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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: Óskarsson, Guðjón R.
Oddsson, Asmundur   orcid.org/0000-0002-4606-5163
Magnusson, Magnus Karl   orcid.org/0000-0001-8593-4934
Kristjansson, Ragnar   orcid.org/0000-0002-3678-5693
Halldorsson, Gisli   orcid.org/0000-0001-7067-9862
Ferkingstad, Egil   orcid.org/0000-0001-8090-7988
Zink, Florian
Helgadottir, Anna   orcid.org/0000-0002-1806-2467
Ívarsdóttir, Erna V.
Arnadottir, Gudny   orcid.org/0000-0001-6571-423X
... 28 more authors Show all authors
Date: 2020-04-23
Language: English
Scope: 189
University/Institute: Háskóli Íslands
University of Iceland
School: Heilbrigðisvísindasvið (HÍ)
School of Health Sciences (UI)
Verkfræði- og náttúruvísindasvið (HÍ)
School of Engineering and Natural Sciences (UI)
Department: Læknadeild (HÍ)
Faculty of Medicine (UI)
Series: Communications Biology;3(1)
ISSN: 2399-3642
DOI: 10.1038/s42003-020-0921-5
Subject: Hemoglobin; ACO1; Genome-wide; Blóðrannsóknir; Erfðarannsóknir; Gen
URI: https://hdl.handle.net/20.500.11815/2151

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Oskarsson, G.R., Oddsson, A., Magnusson, M.K. et al. Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis. Communications Biology 3, 189 (2020). 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.


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