Quantile-Specific Heritability of Mean Platelet Volume, Leukocyte Count, and Other Blood Cell Phenotypes

Abstract

Introduction: “Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., mean platelet volume, MPV) is high or low relative to its distribution. Methods: Offspring-parent regression slopes (β_OP) were estimated by quantile regression, from which quantile-specific heritabilities (h²) were calculated (h² = 2β_OP/[1 + r_spouse]) for blood cell phenotypes in 3,929 parent-offspring pairs from the Framingham Heart Study. Results: Quantile-specific h² (±SE) increased with increasing percentiles of the offspring’s age- and sex-adjusted MPV distribution (p_linear = 0.0001): 0.48 ± 0.09 at the 10th, 0.53 ± 0.04 at the 25th, 0.70 ± 0.06 at the 50th, 0.74 ± 0.06 at the 75th, and 0.90 ± 0.12 at the 90th percentile. Quantile-specific h² also increased with increasing percentiles of the offspring’s white blood cell (WBC, p_linear = 0.002), monocyte (p_linear = 0.01), and eosinophil distributions (p_linear = 0.0005). In contrast, heritibilities of red blood cell (RBC) count, hematocrit (HCT), and hemoglobin (HGB) showed little evidence of quantile dependence. Quantile-dependent expressivity is consistent with gene-environment interactions reported by others, including (1) greater increases in WBC and PLT concentrations in subjects who are glutathione-S-transferase Mu1 (GSTM1) null homozygotes than GSTM1 sufficient when exposed to endotoxin; (2) significantly higher WBC count in AA homozygotes than carriers of the G-allele of the glutathione S-transferase P1 (GSTP1) rs1695 polymorphism at low but not high benzene exposure in shoe factory workers; (3) higher WBC counts in TT homozygotes than C-allele carriers of the interleukin-1β (IL1B) c.315C>T polymorphism after undergoing surgery for infective endocarditis but not before surgery. Discussion/Conclusion: Quantile-dependent expressivity may explain several purported gene-environment interactions involving blood cell phenotypes.