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

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

Title: Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis
Author: Oskarsson, Gudjon R.
Oddsson, Asmundur   orcid.org/0000-0002-4606-5163
Magnusson, Magnus K.
Kristjansson, Ragnar P.
Halldorsson, Gisli H.
Ferkingstad, Egil   orcid.org/0000-0001-8090-7988
Zink, Florian
Helgadottir, Anna
Ivarsdottir, Erna V.
Arnadottir, Gudny A.
... 28 more authors Show all authors
Date: 2020-04-23
Language: English
University/Institute: Landspitali - The National University Hospital of Iceland
School: Health Sciences
Department: Faculty of Medicine
Department of Engineering
Office of Division of Diagnostic and Support Services
Clinical Laboratory Services, Diagnostics and Blood Bank
Series: Communications Biology; 3(1)
ISSN: 2399-3642
DOI: https://doi.org/10.1038/s42003-020-0921-5
Subject: Hemoglobin; ACO1; Genome-wide; Blóðrannsóknir; Erfðarannsóknir; Gen; Hemoglobin; ACO1; Genome-wide; Blóðrannsóknir; Erfðarannsóknir; Gen; Medicine (miscellaneous); Biochemistry, Genetics and Molecular Biology (all); Agricultural and Biological Sciences (all)
URI: https://hdl.handle.net/20.500.11815/3421

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Oskarsson , G R , Oddsson , A , Magnusson , M K , Kristjansson , R P , Halldorsson , G H , Ferkingstad , E , Zink , F , Helgadottir , A , Ivarsdottir , E V , Arnadottir , G A , Jensson , B O , Katrinardottir , H , Sveinbjornsson , G , Kristinsdottir , A M , Lee , A L , Saemundsdottir , J , Stefansdottir , L , Sigurdsson , J K , Davidsson , O B , Benonisdottir , S , Jonasdottir , A , Jonasdottir , A , Jonsson , S , Gudmundsson , R L , Asselbergs , F W , Tragante , V , Gunnarsson , B , Masson , G , Thorleifsson , G , Rafnar , T , Holm , H , Olafsson , I , Onundarson , P T , Gudbjartsson , D F , Norddahl , G L , Thorsteinsdottir , U , Sulem , P & Stefansson , K 2020 , ' Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis ' , Communications Biology , vol. 3 , no. 1 , 189 . https://doi.org/10.1038/s42003-020-0921-5 , https://doi.org/10.1038/s42003-020-0921-5


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.


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).

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