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).
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.
KW - Hemoglobin
KW - ACO1
KW - Genome-wide
KW - Blóðrannsóknir
KW - Erfðarannsóknir
KW - Gen
KW - Hemoglobin
KW - ACO1
KW - Genome-wide
KW - Blóðrannsóknir
KW - Erfðarannsóknir
KW - Gen
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
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 189
ER -