A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis
Bell S., Rigas AS., Magnusson MK., Ferkingstad E., Allara E., Bjornsdottir G., Ramond A., Sørensen E., Halldorsson GH., Paul DS., Burgdorf KS., 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., Stefansson H., Rye D., Andersen S., Burgdorf K., Jemec G., Jennum P., Johansson P., Nielsen KR., Nyegaard M., Petersen M., Werge T., Thorsteinsdóttir U., Peters JE., Westergaard D., Holm H., Soranzo N., Banasik K., Thorleifsson G., Ouwehand WH., Thorsteinsdottir U., Roberts DJ., Sulem P., Butterworth AS., Gudbjartsson DF., Danesh J., Brunak S., Di Angelantonio E., Ullum H., Stefansson K.
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.