p = 0.022; replication HCT β = -0.239, p = 0.002; HGB β = -0.009, p = 0.909). The minor allele T of rs33930165 encodes an abnormal form of hemoglobin, Hb C, which in the homozygous state is associated with mild chronic hemolytic anemia and mild to moderate splenomegaly [39]. In our discovery and replication data sets, there were no individuals homozygous for the Hb C variant, nor any compound heterozygotes for Hb S/C (Hb S is sickling form of hemoglobin and individuals homozygous for Hb S have sickle cell disease), which excludes the possibility that the apparently higher WBC is driven by an “inflammatory response” confined to a small number of individuals clinically affected by sickle cell disease or hemoglobin C disease. We next evaluated the association of HBB rs33930165 with circulating number of WBC subtypes, including neutrophils, monocytes, lymphocytes, basophils, and eosinophils. S15 Table shows the results in our AA imputation-based discovery data sets (S16 Table), and TOPMed freeze 5b WGS replication samples (S17 Table), which suggest that the apparent association of HBB rs33930165 with total WBC is mainly driven by an association with higher lymphocyte count, with perhaps a more modest association with higher neutrophil count. Further
