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

Gudjon R Oskarsson, Asmundur Oddsson, Magnus K Magnusson, Ragnar P Kristjansson, Gisli H Halldorsson, Egil Ferkingstad, Florian Zink, Anna Helgadottir, Erna V Ivarsdottir, Gudny A Arnadottir, Brynjar O Jensson, Hildigunnur Katrinardottir, Gardar Sveinbjornsson, Anna M Kristinsdottir, Amy L Lee, Jona Saemundsdottir, Lilja Stefansdottir, Jon K Sigurdsson, Olafur B Davidsson, Stefania Benonisdottir, Aslaug Jonasdottir, Adalbjorg Jonasdottir, Stefan Jonsson, Reynir L Gudmundsson, Folkert W Asselbergs, Vinicius Tragante, Bjarni Gunnarsson, Gisli Masson, Gudmar Thorleifsson, Thorunn Rafnar, Hilma Holm, Isleifur Olafsson, Pall T Onundarson, Daniel F Gudbjartsson, Gudmundur L Norddahl, Unnur Thorsteinsdottir, Patrick Sulem, Kari Stefansson

Journal: Communications biology 2021;3(1):189

PMID: 32327693

Free Full Text on Nature Publishing Group View on PubMed

Abstract

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 (Effect = -1.61 SD, CI = [-1.98, -1.35]; Effect = 0.63 SD, CI = [0.36, 0.91]). We also find Cys506Ser to associate with increased risk of persistent anemia (OR = 17.1, P = 2 × 10). The strong bidirectional effects seen in this study implicate ACO1, a known iron sensing molecule, as a major homeostatic regulator of hemoglobin concentration.

Address: deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.; Health Data Research UK and Institute of Health Informatics, University College London, London, UK.; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; Department of Clinical Biochemistry, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.; Department of Laboratory Hematology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland.; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.; deCODE genetics/Amgen Inc., Reykjavik, Iceland. [email protected].; deCODE genetics/Amgen Inc., Reykjavik, Iceland. [email protected].; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. [email protected].

DOI: 10.1038/s42003-020-0921-5

Link outs

Free resources

Full Text Sources:

Molecular Biology Databases:

MeSH Terms: Biomarkers, Databases, Genetic, Erythropoiesis, Gain of Function Mutation, Genome-Wide Association Study, Hemoglobins, Humans, Iceland, Iron Regulatory Protein 1, Loss of Function Mutation, United Kingdom