Abstract
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.
Highlights
The cytokine erythropoietin (EPO), signalling through the EPO receptor (EPO-R), is essential for the formation of red blood cells
We tested for association between EPO levels and 32.5 million sequence variants (imputation quality > 0.8, minor allele frequency (MAF) > 0.01%) identified through whole-genome sequencing (WGS) of 15,220 Icelanders (~5% of the population) and subsequently imputed into 151,677 chip-typed individuals (~50% of the population of 320,000), as well as 282,894 first- and second-degree relatives of the chiptyped[27]
We discovered a rare stop-gained mutation, p.Gln82Ter in EPOR, present in one out of 550 Icelanders, associating with a threefold increase in EPO levels without an effect on haemoglobin levels
Summary
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). To search for novel associations of sequence variants with EPO levels, we performed a GWAS on Icelanders with serum EPO measurements
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