to Document

10.1038/ncomms5926

https://repository.ubn.ru.nl//bitstream/handle/2066/137523/137523.pdfLicence: Other

Correction: Corrigendum: Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis
Benyamin, B., Esko, T., Ried, J. S., Radhakrishnan, A., Vermeulen, S. H., Traglia, M., Gögele, M., Anderson, D., Broer, L., Podmore, C., Luan, J., Kutalik, Z., Sanna, S., van der Meer, P., Tanaka, T., Wang, F., Westra, H.-J., Franke, L., Mihailov, E. & Milani, L. & 49 others, Hälldin, J., Winkelmann, J., Meitinger, T., Thiery, J., Peters, A., Waldenberger, M., Rendon, A., Jolley, J., Sambrook, J., Kiemeney, L. A., Sweep, F. C., Sala, C. F., Schwienbacher, C., Pichler, I., Hui, J., Demirkan, A., Isaacs, A., Amin, N., Steri, M., Waeber, G., Verweij, N., Powell, J. E., Nyholt, D. R., Heath, A. C., Madden, P. A. F., Visscher, P. M., Wright, M. J., Montgomery, G. W., Martin, N. G., Hernandez, D., Bandinelli, S., van der Harst, P., Uda, M., Vollenweider, P., Scott, R. A., Langenberg, C., Wareham, N. J., van Duijn, C., Beilby, J., Pramstaller, P. P., Hicks, A. A., Ouwehand, W. H., Oexle, K., Gieger, C., Metspalu, A., Camaschella, C., Toniolo, D., Swinkels, D. W. & Whitfield, J. B., 30 Mar 2015, In: Nature Communications. 6, p. 6542
Research output: Contribution to journal › Erratum / corrigendum › Academic

Open Access

Cite this

Benyamin, B., Esko, T., Ried, J. S., Radhakrishnan, A., Vermeulen, S. H., Traglia, M., Gögele, M., Anderson, D., Broer, L., Podmore, C., Luan, J., 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, 4926. https://doi.org/10.1038/ncomms5926

@article{12007ecf0a6e431bafce417c99e86f76,

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 × 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. ",

keywords = "Adult, Chromosomes, Human, Pair 7/genetics, Ferritins/metabolism, Gene Expression Regulation, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Hemochromatosis/blood, Homeostasis/genetics, Humans, Iron/blood, Lipids/blood, Phenotype, Polymorphism, Single Nucleotide/genetics, Reproducibility of Results, Risk Factors, Transferrin/metabolism",

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 Harm-Jan Westra and Lude Franke and Evelin Mihailov and Lili Milani and Jonas H{\"a}lldin 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 \{InterAct Consortium\} and Whitfield, \{John B\}",

year = "2014",

month = oct,

day = "29",

doi = "10.1038/ncomms5926",

language = "English",

volume = "5",

pages = "4926",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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Benyamin, B, Esko, T, Ried, JS, Radhakrishnan, A, Vermeulen, SH, Traglia, M, Gögele, M, Anderson, D, Broer, L, Podmore, C, Luan, J, Kutalik, Z, Sanna, S, van der Meer, P, Tanaka, T, Wang, F, Westra, H-J, Franke, L, Mihailov, E, Milani, L, Hälldin, J, 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, InterAct Consortium & Whitfield, JB 2014, 'Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis', Nature Communications, vol. 5, pp. 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 - Hälldin, Jonas

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 - InterAct Consortium

AU - Whitfield, John B

PY - 2014/10/29

Y1 - 2014/10/29

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.

KW - Adult

KW - Chromosomes, Human, Pair 7/genetics

KW - Ferritins/metabolism

KW - Gene Expression Regulation

KW - Genetic Association Studies

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Hemochromatosis/blood

KW - Homeostasis/genetics

KW - Humans

KW - Iron/blood

KW - Lipids/blood

KW - Phenotype

KW - Polymorphism, Single Nucleotide/genetics

KW - Reproducibility of Results

KW - Risk Factors

KW - Transferrin/metabolism

U2 - 10.1038/ncomms5926

DO - 10.1038/ncomms5926

M3 - Article

C2 - 25352340

SN - 2041-1723

VL - 5

SP - 4926

JO - Nature Communications

JF - Nature Communications

ER -

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

Abstract

Keywords

Access to Document

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Research output

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

Cite this