Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis.

• Published in: Communications Biology
• Main Authors: Oskarsson, Gudjon R, Oddsson, Asmundur, Magnusson, Magnus K, Kristjansson, Ragnar P, Halldorsson, Gisli H, Ferkingstad, Egil, Zink, Florian, Helgadottir, Anna, Ivarsdottir, Erna V, Arnadottir, Gudny A, Jensson, Brynjar O, Katrinardottir, Hildigunnur, Sveinbjornsson, Gardar, Kristinsdottir, Anna M, Lee, Amy L, Saemundsdottir, Jona, Stefansdottir, Lilja, Sigurdsson, Jon K, Davidsson, Olafur B, Benonisdottir, Stefania, Jonasdottir, Aslaug, Jonasdottir, Adalbjorg, Jonsson, Stefan, Gudmundsson, Reynir L, Asselbergs, Folkert W, Tragante, Vinicius, Gunnarsson, Bjarni, Masson, Gisli, Thorleifsson, Gudmar, Rafnar, Thorunn, Holm, Hilma, Olafsson, Isleifur, Onundarson, Pall T, Gudbjartsson, Daniel F, Norddahl, Gudmundur L, Thorsteinsdottir, Unnur, Sulem, Patrick, Stefansson, Kari
• Other Authors: 1deCODE genetics/Amgen Inc., Reykjavik, Iceland. 2Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 3Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. 4Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK. 5Health Data Research UK and Institute of Health Informatics, University College London, London, UK. 6Department of Clinical Biochemistry, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland. 7Department of Laboratory Hematology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland. 8School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland. 9deCODE genetics/Amgen Inc., Reykjavik, Iceland. [e-mail]. 10deCODE genetics/Amgen Inc., Reykjavik, Iceland. [e-mail]. 11Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. [e-mail].
• Format: Article in Journal/Newspaper
• Language: English
• Published: Nature Publishing Group 2020
• Subjects: Erythropoiesis; Genome-Wide Association Study; Iceland
• Online Access: http://hdl.handle.net/2336/621419; https://doi.org/10.1038/s42003-020-0921-5

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Download Hemoglobin is the essential oxygen-carrying molecule in humans and is regulated by cellular iron and oxygen sensing mechanisms. To search for novel variants associated with hemoglobin concentration, we performed genome-wide association studies of hemoglobin concentration using a combined set of 684,122 individuals from Iceland and the UK. Notably, we found seven novel variants, six rare coding and one common, at the ACO1 locus associating with either decreased or increased hemoglobin concentration. Of these variants, the missense Cys506Ser and the stop-gained Lys334Ter mutations are specific to eight and ten generation pedigrees, respectively, and have the two largest effects in the study (EffectCys506Ser = -1.61 SD, CI95 = [-1.98, -1.35]; EffectLys334Ter = 0.63 SD, CI95 = [0.36, 0.91]). We also find Cys506Ser to associate with increased risk of persistent anemia (OR = 17.1, P = 2 × 10-14). The strong bidirectional effects seen in this study implicate ACO1, a known iron sensing molecule, as a major homeostatic regulator of hemoglobin concentration. UCL Hospitals NIHR Biomedical Research Centre