Abstract
A substantial genetic contribution underlies variation in baseline peripheral blood counts. We performed quantitative trait locus/loci (QTL) analyses to identify chromosome (Chr) regions harboring genes influencing the baseline erythroid parameters in F2 intercrosses between NZW/LacJ, SM/J, and C57BLKS/J inbred mice. We identified multiple significant QTL for red blood cell (RBC) count, hemoglobin (Hgb) and hematocrit (Hct) levels, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean cell hemoglobin concentration (CHCM). We identified four RBC count QTL: Rbcq1 (Chr 1, peak LOD score at 62 cM,), Rbcq2 (Chr 4, 60 cM), Rbcq3 (Chr 11, 34 cM), and Rbcq4 (Chr 10, 60 cM). Three MCV QTL were identified: Mcvq1 (Chr 7, 30 cM), Mvcq2 (Chr 11, 6 cM), and Mcvq3 (Chr 10, 60 cM). Single significant loci for Hgb (Hgbq1, Chr 16, 32 cM), Hct (Hctq1, Chr 3, 42 cM), and MCH (Mchq1, Chr 10, 60 cM) were identified. The data support the existence of a common RBC/MCH/MCV locus on Chr 10. Two QTL for CHCM (Chcmq1, Chr 2, 48 cM; Chcmq2, Chr 9, 44 cM) and an interaction between Chcmq2 with a locus on Chr 19 were identified. These analyses emphasize the genetic complexity underlying the regulation of erythroid peripheral blood traits in normal populations and suggest that genes not previously recognized as significantly impacting normal erythropoiesis exist.
Similar content being viewed by others
References
Abiola O, Angel JM, Avner P, Bachmanov AA, Belknap JK, et al. (2003) The nature and identification of quantitative trait loci: a community’s view. Nat Rev Genet 4: 911–916
Bath P, Algert C, Chapman N, Neal B (2004) Association of mean platelet volume with risk of stroke among 3134 individuals with history of cerebrovascular disease. Stroke 35: 622–626
Cantor AB, Orkin SH (2001) Hematopoietic development: a balancing act. Curr Opin Genet Dev 11: 513–519
Cantor AB, Orkin SH (2002) Transcriptional regulation of erythropoiesis: an affair involving multiple partners. Oncogene 21: 3368–3376
Cantor AB, Orkin SH (2005) Coregulation of GATA factors by the Friend of GATA (FOG) family of multitype zinc finger proteins. Semin Cell Dev Biol 16: 117–128
Castro O, Brambilla DJ, Thorington B, Reindorf CA, Scott RB, et al. (1994) The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood 84: 643–649
Chen J, Harrison DE (2002) Quantitative trait loci regulating relative lymphocyte proportions in mouse peripheral blood. Blood 99: 561–566
Cheung CC, Martin IC, Zenger KR, Donald JA, Thomson PC, et al. (2004) Quantitative trait loci for steady-state platelet count in mice. Mamm Genome 15: 784–797
Churchill GA, Doerge RW (1994) Empirical threshold values for quantitative trait mapping. Genetics 138: 963–971
Cordell HJ, Todd JA, Lathrop GM (1998) Mapping multiple linked quantitative trait loci in non-obese diabetic mice using a stepwise regression strategy. Genet Res 71: 51–64
de Labry LO, Campion EW, Glynn RJ, Vokonas PS (1990) White blood cell count as a predictor of mortality: results over 18 years from the Normative Aging Study. J Clin Epidemiol 43: 153–157
Gagnon DR, Zhang TJ, Brand FN, Kannel WB (1994) Hematocrit and the risk of cardiovascular disease—the Framingham study: a 34-year follow-up. Am Heart J 127: 674–682
Garner C, Tatu T, Reittie JE, Littlewood T, Darley J, et al. (2000) Genetic influences on F cells and other hematologic variables: a twin heritability study. Blood 95: 342–346
Kinney TR, Sleeper LA, Wang WC, Zimmerman RA, Pegelow CH, et al. (1999) Silent cerebral infarcts in sickle cell anemia: a risk factor analysis. The Cooperative Study of Sickle Cell Disease. Pediatrics 103: 640–645
Korstanje R, Li R, Howard T, Kelmenson P, Marshall J, et al. (2004) Influence of sex and diet on quantitative trait loci for HDL cholesterol levels in an SM/J by NZB/BlNJ intercross population. J Lipid Res 45: 881–888
Lal A, Vichinsky E (2004) The role of fetal hemoglobin-enhancing agents in thalassemia. Semin Hematol 41: 17–22
Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11: 241–247
Li R, Lyons MA, Wittenburg H, Paigen B, Churchill GA (2005) Combining data from multiple inbred line crosses improves the power and resolution of quantitative trait loci mapping. Genetics 169: 1699–1709
