Quantitative Trait Loci
for
Baseline White Blood Cell count, Platelet Count, and Mean Platelet Volume
Luanne L. Peters, Weidong Zhang, Amy J. Lambert, Carlo Brugnara,
Gary A. Churchill, and Orah S. Platt
Objective. Baseline WBC count is a significant risk factor for early mortality in the general population and for disease severity in sickle cell disease. Both the WBC and MPV correlate with heart disease and stroke risk in the general population. Hence, identifying the primary genetic determinants underlying these and other peripheral blood indices will not only enhance our understanding of hematopoiesis but also provide novel diagnostic and therapeutic targets for hematological and cardiovascular pathologies. We are utilizing the inbred strains to identify QTL for baseline hematological parameters as a first step in elucidating the genes regulating these traits in normal populations. Here we report the identification of QTL for WBC count, Plt count and MPV.
Methods and Results.We performed quantitative trait locus/loci (QTL) analyses to identify chromosome (Chr) regions harboring genes influencing the baseline white blood cell (WBC) count, platelet (Plt) count, and mean platelet volume (MPV) in F2 intercrosses between NZW/LacJ, SM/J, and C57BLKS/J inbred mice. We identified 6 significant WBC QTL: Wbcq1 (peak LOD score at 38 cM, Chr 1), Wbcq2 (42 cM, Chr 3), Wbcq3 (0 cM, Chr 15), Wbcq4 (58 cM, Chr 1), Wbcq5 (82 cM, Chr 1), and Wbcq6 (8 cM, Chr 14). Three significant Plt QTL were identified: Pltq1 (24 cM, Chr 2), Pltq2 (36 cM, Chr 7), and Pltq3 (10 cM, Chr 12). Two significant MPV QTL were identified, Mpvq1 (62 cM, Chr 15) and Mpvq2 (44 cM, Chr 8). In total, the WBC QTL accounted for up to 31% of the total variance in baseline WBC count, while the Plt and MPV QTL accounted for up to 30% and 49% of the total variance, respectively. These analyses underscore the genetic complexity underlying these traits in normal populations and provide the basis for future studies to identify novel genes involved in the regulation of mammalian hematopoiesis. Peters et al, Mammalian Genome, in press.
Summary of QTL for baseline WBC count, Plt count and MPV identified in two F2 intercrosses between F1 hybrids of NZW/LacJ x SM/J (NZSM cross) and C57BLKS/J x SM/J mice (KSSM cross).
Name |
Trait |
Chr |
Peak, cM (Mb**) |
95% CI (cM) |
Human Location # |
High Allele |
Inheritance |
Peak marker |
LOD |
Wbcq1 * |
WBC |
1 |
38 (71) |
36-52 |
2q37 |
C57BLKS/J, |
Dominant |
D1MIT282 |
7.0 |
Wbcq2 |
WBC |
3 |
42 (89) |
24-74 |
1q21 |
SM/J |
Recessive |
D3MIT142 |
3.2 |
Wbcq3 |
WBC |
15 |
0 (0) |
0-52 |
5p13 |
SM/J |
Dominant |
D15MIT13 |
2.8 |
Wbcq4* |
WBC |
1 |
58 (94) |
50-72 |
2q37 |
NZW/LacJ |
Additive |
D1MIT306 |
4.3 |
Wbcq 5 * |
WBC |
1 |
82 (156) |
76-90 |
1q25 |
NZW/LacJ |
Recessive |
D1MIT227 |
4.2 |
Wbcq6 |
WBC |
14 |
8 (24) |
0-20 |
3p14 |
NZW/LacJ and SM/J |
Heterozygotes low‡ |
D14MIT98 |
2.8 |
Pltq1 |
Plt |
2 |
24 (35) |
14-42 |
9q33-q34 |
SM/J |
Recessive |
D2MIT296 |
3.5 |
Pltq2 |
Plt |
7 |
36 (52) |
24-52 |
11p15 |
NZW/LacJ |
Dominant |
D7MIT30 |
3.3 |
Pltq3 |
Plt |
12 |
10 (23) |
0-31 |
2p25 |
NZW/LacJ |
Additive |
D12MIT182 |
3.2 |
Mpvq1 |
MPV |
15 |
62 (104) 62 (104) |
60-62 58-62 |
12q12-q13 |
SM/J SM/J |
Recessive |
D15MIT16 D15MIT16 |
14.2 24.2 |
Mpvq2 |
MPV |
8 |
44 (92() |
24-49 |
16q13-p21 |
SM/J |
Recessive |
D8MIT211 |
2.7 |
*Data derived from an initial genome wide scan utilizing 186 F2 animals with the exception of Wbcq1, Wbcq4, and Wbcq5 (279 animals).
‡ For QTL for which heterozygotes are low, we hypothesize that there may be closely linked QTL with effects in the opposite direction.
**Estimated peak positions in Mb determined using Mouse Genome Informatics linkage maps ( http://www.informatics.jax.org/searches/linkmap_form.shtml) and Ensemble Mouse Genome Browser (Build 33)( http://www.ensembl.org/Mus_musculus/)
# Human chromosome region conserved with peak QTL position
Genome wide scans for main effect QTL
