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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 (Effect Cys506Ser  = -1.61 SD, CI 95  = [-1.98, -1.35]; Effect Lys334Ter  = 0.63 SD, CI 95  = [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.

The cytokine erythropoietin (EPO), signalling through the EPO receptor (EPO-R), is essential for the formation of red blood cells. We performed a genome-wide association study (GWAS) testing 32.5 million sequence variants for association with serum EPO levels in a set of 4187 individuals. We detect an association between a rare and well imputed stop-gained variant rs370865377[A] (p.Gln82Ter) in EPOR, carried by 1 in 550 Icelanders, and increased serum EPO levels (MAF = 0.09%, Effect = 1.47 SD, P = 3.3 × 10−7). We validated these findings by measuring serum EPO levels in 34 additional pairs of carriers and matched controls and found carriers to have 3.23-fold higher EPO levels than controls (P = 1.7 × 10−6; Pcombined = 1.6 × 10−11). In contrast to previously reported EPOR mutations, p.Gln82Ter does not associate with haemoglobin levels (Effect = −0.045 SD, P = 0.32, N = 273,160), probably due to a compensatory EPO upregulation in response to EPO-R hypo-responsiveness. Gudjon Oskarsson et al. report the association of a rare variant in the erythropoietin (EPO) receptor gene, EPOR, with serum EPO levels in the Icelandic population. The variant leads to a truncation of EPO-R without an effect on hemoglobin levels, indicating a possible feedback mechanism in the generation of red blood cells. [ABSTRACT FROM AUTHOR]