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

Oskarsson, GR; Oddsson, A; Magnusson, MK; Kristjansson, RP; Halldorsson, GH; Ferkingstad, E; Zink, F; ... Stefansson, K; + view all (2020) Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis. Communications Biology , 3 (1) , Article 189. 10.1038/s42003-020-0921-5. Green open access

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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.

Type: Article
Title: Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s42003-020-0921-5
Publisher version: https://doi.org/10.1038/s42003-020-0921-5
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: Science & Technology, Life Sciences & Biomedicine, Biology, Multidisciplinary Sciences, Life Sciences & Biomedicine - Other Topics, Science & Technology - Other Topics, IRON REGULATORY PROTEIN-1, GENETIC-VARIATION, HIGH-RISK, VARIANTS, HOMEOSTASIS, DISEASE, BINDING, MODEL, POWER, LOCI
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics
URI: https://discovery.ucl.ac.uk/id/eprint/10105372
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