Abstract
Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10−8, which together explain 4–9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
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Accession codes
Data deposits
Summary statistics from the genome-wide association study are available from the European Genome‐Phenome Archive (EGA, http://www.ebi.ac.uk/ ega) under accession number EGAS00000000132.
Change history
19 December 2012
Footnote symbols in the Table 1 legend were corrected.
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Acknowledgements
A detailed list of acknowledgements is provided in the Supplementary Material.
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Study organisation: J.C.C., C.G., P.v.d.H., J.S.K., W.H.O. and N.S. Manuscript preparation: H.A., J.S.B., J.C.C., G.V.D., P.D., C.G., P.v.d.H., A.A.Hicks, J.S.K., I.M.-L., W.H.O., A.Radhakrishnan, A.Rendon, S.S., J.Sehmi, N.S., D.S.P., M.U., N.V. and W.Z. All authors reviewed and had the opportunity to comment on the manuscript. Data collection and analysis in the participating genome-wide association, replication and phenotype cohorts: ALSPAC: D.M.E., J.P.K., S.M.R., G.D.S; AMISH: Q.D.G., B.D.M., A.Parsa, A.R.S.; Beta-thalassaemia: F.A., F.D., P.Fortina, R.G, L.Perseu, A.Piga, S.S., M.U.; CBR: A.Attwood, J.D., S.F.G., H.L.-J., C.Moore, W.H.O., J.Sambrook; CoLAUS: F.B., J.S.B., M.H., P.V.; DeCODE: G.I.E., D.F.G., H.H., I.O., P.T.O., K.S., P.S., U.T.; DESIR: B.Balkau, C.D., P.Froguel, R.Sladek; EGCUT: T.E., K.F., A.M., E.M., A.S.; EPIC: K.-T.K., C.L., R.J.F.L., N.J.W., J.-H.Z.; Genebank: H.A., J.H., S.L.H., W.H.W.T.; INGI CARL: P.G., G.G., N.P.; INGI CILENTO: M.C., T.N., D.R., R.Sorice.; INGI FVG: A.P.d.A., A.Robino, S.U.; INGI Val Borbera: G.P., C.S., D.T., M.T.; KORA: A.D., C.G., T.I., C.Meisinger, J.S.R.; LBC: I.J.D., S.E.H., L.M.L., J.M.S.; LIFELINES: R.A.d.B., I.P.K., I.M.-L., G.N., P.v.d.H., L.J.v.P., N.V., B.H.R.W.; LOLIPOP: A.Al-Hussani, J.C.C., D.D., P.E., J.S.K., X.L., K.M., J.Scott, J.Sehmi, S.-T.T., W.Z.; LURIC: B.G., B.O.B., M.E.K., W.M., B.R.W.; MDC: A.F.D., G.E., B.H., C.E.H., O.M., S.P., J.G.S.; MICROS: M.G., A.AHicks, A.S.-P., P.P.P.; NESDA: I.M.N., B.W.P., J.H.S., H.Snieder; NFBC1966: A.-L.H., M.-R.J., P.F.O., A.Pouta, A.Ruokonen.; NTR: A.Abdellaoui, D.I.B., E.J.C.d.G., J.-J.H., M.H.d.M., G.Willemsen; OGP: F.M., D.P., L.Portas, M.P.; PREVEND: R.A.d.B., I.M.-L., G.N., P.v.d.H., W.H.v.G., D.J.v.V., N.V.; QIMR: B.Benyamin, M.A.F., N.G.M., S.E.M., G.W.M., C.S.T., P.M.V., J.B.W.; SardiNIA: F.C., E.P., S.S., M.U.; SHIP: A.G., M.Nauck, C.O.S., A.Teumer, U.V.; SMART: A.Algra, F.W.A., P.I.W.d.B., V.T.; SORBS: V.L., I.P., M.S., A.Tönjes.; TwinsUK: Y.M., S.-Y.S., N.S., T.D.S.; UKBS: J.J., W.H.O., N.S., J.Stephens; Young Finns: M.K., T.L., L.-P.L., O.R. Functional studies: Drosophila, U.E., F.S.D., A.A.Hicks, M.Novatchkova, J.M.P., U.P., C.X.W., G.Wirnsberger; expression profiling, W.O.C., L.Franke, L.L., M.F.M., A.Rendon, E.S., H.-J.W.; FAIRE, C.A.A., P.D., W.H.O., D.S.P., A.Rendon, N.S. Data analysis and bioinformatics: A.Al-Hussani, S.B., J.C.C., M.D., L.Ferrucci, P.v.d.H., S.K., X.L., I.M.-L., K.M., S.M., A.Radhakrishnan, A.Rendon, R.R.-S., H.Schepers, J.Sehmi, N.S., H.H.W.S., S.T., T.T., N.V., K.V., P.V., J.Y., W.Z.
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This file contains Supplementary Notes, Supplementary Tables 1-3 and 6-26 (see separate files for Supplementary Tables 4 and 5), Supplementary References and Supplementary Figures 1-8 – see contents list for details. (PDF 9711 kb)
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van der Harst, P., Zhang, W., Mateo Leach, I. et al. Seventy-five genetic loci influencing the human red blood cell. Nature 492, 369–375 (2012). https://doi.org/10.1038/nature11677
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DOI: https://doi.org/10.1038/nature11677
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