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 BenonisdottirAslaug 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
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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 (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.

Original languageEnglish
Article number189
JournalCommunications Biology
Volume3
Issue number1
DOIs
Publication statusPublished - 23 Apr 2020

Bibliographical note

Funding Information:
We thank the individuals who participated in this study and whose contributions made this work possible. We also thank our valued colleagues who contributed to the data collection and phenotypic characterization of clinical samples as well as to the genotyping and analysis of the whole-genome association data. This research has been conducted using the UK Biobank Resource under application number 24711. F.W.A. is supported by UCL Hospitals NIHR Biomedical Research Centre.

Publisher Copyright:
© 2020, The Author(s).

Other keywords

  • Hemoglobin
  • ACO1
  • Genome-wide
  • Blóðrannsóknir
  • Erfðarannsóknir
  • Gen

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