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; 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; InterAct Consortium; 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

Nat Commun. 2014 Oct 29:5:4926. doi: 10.1038/ncomms5926.

Authors

Beben Benyamin¹, Tonu Esko², Janina S Ried³, Aparna Radhakrishnan⁴, Sita H Vermeulen⁵, Michela Traglia⁶, Martin Gögele⁷, Denise Anderson⁸, Linda Broer⁹, Clara Podmore¹⁰, Jian'an Luan¹⁰, Zoltan Kutalik¹¹, Serena Sanna¹², Peter van der Meer¹³, Toshiko Tanaka¹⁴, Fudi Wang¹⁵, Harm-Jan Westra¹⁶, Lude Franke¹⁶, Evelin Mihailov¹⁷, Lili Milani¹⁸, Jonas Hälldin¹⁸, Juliane Winkelmann¹⁹, Thomas Meitinger²⁰, Joachim Thiery²¹, Annette Peters²², Melanie Waldenberger²², Augusto Rendon²³, Jennifer Jolley²⁴, Jennifer Sambrook²⁴, Lambertus A Kiemeney²⁵, Fred C Sweep²⁶, Cinzia F Sala²⁷, Christine Schwienbacher⁷, Irene Pichler⁷, Jennie Hui²⁸, Ayse Demirkan²⁹, Aaron Isaacs³⁰, Najaf Amin³¹, Maristella Steri¹², Gérard Waeber³², Niek Verweij¹³, Joseph E Powell³³, Dale R Nyholt³⁴, Andrew C Heath³⁵, Pamela A F Madden³⁵, Peter M Visscher³³, Margaret J Wright³⁴, Grant W Montgomery³⁴, Nicholas G Martin³⁴, Dena Hernandez³⁶, Stefania Bandinelli³⁷, Pim van der Harst³⁸, Manuela Uda¹², Peter Vollenweider³², Robert A Scott¹⁰, Claudia Langenberg¹⁰, Nicholas J Wareham¹⁰; InterAct Consortium; Cornelia van Duijn³⁹, John Beilby²⁸, Peter P Pramstaller⁴⁰, Andrew A Hicks⁷, Willem H Ouwehand²⁴, Konrad Oexle⁴¹, Christian Gieger⁴², Andres Metspalu¹⁸, Clara Camaschella⁴³, Daniela Toniolo²⁷, Dorine W Swinkels²⁶, John B Whitfield³⁴

