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

Steven Bell ,Kristoffer Sølvsten Burgdorf ,Michael L Frigge ,Hannes P Eggertsson ,William Astle ,Adam S Butterworth ,Guðmar Þorleifsson ,Praveen Surendran ,Daníel F Guðbjartsson ,Anna Ramond ,Hreinn Stefánsson ,Stephen Kaptoge ,David B Rye ,Magnus I Magnusson ,Kristinn Juliusson ,Ole Birger Pedersen ,Páll T Önundarson ,Ingileif Jónsdóttir ,Willem H Ouwehand ,Snædís Kristmundsdóttir ,Lise Wegner Thørner ,Joanna M M Howson ,John Danesh ,Andreas S Rigas ,Parsa Akbari ,Khoa Manh Dinh ,Sigrún H Lund ,Ísleifur Ólafsson ,Erik Sørensen ,Magnús K Magnússon ,Christian Erikstrup ,Emanuele Di Angelantonio ,Helene M Paarup ,Henrik Hjalgrim ,Angela Wood ,Gyða Björnsdóttir ,Ólöf Sigurðardóttir ,Egil Ferkingstad ,Jon K Sigurdsson ,David Roberts ,Dirk S Paul ,Hilma Hólm ,Brynjar Viðarsson ,Vinicius Tragante ,Patrick Sulem ,Kaspar René Nielsen ,Dragana Vuckovic ,Elias Allara ,Henrik Ullum ,Gudmundur Runarsson ,Tao Jiang ,Thomas Folkmann Hansen ,Gisli H Halldorsson ,Karina Banasik ,Ásmundur Oddsson ,Unnur Þorsteinsdóttir ,James E Peters ,Søren Brunak ,David Westergaard ,Nicole Soranzo ,Kāri Stefánsson

doi:10.1038/s42003-020-01575-z

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.

Highlights

Iron is essential for many biological functions and iron deficiency and overload have major health implications
Four iron biomarkers are used for clinical assessment of iron status: serum ferritin, serum iron, and total iron-binding capacity (TIBC) are measured directly, while transferrin saturation (TSAT) is derived as serum iron divided by TIBC
We performed a meta-analysis of four iron-related biomarkers: ferritin (N = 246,139), serum iron (N = 163,511), TIBC (N = 135,430), and TSAT (N = 131,471), combining GWAS

Summary

Introduction

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). Iron is an essential element for a wide variety of metabolic processes such as oxygen transport, cellular respiration, and redox reactions in numerous metabolic pathways For this reason, iron homeostasis is tightly regulated on cellular and systemic levels to ensure a balance between uptake, transport, storage, and utilization. To search for additional sequence variants associated with iron homeostasis, we performed a GWAS meta-analysis of ferritin, serum iron, TIBC, and TSAT in Iceland and blood donor studies from the UK (INTERVAL study) and Denmark

Methods

Results

Conclusion