We have previously shown that the effect of a high-density lipoprotein (HDL) genetic risk score depends on whether the phenotype (HDL cholesterol) is high or low relative to its distribution (quantile-dependent expressivity).Evidence for quantile-dependent expressivity was sought using a more inclusive genetic measure (quantile-specific heritability, h2) in a larger population (Framingham cohort).Quantile regression was used to test whether the offspring-parent (βOP) and full-sib (βFS) regression slopes increased with the percentiles of the offspring's HDL distribution in 10,650 parent-offspring pairs and 2130 sibships. Quantile-specific heritability was estimated by 2βOP/(1 + rspouse) and [(8βFSrspouse + 1)0.5-1]/(2rspouse), where rspouse is the spouse correlation.HDL cholesterol heritability estimated from βOP increased significantly (P = 4.2 × 10-5) from the 10th (h2 ± SE: 0.44 ± 0.03), 25th (0.45 ± 0.03), 50th (0.47 ± 0.03), and 75th (0.56 ± 0.04) to the 90th percentiles (0.65 ± 0.06) of the offspring's age- and sex-adjusted HDL cholesterol distribution. Heritability estimated from βFS also increased significantly with the percentiles of the offspring's HDL cholesterol (P = .002), apo A1 (P = .006), HDL2 cholesterol (P = .003), and HDL3 cholesterol distribution (P = .02). Consistent with quantile-dependent expressivity, published pharmacologic and nutritional interventions that raised (eg, statin, fibrates, estrogen replacement therapy, efavirenz, and dietary fat) or lowered HDL cholesterol concentrations (tamoxifen, dietary carbohydrate) correspondingly increased and decreased genetic effects.HDL cholesterol heritability increased with increasing percentile of the offspring's HDL distribution. Whereas precision medicine is based on the premise that genetic markers identify patients most likely to benefit from drugs and diet, quantile-dependent expressivity postulates that the strong signals from these genetic markers simply trace the heritability increase with increasing plasma HDL concentrations. Thus, quantile-dependent expressivity provides an alternative interpretation to these genotype-specific effects.