Collaborators

Affiliations

¹ 1] The University of Queensland, Queensland Brain Institute, Brisbane, Queensland 4072, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
² 1] Estonian Genome Center, University of Tartu, Riia 23b, 51010 Tartu, Estonia [2] The Broad Institute of Massachusetts Institute of Technology and Harvard University, 320 Charles St, Cambridge, Massachusetts 02141, USA.
³ Institute of Genetic Epidemiology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
⁴ Department of Haematology, University of Cambridge, Cambridge Biomedical Campus Box 139, Hills Road, Cambridge CB2 0XY, UK.
⁵ 1] Department for Health Evidence, Radboud University Medical Centre, Geert Grooteplein-Zuid 10, 6525GA Nijmegen, The Netherlands [2] Department of Genetics, Radboud University Medical Centre, Geert Grooteplein-Zuid 10, 6525 GA, Nijmegen, The Netherlands.
⁶ 1] Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milano, Italy [2] Institute for Maternal and Child Health-IRCCS ''Burlo Garofolo''- Trieste, 34137 Trieste, Italy.
⁷ Center for Biomedicine, European Academy of Bolzano/Bozen (EURAC), Via Galvani 31, 39100 Bolzano, Italy.
⁸ Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, PO Box 855, West Perth, Western Australia 6872, Australia.
⁹ 1] Department of Epidemiology, Subdivision Genetic Epidemiology, Erasmus Medical Center, Postbus 2040, 3000 CA Rotterdam, The Netherlands [2] Department of Internal Medicine, Erasmus Medical Center, Postbus 2040, 3000 CA Rotterdam, The Netherlands.
¹⁰ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
¹¹ 1] Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Rte de la Corniche 10, 1010 Lausanne, Switzerland [2] Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
¹² Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Monserrato, 09042 Cagliari, Italy.
¹³ University of Groningen, University Medical Center Groningen, Department of Cardiology, 9700 RB Groningen, The Netherlands.
¹⁴ Translational Gerontology Branch, National Institute on Aging, 251 Bayview Boulevard, Suite 100, Baltimore, Maryland 21224-6825, USA.
¹⁵ School of Public Health, Zhejiang University, Hangzhou 310058, P. R. China.
¹⁶ Department of Genetics, University Medical Center Groningen, P.O. Box 30001, 9700 RB Groningen, The Netherlands.
¹⁷ 1] Estonian Genome Center, University of Tartu, Riia 23b, 51010 Tartu, Estonia [2] Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia.
¹⁸ Estonian Genome Center, University of Tartu, Riia 23b, 51010 Tartu, Estonia.
¹⁹ 1] Department of Neurology and Neurosciences and Center for Sleep Sciences and Medicine, Stanford University, Palo Alto, California 94304, USA [2] Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany [3] Institut für Humangenetik, Helmholtz Zentrum München, 85764 Neuherberg, Germany [4] Munich Cluster for Systems Neurology (SyNergy), 81675 Munich, Germany.
²⁰ 1] Institut für Humangenetik, Helmholtz Zentrum München, 85764 Neuherberg, Germany [2] Institute of Human Genetics, Klinikum Rechts der Isar, Technische Universität München, Ismaninger Straße 22, 81675 München, Germany.
²¹ 1] Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Universitätsklinikum Leipzig, Liebigstraße 27, 04103 Leipzig, Germany [2] LIFE Research Center for Civilization Diseases, Medical Faculty, University Leipzig, Philipp-Rosenthal-Straße 27, 04103 Leipzig, Germany.
²² 1] Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany [2] Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
²³ 1] Department of Haematology, University of Cambridge, Cambridge Biomedical Campus Box 139, Hills Road, Cambridge CB2 0XY, UK [2] NHS Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK [3] Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK.
²⁴ 1] Department of Haematology, University of Cambridge, Cambridge Biomedical Campus Box 139, Hills Road, Cambridge CB2 0XY, UK [2] NHS Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK.
²⁵ 1] Department for Health Evidence, Radboud University Medical Centre, Geert Grooteplein-Zuid 10, 6525GA Nijmegen, The Netherlands [2] Department of Urology, Radboud University Medical Centre, Geert Grooteplein-Zuid 10, 6525GA Nijmegen, The Netherlands.
²⁶ Laboratory of Genetic, Endocrine and Metabolic Diseases (LGEM), Department of Laboratory Medicine, Radboud University Medical Centre, Geert Grooteplein-Zuid 10, 6525 GA Nijmegen, The Netherlands.
²⁷ Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milano, Italy.
²⁸ 1] PathWest Laboratory Medicine of WA, Nedlands, Western Australia 6009, Australia [2] Schools of Pathology and Laboratory Medicine, and Population Health, The University of Western Australia, Nedlands, Western Australia 6009, Australia.
²⁹ 1] Department of Epidemiology, Subdivision Genetic Epidemiology, Erasmus Medical Center, Postbus 2040, 3000 CA Rotterdam, The Netherlands [2] Department of Human Genetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
³⁰ 1] Department of Epidemiology, Subdivision Genetic Epidemiology, Erasmus Medical Center, Postbus 2040, 3000 CA Rotterdam, The Netherlands [2] Center of Medical Systems Biology, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
³¹ Department of Epidemiology, Subdivision Genetic Epidemiology, Erasmus Medical Center, Postbus 2040, 3000 CA Rotterdam, The Netherlands.
³² Department of Medicine, Internal Medicine, CHUV, University of Lausanne, Rue du Bugnon 46, 1011 Lausanne, Switzerland.
³³ 1] The University of Queensland, Queensland Brain Institute, Brisbane, Queensland 4072, Australia [2] University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4072, Australia.
³⁴ QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
³⁵ Department of Psychiatry, Washington University, 660S Euclid Avenue, St. Louis, Missouri 63110, USA.
³⁶ Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland 20892, USA.
³⁷ Geriatric Unit, Azienda Sanitaria Firenze (ASF), Via delle Casine, 16, 50122 Firenze, Italy.
³⁸ 1] University of Groningen, University Medical Center Groningen, Department of Cardiology, 9700 RB Groningen, The Netherlands [2] Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, 3511 GC Utrecht, The Netherlands [3] University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, The Netherlands.
³⁹ 1] Department of Epidemiology, Subdivision Genetic Epidemiology, Erasmus Medical Center, Postbus 2040, 3000 CA Rotterdam, The Netherlands [2] Center of Medical Systems Biology, Einthovenweg 20, 2333 ZC Leiden, The Netherlands [3] Member of Netherlands Consortium for Healthy Aging sponsored by Netherlands Genomics Initiative, Postbus 9600, 2300 RC Leiden, The Netherlands.
⁴⁰ 1] Center for Biomedicine, European Academy of Bolzano/Bozen (EURAC), Via Galvani 31, 39100 Bolzano, Italy [2] Department of Neurology, General Central Hospital, Lorenz-Böhler-Straße, 5, 39100 Bolzano, Italy.
⁴¹ Institute of Human Genetics, Klinikum Rechts der Isar, Technische Universität München, Ismaninger Straße 22, 81675 München, Germany.
⁴² 1] Institute of Genetic Epidemiology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany [2] Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany [3] Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
⁴³ 1] Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milano, Italy [2] Vita-Salute University, 20132 Milan, Italy.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Lipids
Transferrin
Ferritins
Iron

Abstract

Publication types

MeSH terms

Substances

Grants and funding