Lin JP, O’Donnell CJ, Levy D, Cupples LA (2005) Evidence for a gene influencing haematocrit on chromosome 6q23–24: genomewide scan in the Framingham Heart Study. J Med Genet 42: 75–79
Lippi G, Manzato F, Franchini M, Guidi G (2002) Relationship between hematocrit, primary hemostasis, and cardiovascular disease in athletes. Am Heart J 144: E14
Lyons MA, Wittenburg H, Li R, Walsh KA, Leonard MR, et al. (2003) New quantitative trait loci that contribute to cholesterol gallstone formation detected in an intercross of CAST/Ei and 129S1/SvImJ inbred mice. Physiol Genomics 14: 225–239
Mahaney MC, Brugnara C, Lease LR, Platt OS (2005) Genetic influences on peripheral blood cell counts: a study in baboons. Blood 106: 1210–1214
Martin JF, Bath PM, Burr ML (1991) Influence of platelet size on outcome after myocardial infarction. Lancet 338: 1409–1411
Martin JF, Bath PM, Burr ML (1992) Mean platelet volume and myocardial infarction. Lancet 339: 1000–1001
Miller ST, Sleeper LA, Pegelow CH, Enos LE, Wang WC, et al. (2000) Prediction of adverse outcomes in children with sickle cell disease. New Engl J Med 342: 83–89
Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, et al. (1998) Cerebrovascular accidents in sickle cell disease: Rates and risk factors. Blood 91: 288–294
Orkin SH (2000) Diversification of haematopoietic stem cells to specific lineages. Nat Rev Genet 1: 57–64
Orkin SH, Zon LI (2002) Hematopoiesis and stem cells: plasticity versus developmental heterogeneity. Nat Immunol 3: 323–328
Orkin SH, Porcher C, Fujiwara Y, Visvader J, Wang LC (1999) Intersections between blood cell development and leukemia genes. Cancer Res 59: 1784S–1787S
Paigen K (2002) Understanding the human condition: experimental strategies in mammalian genetics. ILAR J 43: 123–135
Peters LL, Barker JE (2001) Spontaneous and targeted mutations in erythrocyte membrane skeleton genes: mouse models of hereditary spherocytosis. In: Hematopoiesis A Developmental Approach, LI Zon (ed). (New York: Oxford University Press), pp 582–608
Peters LL, Barker JE (2005) Hematology, clotting, and thrombosis. MPD:62, Mouse Phenome Database web site at http://www.jax.org/phenome (The Jackson Laboratory, Bar Harbor, ME)
Peters LL, Swearingen RA, Andersen SG, Gwynn B, Lambert AJ, et al. (2004) Identification of quantitative trait loci that modify the severity of hereditary spherocytosis in wan, a new mouse model of band-3 deficiency. Blood 103: 3233–3240
Peters LL, Zhang W, Lambert AJ, Brugnara C, Churchill GA, et al. (2005) Quantitative trait loci for baseline white blood cell count, platelet count, and mean platelet volume. Mamm Genome 16: 749–763
Platt OS, Falcone JF, Lux SE (1989) A 12 kD tryptic peptide of ankyrin retains spectrin binding capacity. Blood 74: 104a
Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, et al. (1994) Mortality in sickle cell disease. Life expectancy and risk factors for early death. New Engl J Med 330: 1639–1644
Sen S, Churchill GA (2001) A statistical framework for quantitative trait mapping. Genetics 159: 371–387
Sokal RR, Rohlf FJ (1981) Biometry, 2nd edn. (San Francisco: WH Freeman)
Sugiyama F, Churchill GA, Higgins DC, Johns C, Makaritsis KP, et al. (2001) Concordance of murine quantitative trait loci for salt-induced hypertension with rat and human loci. Genomics 71: 70–77
Wang X, Paigen B (2005a) Genetics of variation in HDL cholesterol in humans and mice. Circ Res 96: 27–42
Wang X, Paigen B (2005b) Genome-wide search for new genes controlling plasma lipid concentrations in mice and humans. Curr Opin Lipidol 16: 127–137
Wang X, Korstanje R, Higgins D, Paigen B (2004) Haplotype analysis in multiple crosses to identify a QTL gene. Genome Res 14: 1767–1772
Wannamethee G, Perry IJ, Shaper AG (1994) Haematocrit, hypertension and risk of stroke. J Intern Med 235: 163–168
Acknowledgments
The authors thank Drs. Beverly Paigen and David Harrison for critical review of the manuscript. This work was supported by National Institutes of Health grants HL68922 (OSP) and HL64885 and HL66611 (LLP), and The National Cancer Institute CA34196 (The Jackson Laboratory).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Peters, L.L., Lambert, A.J., Zhang, W. et al. Quantitative trait loci for baseline erythroid traits. Mamm Genome 17, 298–309 (2006). https://doi.org/10.1007/s00335-005-0147-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00335-005-0147-3