The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.

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Mean platelet volume (MPV) and platelet count (PLT) are highly heritable and tightly regulated traits. We performed a genomewide association study for MPV and identified one SNP, rs342293, as having highly significant and reproducible association with MPV (per-G allele effect 0.016 ؎ 0.001 log fL; P < 1.08 ؋ 10 ؊24 ) and PLT (per-G effect ؊4.55 ؎ 0.80 10 9 /L; P < 7.19 ؋ 10 ؊8 ) in 8586 healthy subjects. Whole-genome expression analysis in the 1-MB region showed a significant association with platelet transcript levels for PIK3CG (n ‫؍‬ 35; P ‫؍‬ .047). The G allele at rs342293 was also associated with decreased binding of annexin V to platelets activated with collagen-related peptide (n ‫؍‬ 84; P ‫؍‬ .003). The region 7q22.3 identifies the first QTL influencing platelet volume, counts, and function in healthy subjects. Notably, the association signal maps to a chromosome region implicated in myeloid malignancies, indicating this site as an important regulatory site for hematopoiesis. The identification of loci regulating MPV by this and other studies will increase our insight in the processes of megakaryopoiesis and proplatelet formation, and it may aid the identification of genes that are somatically mutated in essential thrombocytosis. (Blood. 2009; 113:3831-3837) IntroductionPlatelets are anucleate blood cell fragments that play a key role in maintaining primary hemostasis and in wound healing. Mean platelet volume (MPV) and platelet count (PLT) are tightly regulated and inversely correlated in the healthy population. Increased MPV represents a strong, independent predictor of postevent outcome in coronary disease and myocardial infarction, 1,2 and changes of either parameter outside the normal ranges are routinely used to ascertain and manage a large number of clinical conditions. Studies in rodents, primates, and twins have confirmed that blood cell quantitative traits, such as MPV and PLT, have high heritability levels. [3][4][5] Genome-wide association studies that used dense genotyping in thousands of subjects have greatly improved the resolution of such complex polygenic traits in humans. 6,7 We therefore reasoned that it should be possible to identify novel quantitative trait loci (QTLs) for MPV and PLT by a similar approach. The identification of such loci will provide new insights in the complex cellular processes of megakaryopoiesis and platelet formation. In addition, it may contribute to our understanding of premalignant conditions such as polycythemia vera and particularly essential thrombocytosis (ET), in which somatically acquired mutations in the JAK2 gene explain only a fraction of cases. 8 Megakaryocytes (MKs), the platelet precursor cells, originate from pluripotent hematopoietic stem cells (HSCs) in a stepwise process of fate determination and proliferation controlled by the cytokine thrombopoietin 9 and several extracellular matrix proteins (ECMPs). [10][11][12] After migration of the MK progenitors from the HSC niche to the bone marrow, platelets are formed via the tightly regulated pro...