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

doi:10.1038/s42003-020-0921-5

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

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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 language	English
Article number	189
Pages (from-to)	1-10
Journal	Communications biology
Volume	3
Issue number	1
DOIs	https://doi.org/10.1038/s42003-020-0921-5
Publication status	Published - 23 Apr 2020

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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., ... Stefansson, K. (2020). Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis. Communications biology, 3(1), 1-10. Article 189. https://doi.org/10.1038/s42003-020-0921-5

@article{89f845374f12467a83dc7c61f384f9dc,

title = "Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis",

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.",

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

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: {\textcopyright} 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = apr,

day = "23",

doi = "10.1038/s42003-020-0921-5",

language = "English",

volume = "3",

pages = "1--10",

number = "1",

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Oskarsson, GR, Oddsson, A, Magnusson, MK, Kristjansson, RP, Halldorsson, GH, Ferkingstad, E, Zink, F, Helgadottir, A, Ivarsdottir, EV, Arnadottir, GA, Jensson, BO, Katrinardottir, H, Sveinbjornsson, G, Kristinsdottir, AM, Lee, AL, Saemundsdottir, J, Stefansdottir, L, Sigurdsson, JK, Davidsson, OB, Benonisdottir, S, Jonasdottir, A, Jonasdottir, A, Jonsson, S, Gudmundsson, RL, Asselbergs, FW, Tragante, V, Gunnarsson, B, Masson, G, Thorleifsson, G, Rafnar, T, Holm, H, Olafsson, I, Onundarson, PT, Gudbjartsson, DF, Norddahl, GL, 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, pp. 1-10. https://doi.org/10.1038/s42003-020-0921-5

TY - JOUR

T1 - Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis

AU - Oskarsson, Gudjon R

AU - Oddsson, Asmundur

AU - Magnusson, Magnus K

AU - Kristjansson, Ragnar P

AU - Halldorsson, Gisli H

AU - Ferkingstad, Egil

AU - Zink, Florian

AU - Helgadottir, Anna

AU - Ivarsdottir, Erna V

AU - Arnadottir, Gudny A

AU - Jensson, Brynjar O

AU - Katrinardottir, Hildigunnur

AU - Sveinbjornsson, Gardar

AU - Kristinsdottir, Anna M

AU - Lee, Amy L

AU - Saemundsdottir, Jona

AU - Stefansdottir, Lilja

AU - Sigurdsson, Jon K

AU - Davidsson, Olafur B

AU - Benonisdottir, Stefania

AU - Jonasdottir, Aslaug

AU - Jonasdottir, Adalbjorg

AU - Jonsson, Stefan

AU - Gudmundsson, Reynir L

AU - Asselbergs, Folkert W

AU - Tragante, Vinicius

AU - Gunnarsson, Bjarni

AU - Masson, Gisli

AU - Thorleifsson, Gudmar

AU - Rafnar, Thorunn

AU - Holm, Hilma

AU - Olafsson, Isleifur

AU - Onundarson, Pall T

AU - Gudbjartsson, Daniel F

AU - Norddahl, Gudmundur L

AU - Thorsteinsdottir, Unnur

AU - Sulem, Patrick

AU - Stefansson, Kari

N1 - 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). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/4/23

Y1 - 2020/4/23

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85083835120&partnerID=8YFLogxK

U2 - 10.1038/s42003-020-0921-5

DO - 10.1038/s42003-020-0921-5

M3 - Article

C2 - 32327693

SN - 2399-3642

VL - 3

SP - 1

EP - 10

JO - Communications biology

JF - Communications biology

IS - 1

M1 - 189

ER -

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

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